ROLE OF TYROSINE-SULFATED PROTEINS IN RETINAL STRUCTURE AND FUNCTION

PubMed Central

Kanan, Y.; Al-Ubaidi, M.R.

2014-01-01

The extracellular matrix (ECM) plays a significant role in cellular and retinal health. The study of retinal tyrosine-sulfated proteins is an important first step toward understanding the role of ECM in retinal health and diseases. These secreted proteins are members of the retinal ECM. Tyrosine sulfation was shown to be necessary for the development of proper retinal structure and function. The importance of tyrosine sulfation is further demonstrated by the evolutionary presence of tyrosylprotein sulfotransferases, enzymes that catalyze proteins’ tyrosine sulfation, and the compensatory abilities of these enzymes. Research has identified four tyrosine-sulfated retinal proteins: fibulin 2, vitronectin, complement factor H (CFH), and opticin. Vitronectin and CFH regulate the activation of the complement system and are involved in the etiology of some cases of age-related macular degeneration. Analysis of the role of tyrosine sulfation in fibulin function showed that sulfation influences the protein's ability to regulate growth and migration. Although opticin was recently shown to exhibit anti-angiogenic properties, it is not yet determined what role sulfation plays in that function. Future studies focusing on identifying all of the tyrosine-sulfated retinal proteins would be instrumental in determining the impact of sulfation on retinal protein function in retinal homeostasis and diseases. PMID:25819460

Differentiation of RPE cells from integration-free iPS cells and their cell biological characterization.

PubMed

Hazim, Roni A; Karumbayaram, Saravanan; Jiang, Mei; Dimashkie, Anupama; Lopes, Vanda S; Li, Douran; Burgess, Barry L; Vijayaraj, Preethi; Alva-Ornelas, Jackelyn A; Zack, Jerome A; Kohn, Donald B; Gomperts, Brigitte N; Pyle, April D; Lowry, William E; Williams, David S

2017-10-02

Dysfunction of the retinal pigment epithelium (RPE) is implicated in numerous forms of retinal degeneration. The readily accessible environment of the eye makes it particularly suitable for the transplantation of RPE cells, which can now be derived from autologous induced pluripotent stem cells (iPSCs), to treat retinal degeneration. For RPE transplantation to become feasible in the clinic, patient-specific somatic cells should be reprogrammed to iPSCs without the introduction of reprogramming genes into the genome of the host cell, and then subsequently differentiated into RPE cells that are well characterized for safety and functionality prior to transplantation. We have reprogrammed human dermal fibroblasts to iPSCs using nonintegrating RNA, and differentiated the iPSCs toward an RPE fate (iPSC-RPE), under Good Manufacturing Practice (GMP)-compatible conditions. Using highly sensitive assays for cell polarity, structure, organelle trafficking, and function, we found that iPSC-RPE cells in culture exhibited key characteristics of native RPE. Importantly, we demonstrate for the first time with any stem cell-derived RPE cell that live cells are able to support dynamic organelle transport. This highly sensitive test is critical for RPE cells intended for transplantation, since defects in intracellular motility have been shown to promote RPE pathogenesis akin to that found in macular degeneration. To test their capabilities for in-vivo transplantation, we injected the iPSC-RPE cells into the subretinal space of a mouse model of retinal degeneration, and demonstrated that the transplanted cells are capable of rescuing lost RPE function. This report documents the successful generation, under GMP-compatible conditions, of human iPSC-RPE cells that possess specific characteristics of healthy RPE. The report adds to a growing literature on the utility of human iPSC-RPE cells for cell culture investigations on pathogenicity and for therapeutic transplantation, by corroborating findings of others, and providing important new information on essential RPE cell biological properties.

A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

PubMed

Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

2004-06-01

This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients.

Protection of retinal function by sulforaphane following retinal ischemic injury.

PubMed

Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

2015-09-01

Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

R Script Approach to Infer Toxoplasma Infection Mechanisms From Microarrays and Domain-Domain Protein Interactions

PubMed Central

Arenas, Ailan F; Salcedo, Gladys E; Gomez-Marin, Jorge E

2017-01-01

Pathogen-host protein-protein interaction systems examine the interactions between the protein repertoires of 2 distinct organisms. Some of these pathogen proteins interact with the host protein system and may manipulate it for their own advantages. In this work, we designed an R script by concatenating 2 functions called rowDM and rowCVmed to infer pathogen-host interaction using previously reported microarray data, including host gene enrichment analysis and the crossing of interspecific domain-domain interactions. We applied this script to the Toxoplasma-host system to describe pathogen survival mechanisms from human, mouse, and Toxoplasma Gene Expression Omnibus series. Our outcomes exhibited similar results with previously reported microarray analyses, but we found other important proteins that could contribute to toxoplasma pathogenesis. We observed that Toxoplasma ROP38 is the most differentially expressed protein among toxoplasma strains. Enrichment analysis and KEGG mapping indicated that the human retinal genes most affected by Toxoplasma infections are those related to antiapoptotic mechanisms. We suggest that proteins PIK3R1, PRKCA, PRKCG, PRKCB, HRAS, and c-JUN could be the possible substrates for differentially expressed Toxoplasma kinase ROP38. Likewise, we propose that Toxoplasma causes overexpression of apoptotic suppression human genes. PMID:29317802

Progress toward the maintenance and repair of degenerating retinal circuitry.

PubMed

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.

Reprogramming Human Retinal Pigmented Epithelial Cells to Neurons Using Recombinant Proteins

PubMed Central

Hu, Qirui; Chen, Renwei; Teesalu, Tambet; Ruoslahti, Erkki

2014-01-01

Somatic cells can be reprogrammed to an altered lineage by overexpressing specific transcription factors. To avoid introducing exogenous genetic material into the genome of host cells, cell-penetrating peptides can be used to deliver transcription factors into cells for reprogramming. Position-dependent C-end rule (CendR) cell- and tissue-penetrating peptides provide an alternative to the conventional cell-penetrating peptides, such as polyarginine. In this study, we used a prototypic, already active CendR peptide, RPARPAR, to deliver the transcription factor SOX2 to retinal pigmented epithelial (RPE) cells. We demonstrated that RPE cells can be directly reprogrammed to a neuronal fate by introduction of SOX2. Resulting neuronal cells expressed neuronal marker mRNAs and proteins and downregulated expression of RPE markers. Cells produced extensive neurites and developed synaptic machinery capable of dye uptake after depolarization with potassium. The RPARPAR-mediated delivery of SOX2 alone was sufficient to allow cell lineage reprogramming of both fetal and stem cell-derived RPE cells to become functional neurons. PMID:25298373

Suppression of HSP27 Restores Retinal Function and Protects Photoreceptors From Apoptosis in a Light-Induced Retinal Degeneration Animal Model.

PubMed

Chien, Chih-Cheng; Huang, Chi-Jung; Tien, Lu-Tai; Cheng, Yu-Che; Ke, Chia-Ying; Lee, Yih-Jing

2017-06-01

We used a light-induced retinal degeneration animal model to investigate possible roles of heat shock protein 27 (HSP27) in retinal/photoreceptor protection. Sprague-Dawley rats were used for the light-induced retinal degeneration animal model. The histology of eye sections was observed for morphologic changes in the retina. Cell apoptosis was examined in each group using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electroretinography was used to evaluate retinal function. Protein and mRNA expression levels of different retinal cell markers were also detected through immunofluorescence staining, Western blotting, and real-time PCR. The thickness of the outer nuclear layer significantly decreased after 7-day light exposure. Moreover, we injected a viral vector for silencing HSP27 expression into the eyes and observed that photoreceptors were better preserved in the HSP27-suppressed (sHSP27) retina 2 weeks after injection. HSP27 suppression also reduced retinal cell apoptosis caused by light exposure. In addition, the loss of retinal function caused by light exposure was reversed on suppressing HSP27 expression. We subsequently found that the expression of the Rho gene and immunofluorescence staining of rhodopsin and arrestin (cell markers for photoreceptors) increased in sHSP27-treated retinas. HSP27 suppression did not affect the survival of ganglion and amacrine cells. Retinal cell apoptosis and functional loss were observed after 7-day light exposure. However, in the following 2 weeks after light exposure, HSP27 suppression may initiate a protective effect for retinal cells, particularly photoreceptors, from light-induced retinal degeneration.

Engineering retinal progenitor cell and scrollable poly(glycerol-sebacate) composites for expansion and subretinal transplantation

PubMed Central

Redenti, Stephen; Neeley, William L.; Rompani, Santiago; Saigal, Sunita; Yang, Jing; Klassen, Henry; Langer, Robert; Young, Michael J.

2014-01-01

Retinal degenerations cause permanent visual loss and affect millions world-wide. Presently, a novel treatment highlights the potential of using biodegradable polymer scaffolds to induce differentiation and deliver retinal progenitor cells for cell replacement therapy. In this study, we engineered and analyzed a micro-fabricated polymer, poly(glycerol sebacate) (PGS) scaffold, whose useful properties include biocompatibility, elasticity, porosity, and a microtopology conducive to mouse retinal progenitor cell (mRPC) differentiation. In vitro proliferation assays revealed that PGS held up to 86,610 (±9993) mRPCs per square millimeter, which were retained through simulated transplantations. mRPCs adherent to PGS differentiated toward mature phenotypes as evidenced by changes in mRNA, protein levels, and enhanced sensitivity to glutamate. Transplanted composites demonstrated long-term mRPC survival and migrated cells exhibited mature marker expression in host retina. These results suggest that combining mRPCs with PGS scaffolds for subretinal transplantation is a practical strategy for advancing retinal tissue engineering as a restorative therapy. PMID:19361860

RNCR3: A regulator of diabetes mellitus-related retinal microvascular dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shan, Kun; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing

Retinal microvascular abnormality is an important pathological feature of diabetic retinopathy. Herein, we report the role of lncRNA-RNCR3 in diabetes mellitus-induced retinal microvascular abnormalities. We show that RNCR3 is significantly up-regulated upon high glucose stress in vivo and in vitro. RNCR3 knockdown alleviates retinal vascular dysfunction in vivo, as shown by decreased acellular capillaries, decreased vascular leakage, and reduced inflammatory response. RNCR3 knockdown decreases retinal endothelial cell proliferation, and reduces cell migration and tube formation in vitro. RNCR3 regulates endothelial cell function through RNCR3/KLF2/miR-185-5p regulatory network. RNCR3 inhibition may be a treatment option for the prevention of diabetes mellitus-induced retinal microvascular abnormalities. - Highlights:more » • RNCR3 expression is significantly up-regulated upon high glucose stress. • RNCR3 knockdown alleviates retinal vascular dysfunction in vivo. • RNCR3 regulates retinal endothelial cell function in vitro. • RNCR3 regulates retinal endothelial cell function via RNCR3/KLF2/miR-185-5p pathway.« less

Circadian perinatal photoperiod has enduring effects on retinal dopamine and visual function.

PubMed

Jackson, Chad R; Capozzi, Megan; Dai, Heng; McMahon, Douglas G

2014-03-26

Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.

Retinal compensatory changes after light damage in albino mice

PubMed Central

Montalbán-Soler, Luis; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Salinas-Navarro, Manuel; Galindo-Romero, Caridad; Bezerra de Sá, Fabrízio; García-Ayuso, Diego; Avilés-Trigueros, Marcelino; Vidal-Sanz, Manuel; Agudo-Barriuso, Marta

2012-01-01

Purpose To investigate the anatomic and functional changes triggered by light exposure in the albino mouse retina and compare them with those observed in the albino rat. Methods BALB/c albino mice were exposed to 3,000 lx of white light during 24 h and their retinas analyzed from 1 to 180 days after light exposure (ALE). Left pupil mydriasis was induced with topical atropine. Retinal function was analyzed by electroretinographic (ERG) recording. To assess retinal degeneration, hematoxylin and eosin staining, the TdT-mediated dUTP nick-end labeling (TUNEL) technique, and quantitative immunohistofluorescence for synaptophysin and protein kinase Cα (PKCα) were used in cross sections. Intravenous injection of horseradish peroxidase and Fluoro-Gold™ tracing were used in whole-mounted retinas to study the retinal vasculature and the retinal ganglion cell (RGC) population, respectively. Results Light exposure caused apoptotic photoreceptor death in the central retina. This death was more severe in the dorsal than in the ventral retina, sparing the periphery. Neither retinal vascular leakage nor retinal ganglion cell death was observed ALE. The electroretinographic a-wave was permanently impaired, while the b-wave decreased but recovered gradually by 180 days ALE. The scotopic threshold responses, associated with the inner retinal function, diminished at first but recovered completely by 14 days ALE. This functional recovery was concomitant with the upregulation of protein kinase Cα and synaptophysin. Similar results were obtained in both eyes, irrespective of mydriasis. Conclusions In albino mice, light exposure induces substantial retinal damage, but the surviving photoreceptors, together with compensatory morphological/molecular changes, allow an important restoration of the retinal function. PMID:22509098

Pluripotent Stem Cells for Retinal Tissue Engineering: Current Status and Future Prospects.

PubMed

Singh, Ratnesh; Cuzzani, Oscar; Binette, François; Sternberg, Hal; West, Michael D; Nasonkin, Igor O

2018-04-19

The retina is a very fine and layered neural tissue, which vitally depends on the preservation of cells, structure, connectivity and vasculature to maintain vision. There is an urgent need to find technical and biological solutions to major challenges associated with functional replacement of retinal cells. The major unmet challenges include generating sufficient numbers of specific cell types, achieving functional integration of transplanted cells, especially photoreceptors, and surgical delivery of retinal cells or tissue without triggering immune responses, inflammation and/or remodeling. The advances of regenerative medicine enabled generation of three-dimensional tissues (organoids), partially recreating the anatomical structure, biological complexity and physiology of several tissues, which are important targets for stem cell replacement therapies. Derivation of retinal tissue in a dish creates new opportunities for cell replacement therapies of blindness and addresses the need to preserve retinal architecture to restore vision. Retinal cell therapies aimed at preserving and improving vision have achieved many improvements in the past ten years. Retinal organoid technologies provide a number of solutions to technical and biological challenges associated with functional replacement of retinal cells to achieve long-term vision restoration. Our review summarizes the progress in cell therapies of retina, with focus on human pluripotent stem cell-derived retinal tissue, and critically evaluates the potential of retinal organoid approaches to solve a major unmet clinical need-retinal repair and vision restoration in conditions caused by retinal degeneration and traumatic ocular injuries. We also analyze obstacles in commercialization of retinal organoid technology for clinical application.

Carotenoid Antenna Binding and Function in Retinal Proteins

DTIC Science & Technology

2012-08-13

REPORT Carotenoid antenna binding and function in retinal proteins 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: Xanthorhodopsin, a proton pump from the...eubacterium Salinibacter ruber, is a unique dual chromophore system that contains, in addition to retinal, the carotenoid salinixanthin as a light... carotenoid ring near the retinal ring. Substitution of the small glycine with bulky tryptophan in this site eliminates binding. The second factor is the 4

Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression.

PubMed

Alston, Christine I; Dix, Richard D

2017-09-01

AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Functional Imaging of Retinal Photoreceptors and Inner Neurons Using Stimulus-Evoked Intrinsic Optical Signals

PubMed Central

Yao, Xin-Cheng; Li, Yi-Chao

2013-01-01

Retinal development is a dynamic process both anatomically and functionally. High-resolution imaging and dynamic monitoring of photoreceptors and inner neurons can provide important information regarding the structure and function of the developing retina. In this chapter, we describe intrinsic optical signal (IOS) imaging as a high spatiotemporal resolution method for functional study of living retinal tissues. IOS imaging is based on near infrared (NIR) light detection of stimulus-evoked transient change of inherent optical characteristics of the cells. With no requirement for exogenous biomarkers, IOS imaging is totally noninvasive for functional mapping of stimulus-evoked spatiotemporal dynamics of the photoreceptors and inner retinal neurons. PMID:22688714

Versatile functional roles of horizontal cells in the retinal circuit.

PubMed

Chaya, Taro; Matsumoto, Akihiro; Sugita, Yuko; Watanabe, Satoshi; Kuwahara, Ryusuke; Tachibana, Masao; Furukawa, Takahisa

2017-07-17

In the retinal circuit, environmental light signals are converted into electrical signals that can be decoded properly by the brain. At the first synapse of the visual system, information flow from photoreceptors to bipolar cells is modulated by horizontal cells (HCs), however, their functional contribution to retinal output and individual visual function is not fully understood. In the current study, we investigated functional roles for HCs in retinal ganglion cell (RGC) response properties and optokinetic responses by establishing a HC-depleted mouse line. We observed that HC depletion impairs the antagonistic center-surround receptive field formation of RGCs, supporting a previously reported HC function revealed by pharmacological approaches. In addition, we found that HC loss reduces both the ON and OFF response diversities of RGCs, impairs adjustment of the sensitivity to ambient light at the retinal output level, and alters spatial frequency tuning at an individual level. Taken together, our current study suggests multiple functional aspects of HCs crucial for visual processing.

K+ channels of Müller glial cells in retinal disorders.

PubMed

Gao, Feng; Xu, Linjie; Zhao, Yuan; Sun, Xinghuai; Wang, Zhongfeng

2018-02-01

Müller cell is the major type glial cell in the vertebrate retina. Müller cells express various types of K+ channels, such as inwardly rectifying K+ (Kir) channels, big conductance Ca2+-activated K+ (BKCa) channels, delayed rectifier K+ channels (KDR), and transient A-type K+ channels. These K+ channels play important roles in maintaining physiological functions of Müller cells. Under some retinal pathological conditions, the changed expression and functions of K+ channels may contribute to retinal pathogenesis. In this article, we reviewed the physiological properties of K+ channels in retinal Müller cells and the functional changes of these channels in retinal disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Excitation spectra of retinal by multiconfiguration pair-density functional theory.

PubMed

Dong, Sijia S; Gagliardi, Laura; Truhlar, Donald G

2018-03-07

Retinal is the chromophore in proteins responsible for vision. The absorption maximum of retinal is sensitive to mutations of the protein. However, it is not easy to predict the absorption spectrum of retinal accurately, and questions remain even after intensive investigation. Retinal poses a challenge for Kohn-Sham density functional theory (KS-DFT) because of the charge transfer character in its excitations, and it poses a challenge for wave function theory because the large size of the molecule makes multiconfigurational perturbation theory methods expensive. In this study, we demonstrate that multiconfiguration pair-density functional theory (MC-PDFT) provides an efficient way to predict the vertical excitation energies of 11-Z retinal, and it reproduces the experimentally determined absorption band widths and peak positions better than complete active space second-order perturbation theory (CASPT2). The consistency between complete active space self-consistent field (CASSCF) and KS-DFT dipole moments is demonstrated to be a useful criterion in selecting the active space. We also found that the nature of the terminal groups and the conformations of retinal play a significant role in the absorption spectrum. By considering a thermal distribution of conformations, we predict an absorption spectrum of retinal that is consistent with the experimental gas-phase spectrum. The location of the absorption peak and the spectral broadening based on MC-PDFT calculations agree better with experiments than those of CASPT2.

Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment

PubMed Central

Lee, Christine; Tu, Hong Anh; Weir, Mark; Holubowich, Corinne

2016-01-01

Background Retinitis pigmentosa is a group of genetic disorders that involves the breakdown and loss of photoreceptors in the retina, resulting in progressive retinal degeneration and eventual blindness. The Argus II Retinal Prosthesis System is the only currently available surgical implantable device approved by Health Canada. It has been shown to improve visual function in patients with severe visual loss from advanced retinitis pigmentosa. The objective of this analysis was to examine the clinical effectiveness, cost-effectiveness, budget impact, and safety of the Argus II system in improving visual function, as well as exploring patient experiences with the system. Methods We performed a systematic search of the literature for studies examining the effects of the Argus II retinal prosthesis system in patients with advanced retinitis pigmentosa, and appraised the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria, focusing on visual function, functional outcomes, quality of life, and adverse events. We developed a Markov decision-analytic model to assess the cost-effectiveness of the Argus II system compared with standard care over a 10-year time horizon. We also conducted a 5-year budget impact analysis. We used a qualitative design and an interview methodology to examine patients’ lived experience, and we used a modified grounded theory methodology to analyze information from interviews. Transcripts were coded, and themes were compared against one another. Results One multicentre international study and one single-centre study were included in the clinical review. In both studies, patients showed improved visual function with the Argus II system. However, the sight-threatening surgical complication rate was substantial. In the base-case analysis, the Argus II system was cost-effective compared with standard care only if willingness-to-pay was more than $207,616 per quality-adjusted life-year. The 5-year budget impact of funding the Argus II system ranged from $800,404 to $837,596. Retinitis pigmentosa significantly affects people's ability to navigate physical and virtual environments. Argus II was described as enabling the fundamental elements of sight. As such, it had a positive impact on quality of life for people with retinitis pigmentosa. Conclusions Based on evidence of moderate quality, patients with advanced retinitis pigmentosa who were implanted with the Argus II retinal prosthesis system showed significant improvement in visual function, real-life functional outcomes, and quality of life, but there were complications associated with the surgery that could be managed through standard ophthalmologic treatments. The costs for the technology are high. PMID:27468325

Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment.

PubMed

2016-01-01

Retinitis pigmentosa is a group of genetic disorders that involves the breakdown and loss of photoreceptors in the retina, resulting in progressive retinal degeneration and eventual blindness. The Argus II Retinal Prosthesis System is the only currently available surgical implantable device approved by Health Canada. It has been shown to improve visual function in patients with severe visual loss from advanced retinitis pigmentosa. The objective of this analysis was to examine the clinical effectiveness, cost-effectiveness, budget impact, and safety of the Argus II system in improving visual function, as well as exploring patient experiences with the system. We performed a systematic search of the literature for studies examining the effects of the Argus II retinal prosthesis system in patients with advanced retinitis pigmentosa, and appraised the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria, focusing on visual function, functional outcomes, quality of life, and adverse events. We developed a Markov decision-analytic model to assess the cost-effectiveness of the Argus II system compared with standard care over a 10-year time horizon. We also conducted a 5-year budget impact analysis. We used a qualitative design and an interview methodology to examine patients' lived experience, and we used a modified grounded theory methodology to analyze information from interviews. Transcripts were coded, and themes were compared against one another. One multicentre international study and one single-centre study were included in the clinical review. In both studies, patients showed improved visual function with the Argus II system. However, the sight-threatening surgical complication rate was substantial. In the base-case analysis, the Argus II system was cost-effective compared with standard care only if willingness-to-pay was more than $207,616 per quality-adjusted life-year. The 5-year budget impact of funding the Argus II system ranged from $800,404 to $837,596. Retinitis pigmentosa significantly affects people's ability to navigate physical and virtual environments. Argus II was described as enabling the fundamental elements of sight. As such, it had a positive impact on quality of life for people with retinitis pigmentosa. Based on evidence of moderate quality, patients with advanced retinitis pigmentosa who were implanted with the Argus II retinal prosthesis system showed significant improvement in visual function, real-life functional outcomes, and quality of life, but there were complications associated with the surgery that could be managed through standard ophthalmologic treatments. The costs for the technology are high.

Loss of Retinal Function and Pigment Epithelium Changes in a Patient with Common Variable Immunodeficiency

PubMed Central

Halborg, Jakob; Sørensen, Torben L.

2012-01-01

Common variable immunodeficiency (CVID) has only scarcely been associated with ocular symptoms and rarely with retinal disease. In this case we describe a patient with distinct morphological and functional alterations in the retina. The patient presents with characteristic changes in retinal pigment epithelium, autofluorescence, and electrophysiology. PMID:23056974

Repetitive magnetic stimulation improves retinal function in a rat model of retinal dystrophy

NASA Astrophysics Data System (ADS)

Rotenstreich, Ygal; Tzameret, Adi; Levi, Nir; Kalish, Sapir; Sher, Ifat; Zangen, Avraham; Belkin, Michael

2014-02-01

Vision incapacitation and blindness associated with retinal dystrophies affect millions of people worldwide. Retinal degeneration is characterized by photoreceptor cell death and concomitant remodeling of remaining retinal cells. Repetitive Magnetic Stimulation (RMS) is a non-invasive technique that creates alternating magnetic fields by brief electric currents transmitted through an insulated coil. These magnetic field generate action potentials in neurons, and modulate the expression of neurotransmitter receptors, growth factors and transcription factors which mediate plasticity. This technology has been proven effective and safe in various psychiatric disorders. Here we determined the effect of RMS on retinal function in Royal College of Surgeons (RCS) rats, a model for retinal dystrophy. Four week-old RCS and control Spargue Dawley (SD) rats received sham or RMS treatment over the right eye (12 sessions on 4 weeks). RMS treatment at intensity of at 40% of the maximal output of a Rapid2 stimulator significantly increased the electroretinogram (ERG) b-wave responses by up to 6- or 10-fold in the left and right eye respectively, 3-5 weeks following end of treatment. RMS treatment at intensity of 25% of the maximal output did not significant effect b-wave responses following end of treatment with no adverse effect on ERG response or retinal structure of SD rats. Our findings suggest that RMS treatment induces delayed improvement of retinal functions and may induce plasticity in the retinal tissue. Furthermore, this non-invasive treatment may possibly be used in the future as a primary or adjuvant treatment for retinal dystrophy.

Structural, functional and blood perfusion changes in the rat retina associated with elevated intraocular pressure, measured simultaneously with a combined OCT+ERG system

PubMed Central

Tan, Bingyao; MacLellan, Benjamin; Mason, Erik

2018-01-01

Acute elevation of intraocular pressure (IOP) to ischemic and non-ischemic levels can cause temporary or permanent changes in the retinal morphology, function and blood flow/blood perfusion. Previously, such changes in the retina were assessed separately with different methods in clinical studies and animal models. In this study, we used a combined OCT+ ERG system in combination with Doppler OCT and OCT angiography (OCTA) imaging protocols, in order to evaluate simultaneously and correlate changes in the retinal morphology, the retinal functional response to visual stimulation, and the retinal blood flow/blood perfusion, associated with IOP elevation to ischemic and non-ischemic levels in rats. Results from this study suggest that the inner retina responds faster to IOP elevation to levels greater than 30 mmHg with significant reduction of the total retinal blood flow (TRBF), decrease of the capillaries’ perfusion and reduction of the ON bipolar cells contribution to the ERG traces. Furthermore, this study showed that ischemic levels of IOP elevation cause an additional significant decrease in the ERG photoreceptor response in the posterior retina. Thirty minutes after IOP normalization, retinal morphology, blood flow and blood perfusion recovered to baseline values, while retinal function did not recover completely. PMID:29509807

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

PubMed

Fu, Zhongjie; Wang, Zhongxiao; Liu, Chi-Hsiu; Gong, Yan; Cakir, Bertan; Liegl, Raffael; Sun, Ye; Meng, Steven S; Burnim, Samuel B; Arellano, Ivana; Moran, Elizabeth; Duran, Rubi; Poblete, Alexander; Cho, Steve S; Talukdar, Saswata; Akula, James D; Hellström, Ann; Smith, Lois E H

2018-05-01

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes. © 2018 by the American Diabetes Association.

Microarray analysis of gene expression in West Nile virus–infected human retinal pigment epithelium

PubMed Central

Munoz-Erazo, Luis; Natoli, Ricardo; Provis, Jan Marie; Madigan, Michelle Catherine

2012-01-01

Purpose To identify key genes differentially expressed in the human retinal pigment epithelium (hRPE) following low-level West Nile virus (WNV) infection. Methods Primary hRPE and retinal pigment epithelium cell line (ARPE-19) cells were infected with WNV (multiplicity of infection 1). RNA extracted from mock-infected and WNV-infected cells was assessed for differential expression of genes using Affymetrix microarray. Quantitative real-time PCR analysis of 23 genes was used to validate the microarray results. Results Functional annotation clustering of the microarray data showed that gene clusters involved in immune and antiviral responses ranked highly, involving genes such as chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 5 (CCL5), chemokine (C-X-C motif) ligand 10 (CXCL10), and toll like receptor 3 (TLR3). In conjunction with the quantitative real-time PCR analysis, other novel genes regulated by WNV infection included indoleamine 2,3-dioxygenase (IDO1), genes involved in the transforming growth factor–β pathway (bone morphogenetic protein and activin membrane-bound inhibitor homolog [BAMBI] and activating transcription factor 3 [ATF3]), and genes involved in apoptosis (tumor necrosis factor receptor superfamily, member 10d [TNFRSF10D]). WNV-infected RPE did not produce any interferon-γ, suggesting that IDO1 is induced by other soluble factors, by the virus alone, or both. Conclusions Low-level WNV infection of hRPE cells induced expression of genes that are typically associated with the host cell response to virus infection. We also identified other genes, including IDO1 and BAMBI, that may influence the RPE and therefore outer blood-retinal barrier integrity during ocular infection and inflammation, or are associated with degeneration, as seen for example in aging. PMID:22509103

Critical Endothelial Regulation by LRP5 during Retinal Vascular Development.

PubMed

Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood; Hokama, Madoka; Sardi, Sylvia H; Nagao, Masashi; Warman, Matthew L; Olsen, Bjorn R

2016-01-01

Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature.

Critical Endothelial Regulation by LRP5 during Retinal Vascular Development

PubMed Central

Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood; Hokama, Madoka; Sardi, Sylvia H.; Nagao, Masashi; Warman, Matthew L.; Olsen, Bjorn R.

2016-01-01

Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature. PMID:27031698

Retinal vessel caliber among people with acquired immunodeficiency syndrome: relationships with visual function.

PubMed

Kalyani, Partho S; Fawzi, Amani A; Gangaputra, Sapna; van Natta, Mark L; Hubbard, Larry D; Danis, Ronald P; Thorne, Jennifer E; Holland, Gary N

2012-03-01

To evaluate relationships between retinal vessel caliber and tests of visual function among people with AIDS. Longitudinal, observational cohort study. We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Visual function was evaluated with best-corrected visual acuity, Goldmann perimetry, automated perimetry (Humphrey Field Analyzer), and contrast sensitivity (CS) testing. Semi-automated grading of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, sought independent relationships between indices and visual function variables. Included were 1250 participants. Smaller AVR was associated with reduced visual field by Goldmann perimetry (P = .003) and worse mean deviation (P = .02) on automated perimetry and possibly with worse pattern standard deviation (PSD) on automated perimetry (P = .06). There was a weak association between smaller AVR and worse CS (P = .07). Relationships were independent of antiretroviral therapy and level of immunodeficiency (CD4+ T lymphocyte count, human immunodeficiency virus [HIV] RNA blood level). On longitudinal analysis, retinal vascular indices at baseline did not predict changes in visual function. Variation in retinal vascular indices is associated with abnormal visual function in people with AIDS, manifested by visual field loss and possibly by reduced CS. Relationships are consistent with the hypothesis that HIV-related retinal vasculopathy is a contributing factor to vision dysfunction among HIV-infected individuals. Longitudinal studies are needed to determine whether changes in indices predict change in visual function. Copyright © 2012 Elsevier Inc. All rights reserved.

Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal.

PubMed

McNeill, Brian; Mazerolle, Chantal; Bassett, Erin A; Mears, Alan J; Ringuette, Randy; Lagali, Pamela; Picketts, David J; Paes, Kim; Rice, Dennis; Wallace, Valerie A

2013-03-01

Norrie disease (ND) is a congenital disorder characterized by retinal hypovascularization and cognitive delay. ND has been linked to mutations in 'Norrie Disease Protein' (Ndp), which encodes the secreted protein Norrin. Norrin functions as a secreted angiogenic factor, although its role in neural development has not been assessed. Here, we show that Ndp expression is initiated in retinal progenitors in response to Hedgehog (Hh) signaling, which induces Gli2 binding to the Ndp promoter. Using a combination of genetic epistasis and acute RNAi-knockdown approaches, we show that Ndp is required downstream of Hh activation to induce retinal progenitor proliferation in the retina. Strikingly, Ndp regulates the rate of cell-cycle re-entry and not cell-cycle kinetics, thereby uncoupling the self-renewal and cell-cycle progression functions of Hh. Taken together, we have uncovered a cell autonomous function for Ndp in retinal progenitor proliferation that is independent of its function in the retinal vasculature, which could explain the neural defects associated with ND.

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

PubMed

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.

Features specific to retinal pigment epithelium cells derived from three-dimensional human embryonic stem cell cultures - a new donor for cell therapy.

PubMed

Wu, Wei; Zeng, Yuxiao; Li, Zhengya; Li, Qiyou; Xu, Haiwei; Yin, Zheng Qin

2016-04-19

Retinal pigment epithelium (RPE) transplantation is a particularly promising treatment of retinal degenerative diseases affecting RPE-photoreceptor complex. Embryonic stem cells (ESCs) provide an abundant donor source for RPE transplantation. Herein, we studied the time-course characteristics of RPE cells derived from three-dimensional human ESCs cultures (3D-RPE). We showed that 3D-RPE cells possessed morphology, ultrastructure, gene expression profile, and functions of authentic RPE. As differentiation proceeded, 3D-RPE cells could mature gradually with decreasing proliferation but increasing functions. Besides, 3D-RPE cells could form polarized monolayer with functional tight junction and gap junction. When grafted into the subretinal space of Royal College of Surgeons rats, 3D-RPE cells were safe and efficient to rescue retinal degeneration. This study showed that 3D-RPE cells were a new donor for cell therapy of retinal degenerative diseases.

Evaluation of patient suitability for a retinal prosthesis using structural and functional tests of inner retinal integrity

NASA Astrophysics Data System (ADS)

Huang, Qiuhen; Chowdhury, Vivek; Coroneo, Minas Theodore

2009-06-01

The purpose of this study was to assess inner retinal structure and function in patients with retinitis pigmentosa (RP) using optical coherence tomography (OCT) imaging of the retina, and electrical stimulation of the retina with a contact lens electrode. OCT images of 17 RP patients were acquired at the macula and at four quadrants of the peripheral retina in both eyes. Analysis was made of the residual inner retinal thickness and nerve fibre layer thickness in RP patients, and this was compared to normal controls. Eight of these patients further underwent contact lens electrical stimulation of one eye and thresholds for phosphene perception were obtained. OCT imaging showed a significant amount of inner retinal preservation in the peripheral retina and the macula of RP patients despite severe visual acuity and visual field loss. Phosphene thresholds were obtained across the range of pulse durations tested but were much higher than those obtained in normal controls. Phosphene thresholds in RP patients moderately correlated with inner retinal thicknesses as measured by OCT. Preservation of inner retinal structure in patients with RP and the responsiveness of these eyes to electrical stimulation suggest adequate inner retinal preservation for a retinal prosthesis to be successful.

RNCR3 knockdown inhibits diabetes mellitus-induced retinal reactive gliosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Chang; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing

Retinal reactive gliosis is an important pathological feature of diabetic retinopathy. Identifying the underlying mechanisms causing reactive gliosis will be important for developing new therapeutic strategies for treating diabetic retinopathy. Herein, we show that long noncoding RNA-RNCR3 knockdown significantly inhibits retinal reactive gliosis. RNCR3 knockdown leads to a marked reduction in the release of several cytokines. RNCR3 knockdown alleviates diabetes mellitus-induced retinal neurodegeneration, as shown by less apoptotic retinal cells and ameliorative visual function. RNCR3 knockdown could also decrease Müller glial cell viability and proliferation, and reduce the expression of glial reactivity-related genes including GFAP and vimentin in vitro. Collectively, thismore » study shows that RNCR3 knockdown may be a promising strategy for the prevention of diabetes mellitus-induced retinal neurodegeneration. - Highlights: • RNCR3 knockdown inhibits retinal reactive gliosis. • RNCR3 knockdown causes a significant change in cytokine profile. • RNCR3 knockdown alleviates diabetes mellitus-induced retinal neurodegeneration. • RNCR3 knockdown affects Müller glial cell function in vitro.« less

Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice.

PubMed

Sapieha, P; Chen, J; Stahl, A; Seaward, M R; Favazza, T L; Juan, A M; Hatton, C J; Joyal, J-S; Krah, N M; Dennison, R J; Tang, J; Kern, T S; Akula, J D; Smith, L E H

2012-07-23

Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks-26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM.

Small-spot laser-exposure effects on visual function

NASA Astrophysics Data System (ADS)

Zwick, Harry; Robbins, David O.; Stuck, Bruce E.; Lund, David J.; Reynolds, Scottie B.; Nawim, Maqsood; Schuschereba, Steven T.

1990-07-01

Laser field exposure effects on visual function involve produc tJon of minimal spot irradiation on or near the huntan fovea. Functional effects of such exposure may involve transient or perinanent change in visual function depending upon exposure dose. While Maximun Permissible Exposure (MPE) lirrtits define exposure in terins of threshold retinal niorphological change such limits are not applicable with regard to transient changes in visual function below MPE limits induced by alteration in retinal physiological processes. Mechanisms of transient and permanent functional change reported in these exper iments point out the need to examine laser safety limits in terms of both the functional as well as the morphological disturbance induced in retinal tissue. L

Establishing a Surgical Procedure for Rhesus Epiretinal Scaffold Implantation with HiPSC-Derived Retinal Progenitors

PubMed Central

Luo, Ziming; Li, Kang; Li, Kaijing; Xian, Bikun; Liu, Ying; Yang, Sijing; Xu, Chaochao; Lu, Shoutao; Zhang, Haijun

2018-01-01

Background To develop an effective surgical procedure for cellular scaffold epiretinal implantation in rhesus, facilitating subsequent epiretinal stem cell transplantation. Methods Retinal progenitors were seeded onto a poly(lactic-co-glycolic) acid (PLGA) scaffold. First, the cellular scaffolds were delivered by 18G catheter or retinal forceps into rabbit epiretinal space (n = 50). Then, the cell survival rate was evaluated by Cell Counting Kit-8 (CCK-8). Second, three methods of scaffold fixation, including adhesion after gas-liquid exchange (n = 1), tamponade by hydrogel (n = 1), and fixation by retinal tacks (n = 4), were performed in rhesus monkeys. After one month, fundus photography and SD-OCT were performed to assess the outcomes, and histological examination was performed to evaluate proliferation. Results The cell survival rate was significantly higher in the catheter group. Follow-up examination showed that retinal tack fixation was the only method to maintain the scaffolds attached to host retina for at least 3 weeks, which is the minimal time required for cell integration. Histological staining demonstrated slight glial fibrillary acidic protein (GFAP) accumulation in the retinal tack insertion area. Conclusions The established surgical procedure offers a new insight into research of epiretinal cell replacement therapy in rhesus eyes. The successful delivery and long-term fixation provide a prerequisite for cell migration and integration. PMID:29760741

Fundus autofluorescence and retinal structure as determined by spectral domain optical coherence tomography, and retinal function in retinitis pigmentosa.

PubMed

Iriyama, Aya; Yanagi, Yasuo

2012-03-01

To investigate the association between fundus autofluorescence (FAF) and retinal structure and function in retinitis pigmentosa (RP). For image acquisition, HRA2 (Heidelberg Engineering) and 3D-OCT1000 (Topcon Corp.) were used. Based on FAF examination, 88 eyes of 44 RP patients were categorized into three types. The area within the hyperautofluorescent ring and the area of preserved retinal autofluorescence with FAF was calculated. The association between the pattern of FAF and the residual area of the junction between the inner and outer segments of the photoreceptors (IS/OS line), and the relationship between the area within hyperautofluorescent ring, the area of preserved retinal autofluorescence and the mean deviation (MD) of static perimetry were assessed. Twenty-four eyes were with preserved retinal autofluorescence without hyperautofluorescent ring, 54 eyes were with hyperautofluorescent ring and ten eyes were with abnormal foveal autofluorescence both in the fovea and the periphery of the 30° scan. In the first type, the IS/OS line was clearly detected. In the second type, the residual area of the partially distinct IS/OS line corresponded with the area within hyperautofluorescent ring with significant correlation between the area within hyperautofluorescent ring and the MD (R(2) = 0.705, p < 0.001); however, there was no correlation between the area of preserved retinal autofluorescence and the MD, or between the area of preserved retinal autofluorescence and the area within hyperautofluorescent ring. In the third type, the IS/OS line was completely absent. The residual IS/OS line can be found in the area inside the hyperautofluorescent ring and correlates with residual visual function.

The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function.

PubMed

Turturro, Sanja B; Guthrie, Micah J; Appel, Alyssa A; Drapala, Pawel W; Brey, Eric M; Pérez-Luna, Victor H; Mieler, William F; Kang-Mieler, Jennifer J

2011-05-01

There is significant interest in biomaterials that provide sustained release of therapeutic molecules to the retina. Poly(N-isopropylacrylamide) (PNIPAAm)-based materials have received significant attention as injectable drug delivery platforms due to PNIPAAm's thermo-responsive properties at approximately 32 °C. While the drug delivery properties of PNIPAAm materials have been studied extensively, there is a need to evaluate the safety effects of hydrogel injection on retinal function. The purpose of this study was to examine the effect of poly(ethylene glycol) diacrylate (PEG-DA) crosslinked PNIPAAm hydrogel injection on retinal function. Utilizing scanning laser ophthalmoscopy (SLO), optical coherent tomography (OCT), and electroretinography (ERG), retinal function was assessed following hydrogel injection. In region near the hydrogel, there was a significant decrease in arterial and venous diameters (∼4%) and an increase in venous blood velocity (∼8%) 1 week post-injection. Retinal thickness decreased (∼6%) at 1 week and the maximum a- and b-wave amplitudes of ERG decreased (∼15%). All data returned to baseline values after week 1. These data suggest that the injection of PEG-DA crosslinked PNIPAAm hydrogel results in a small transient effect on retinal function without any long-term effects. These results further support the potential of PNIPAAm-based materials as an ocular drug delivery platform. Copyright © 2011 Elsevier Ltd. All rights reserved.

Clinical Outcomes of Retinal Detachment Surgery following Cytomegalovirus Retinitis in Patients on Highly Active Anti-retroviral Therapy for Acquired Immune Deficiency Syndrome.

PubMed

Mathur, Gaurav; Ratra, Dhanashree; Bhuibhar, Sagar Sudhakar; Roy, Rupak

2015-01-01

The objective of this study is to describe the surgical outcomes of patients of HIV on HAART who underwent surgery for CMV retinitis related retinal detachment. A retrospective analysis of the medical records of 40 eyes of 35 consecutive HIV positive patients who underwent surgical repair for CMV retinitis associated rhegmatogenous retinal detachment between January 2000 to August 2010 was done. All patients had an adequate follow up of atleast 6 months. Favourable anatomical outcome was achieved in 78 % of eyes with the eyes having a attached retina, clear media and controlled intraocular pressure.Favourable functional outcome (vision >3/60) was achieved in 56%. Though anatomical outcomes have not changed from the pre HAART era but there has been an increase in favorable functional outcomes possibly due to effects of antiretroviral therapy.

Wide-field optical coherence tomography based microangiography for retinal imaging

PubMed Central

Zhang, Qinqin; Lee, Cecilia S.; Chao, Jennifer; Chen, Chieh-Li; Zhang, Thomas; Sharma, Utkarsh; Zhang, Anqi; Liu, Jin; Rezaei, Kasra; Pepple, Kathryn L.; Munsen, Richard; Kinyoun, James; Johnstone, Murray; Van Gelder, Russell N.; Wang, Ruikang K.

2016-01-01

Optical coherence tomography angiography (OCTA) allows for the evaluation of functional retinal vascular networks without a need for contrast dyes. For sophisticated monitoring and diagnosis of retinal diseases, OCTA capable of providing wide-field and high definition images of retinal vasculature in a single image is desirable. We report OCTA with motion tracking through an auxiliary real-time line scan ophthalmoscope that is clinically feasible to image functional retinal vasculature in patients, with a coverage of more than 60 degrees of retina while still maintaining high definition and resolution. We demonstrate six illustrative cases with unprecedented details of vascular involvement in retinal diseases. In each case, OCTA yields images of the normal and diseased microvasculature at all levels of the retina, with higher resolution than observed with fluorescein angiography. Wide-field OCTA technology will be an important next step in augmenting the utility of OCT technology in clinical practice. PMID:26912261

Wide-field optical coherence tomography based microangiography for retinal imaging

NASA Astrophysics Data System (ADS)

Zhang, Qinqin; Lee, Cecilia S.; Chao, Jennifer; Chen, Chieh-Li; Zhang, Thomas; Sharma, Utkarsh; Zhang, Anqi; Liu, Jin; Rezaei, Kasra; Pepple, Kathryn L.; Munsen, Richard; Kinyoun, James; Johnstone, Murray; van Gelder, Russell N.; Wang, Ruikang K.

2016-02-01

Optical coherence tomography angiography (OCTA) allows for the evaluation of functional retinal vascular networks without a need for contrast dyes. For sophisticated monitoring and diagnosis of retinal diseases, OCTA capable of providing wide-field and high definition images of retinal vasculature in a single image is desirable. We report OCTA with motion tracking through an auxiliary real-time line scan ophthalmoscope that is clinically feasible to image functional retinal vasculature in patients, with a coverage of more than 60 degrees of retina while still maintaining high definition and resolution. We demonstrate six illustrative cases with unprecedented details of vascular involvement in retinal diseases. In each case, OCTA yields images of the normal and diseased microvasculature at all levels of the retina, with higher resolution than observed with fluorescein angiography. Wide-field OCTA technology will be an important next step in augmenting the utility of OCT technology in clinical practice.

Wide-field optical coherence tomography based microangiography for retinal imaging.

PubMed

Zhang, Qinqin; Lee, Cecilia S; Chao, Jennifer; Chen, Chieh-Li; Zhang, Thomas; Sharma, Utkarsh; Zhang, Anqi; Liu, Jin; Rezaei, Kasra; Pepple, Kathryn L; Munsen, Richard; Kinyoun, James; Johnstone, Murray; Van Gelder, Russell N; Wang, Ruikang K

2016-02-25

Optical coherence tomography angiography (OCTA) allows for the evaluation of functional retinal vascular networks without a need for contrast dyes. For sophisticated monitoring and diagnosis of retinal diseases, OCTA capable of providing wide-field and high definition images of retinal vasculature in a single image is desirable. We report OCTA with motion tracking through an auxiliary real-time line scan ophthalmoscope that is clinically feasible to image functional retinal vasculature in patients, with a coverage of more than 60 degrees of retina while still maintaining high definition and resolution. We demonstrate six illustrative cases with unprecedented details of vascular involvement in retinal diseases. In each case, OCTA yields images of the normal and diseased microvasculature at all levels of the retina, with higher resolution than observed with fluorescein angiography. Wide-field OCTA technology will be an important next step in augmenting the utility of OCT technology in clinical practice.

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina

PubMed Central

2012-01-01

Background Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina’s stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. Results The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. Conclusions These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins. PMID:23111152

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina.

PubMed

Luo, Jing; Uribe, Rosa A; Hayton, Sarah; Calinescu, Anda-Alexandra; Gross, Jeffrey M; Hitchcock, Peter F

2012-10-30

Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.

Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice: A Novel Model for Investigating the Early Pathogenesis of Age-Related Macular Degeneration.

PubMed

Vessey, Kirstan A; Gu, Ben J; Jobling, Andrew I; Phipps, Joanna A; Greferath, Ursula; Tran, Mai X; Dixon, Michael A; Baird, Paul N; Guymer, Robyn H; Wiley, James S; Fletcher, Erica L

2017-08-01

Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

JPRS Report, Science & Technology, USSR: Life Sciences

DTIC Science & Technology

1989-02-10

29 Effects of Regulatory Peptides on Recovery of Visual Functions in Retinitis Pigmentosa [N. B. Kostelyanets, O. B. Ilyinskiy, et al; FIZIOLOGIYA...Western. UDC 612.812 Effects of Regulatory Peptides on Recovery of Visual Functions in Retinitis Pigmentosa 18400030a Moscow FIZIOLOGIYA CHELOVEKA in...et al.; BIOORGANICHESKAYA KHIMIYA, Vol 14 No 3, Mar 88] .. 3 Synthesis and Properties of C13-Dependent Retinals [S. V. Yeremin, B. I. Mitsner, et

Iron, zinc, and copper in retinal physiology and disease.

PubMed

Ugarte, Marta; Osborne, Neville N; Brown, Laurence A; Bishop, Paul N

2013-01-01

The essential trace metals iron, zinc, and copper play important roles both in retinal physiology and disease. They are involved in various retinal functions such as phototransduction, the visual cycle, and the process of neurotransmission, being tightly bound to proteins and other molecules to regulate their structure and/or function or as unbound free metal ions. Elevated levels of "free" or loosely bound metal ions can exert toxic effects, and in order to maintain homeostatic levels to protect retinal cells from their toxicity, appropriate mechanisms exist such as metal transporters, chaperones, and the presence of certain storage molecules that tightly bind metals to form nontoxic products. The pathways to maintain homeostatic levels of metals are closely interlinked, with various metabolic pathways directly and/or indirectly affecting their concentrations, compartmentalization, and oxidation/reduction states. Retinal deficiency or excess of these metals can result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal metal homeostasis, and this is associated with retinal dysfunction and pathology. Iron accumulation in the retina, a characteristic of aging, may be involved in the pathogenesis of retinal diseases such as age-related macular degeneration (AMD). Zinc deficiency is associated with poor dark adaptation. Zinc levels in the human retina and RPE decrease with age in AMD. Copper deficiency is associated with optic neuropathy, but retinal function is maintained. The changes in iron and zinc homeostasis in AMD have led to the speculation that iron chelation and/or zinc supplements may help in its treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration.

PubMed

Patel, Amit K; Davis, Ashley; Rodriguez, Maria Esperanza; Agron, Samantha; Hackam, Abigail S

2016-03-01

Retinal degenerations are a class of devastating blinding diseases that are characterized by photoreceptor dysfunction and death. In this study, we tested whether grape consumption, in the form of freeze-dried grape powder (FDGP), improves photoreceptor survival in a mouse model of retinal degeneration. Retinal degeneration was induced in mice by acute oxidative stress using subretinal injection of paraquat. The grape-supplemented diet was made by formulating base mouse chow with FDGP, corresponding to three daily human servings of grapes, and a control diet was formulated with equivalent sugar composition as FDGP (0.68% glucose-0.68% fructose mixture). Mice were placed on the diets at weaning for 5 wk before oxidative stress injury until analysis at 2 wk post-injection. Retinal function was measured using electroretinography, thickness of the photoreceptor layer was measured using optical coherence tomography, and rows of photoreceptor nuclei were counted on histologic sections. In mice fed the control diet, oxidative stress significantly reduced photoreceptor layer thickness and photoreceptor numbers. In contrast, retinal thickness and photoreceptor numbers were not reduced by oxidative stress in mice on the grape-supplemented diet, indicating significantly higher photoreceptor survival after injury than mice on the control diet. Furthermore, mice on the grape diet showed preservation of retinal function after oxidative stress injury compared with mice on the control diet. A diet supplemented with grapes rescued retinal structure and function in an oxidative stress-induced mouse model of retinal degeneration, which demonstrates the beneficial effect of grapes on photoreceptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Macroglia-derived thrombospondin 2 regulates alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure.

PubMed

Wang, Shuchao; Hu, Tu; Wang, Zhen; Li, Na; Zhou, Lihong; Liao, Lvshuang; Wang, Mi; Liao, Libin; Wang, Hui; Zeng, Leping; Fan, Chunling; Zhou, Hongkang; Xiong, Kun; Huang, Jufang; Chen, Dan

2017-01-01

Many studies on retinal injury and repair following elevated intraocular pressure suggest that the survival ratio of retinal neurons has been improved by various measures. However, the visual function recovery is far lower than expected. The homeostasis of retinal synapses in the visual signal pathway is the key structural basis for the delivery of visual signals. Our previous studies found that complicated changes in the synaptic structure between retinal neurons occurred much earlier than obvious degeneration of retinal ganglion cells in rat retinae. The lack of consideration of these earlier retinal synaptic changes in the rescue strategy may be partly responsible for the limited visual function recovery with the types of protective methods for retinal neurons used following elevated intraocular pressure. Thus, research on the modulatory mechanisms of the synaptic changes after elevated intraocular pressure injury may give new light to visual function rescue. In this study, we found that thrombospondin 2, an important regulator of synaptogenesis in central nervous system development, was distributed in retinal macroglia cells, and its receptor α2δ-1 was in retinal neurons. Cell cultures including mixed retinal macroglia cells/neuron cultures and retinal neuron cultures were exposed to elevated hydrostatic pressure for 2 h. The expression levels of glial fibrillary acidic protein (the marker of activated macroglia cells), thrombospondin 2, α2δ-1 and presynaptic proteins were increased following elevated hydrostatic pressure in mixed cultures, but the expression levels of postsynaptic proteins were not changed. SiRNA targeting thrombospondin 2 could decrease the upregulation of presynaptic proteins induced by the elevated hydrostatic pressure. However, in retinal neuron cultures, elevated hydrostatic pressure did not affect the expression of presynaptic or postsynaptic proteins. Rather, the retinal neuron cultures with added recombinant thrombospondin 2 protein upregulated the level of presynaptic proteins. Finally, gabapentin decreased the expression of presynaptic proteins in mixed cultures by blocking the interaction of thrombospondin 2 and α2δ-1. Taken together, these results indicate that activated macroglia cells may participate in alterations of presynaptic proteins of retinal neurons following elevated hydrostatic pressure, and macroglia-derived thrombospondin 2 may modulate these changes via binding to its neuronal receptor α2δ-1.

Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells.

PubMed

Aoki, Hitomi; Hara, Akira; Niwa, Masayuki; Motohashi, Tsutomu; Suzuki, Takashi; Kunisada, Takahiro

2008-02-01

An embryonic stem (ES) cell-derived eye-like structure, made up of neural retinal lineage cells, retinal pigment epithelial (RPE) cells, and lens cells was constructed in our laboratory. We have shown that cells from these eye-like structures can be integrated into the developing optic vesicle of chicks. The purpose of this study was to determine whether the cells from these eye-like structures can differentiate into retinal ganglion cells (RGCs) when transplanted into the vitreous of an injured adult mouse retina. ES cells were induced to differentiate into eye-like structures in vitro for 6 or 11 days. Recipient mouse eyes were injected with NMDA to injure the RGCs prior to the transplantation. Sham-treated eyes received the same amount of carrier vehicle. Cells were extracted from the eye-like structures and transplanted into the vitreous of damaged and control eyes. The host eyes were analyzed both qualitatively and quantitatively by immunohistochemistry 10 days or 8 weeks after transplantation. Cells from the ES cell-derived eye-like structures were integrated into the RGC layer, and differentiated into neurons when transplanted into control (non-NMDA-treated) adult eyes. However, they rarely expressed RGC markers. When they were transplanted into NMDA-treated eyes, the cells spread on the surface of the retina and covered a relatively large area of the host RGC layer that had been injured by the NMDA. The cells from the ES cell-derived eye cells frequently differentiated into cells expressing RGC-specific markers, and formed a new RGC layer. In addition, a small number of these ES cell-derived cells were observed to extend axon-like processes toward the optic disc of the host. However, visually evoked responses could not be recorded from the visual cortex. These findings suggest that ES cell-derived eye-like structures contain cells that can differentiate into RG-like cells and regenerate a new RGC layer. These cells also appeared to be integrated into the retina and extend axon-like processes toward the optic nerve head.

A Novel Role for the Immunoproteasome in Retinal Function

PubMed Central

Hussong, Stacy A.; Roehrich, Heidi; Kapphahn, Rebecca J.; Maldonado, Marcela; Pardue, Machelle T.

2011-01-01

Purpose. The immunoproteasome is a proteasome subtype with a well-characterized role in the immune system. The presence of high immunoproteasome concentrations in the photoreceptors and synaptic regions of the immune-privileged retina implies a role in visual transmission. In this study, immunoproteasome knockout (KO) mice lacking either one (lmp7−/−, L7) or two (lmp7−/−/mecl-1−/−, L7M1) catalytic subunits of the immunoproteasome were used to test the hypothesis that it is essential for the maintenance of normal retinal function. Methods. Wild-type (WT) and immunoproteasome KO mice lacking either one (L7) or two (L7M1) catalytic subunits of the immunoproteasome were studied to determine the importance of the immunoproteasome in maintaining normal retinal function and morphology. Changes in retinal morphology were assessed in mice 2 to 24 months of age. Retinal function was measured with electroretinography (ERG), and relative content of select retinal proteins was assessed by immunoblot analysis. Results. Retinal morphometry showed no major abnormalities in age-matched WT or KO mice. No significant difference was observed in the levels of proteins involved in vision transmission. ERGs from KO mice exhibited an approximate 25% decrease in amplitude of the dark- and light-adapted b-waves and faster dark-adapted b-wave implicit times. Conclusions. Immunoproteasome deficiency causes defects in bipolar cell response. These results support a previously unrecognized role for the immunoproteasome in vision transmission. PMID:20881299

Characteristics of untreated AIDS-related cytomegalovirus retinitis. II. Findings in the era of highly active antiretroviral therapy (1997 to 2000).

PubMed

Holland, Gary N; Vaudaux, Jean D; Shiramizu, Kevin M; Yu, Fei; Goldenberg, David T; Gupta, Anurag; Carlson, Margrit; Read, Russell W; Novack, Roger D; Kuppermann, Baruch D

2008-01-01

To describe host characteristics (use of highly active antiretroviral therapy [HAART]; CD4+ T-lymphocyte count; HIV ribonucleic acid [RNA] blood level) of people who were diagnosed with AIDS-related cytomegalovirus (CMV) retinitis after HAART became available and to investigate effects of HAART on ophthalmic findings. Retrospective, observational case series. We collected demographic, medical, laboratory, and ophthalmic data for all patients with AIDS and newly diagnosed, untreated CMV retinitis from January 1997 through December 2000 at 10 sites in Los Angeles and Orange Counties, California. The proportions of Hispanic and African-American patients were equivalent to or greater than their prevalences in the AIDS and general populations of Los Angeles County. Most patients (n = 80; 63.5%) were known to be receiving HAART at the time of CMV retinitis diagnosis; only 22 patients (17.5%) were HAART-naïve. Median CD4+ T-lymphocyte count was 15 cells/microl and median HIV RNA blood level was 103,000 copies/ml for all patients, but in 10 patients, CMV retinitis developed despite good immunologic and virologic responses to HAART. When compared with HAART-naïve patients, HAART-failure patients with CMV retinitis had more asymptomatic disease (P = .073), better visual acuity in the better eye (P = .003), more bilateral disease (P = .007), less zone 1 involvement (P = .042), and lower lesion border opacity scores (P = .054). Most patients with AIDS and newly diagnosed CMV retinitis in an urban setting are HAART-experienced. HAART may influence characteristics of new CMV retinitis lesions at presentation, despite laboratory evidence of treatment failure, possibly because of residual CMV-specific immunity.

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

PubMed

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.

The structure and function of the macula in patients with advanced retinitis pigmentosa.

PubMed

Vámos, Rita; Tátrai, Erika; Németh, János; Holder, Graham E; DeBuc, Delia Cabrera; Somfai, Gábor Márk

2011-10-28

To assess the structure and function of the macula in advanced retinitis pigmentosa (RP). Twenty-nine eyes of 22 patients with RP were compared against 17 control eyes. Time-domain optical coherence tomography (OCT) data were processed using OCTRIMA (optical coherence tomography retinal image analysis) as a means of quantifying commercial OCT system images. The thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer and outer plexiform layer complex (INL+OPL), and the outer nuclear layer (ONL) were measured. Multifocal electroretinography (mfERG) was performed; two groups were formed based on the mfERG findings. Fourteen eyes had no detectable central retinal function (NCRF) on mfERG; detectable but abnormal retinal function (DRF) was present in the mfERG of the other 15 eyes. The thickness of the ONL in the central macular region was significantly less in the NCRF eyes compared with that in both DRF eyes and controls. The ONL was significantly thinner in the pericentral region in both patient groups compared with that in controls, whereas the thickness of the GCL+IPL and INL+OPL was significantly decreased only in the NCRF eyes. The RNFL in the peripheral region was significantly thicker, whereas the thickness of the GCL+IPL and ONL was significantly thinner in both patient groups compared with that in controls. The results are consistent with degeneration of the outer retina preceding inner retinal changes in RP. OCT image segmentation enables objective evaluation of retinal structural changes in RP, with potential use in the planning of therapeutic interventions and conceivably as an outcome measure.

The Structure and Function of the Macula in Patients with Advanced Retinitis Pigmentosa

PubMed Central

Vámos, Rita; Tátrai, Erika; Németh, János; Holder, Graham E.; DeBuc, Delia Cabrera

2011-01-01

Purpose. To assess the structure and function of the macula in advanced retinitis pigmentosa (RP). Methods. Twenty-nine eyes of 22 patients with RP were compared against 17 control eyes. Time-domain optical coherence tomography (OCT) data were processed using OCTRIMA (optical coherence tomography retinal image analysis) as a means of quantifying commercial OCT system images. The thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer and outer plexiform layer complex (INL+OPL), and the outer nuclear layer (ONL) were measured. Multifocal electroretinography (mfERG) was performed; two groups were formed based on the mfERG findings. Fourteen eyes had no detectable central retinal function (NCRF) on mfERG; detectable but abnormal retinal function (DRF) was present in the mfERG of the other 15 eyes. Results. The thickness of the ONL in the central macular region was significantly less in the NCRF eyes compared with that in both DRF eyes and controls. The ONL was significantly thinner in the pericentral region in both patient groups compared with that in controls, whereas the thickness of the GCL+IPL and INL+OPL was significantly decreased only in the NCRF eyes. The RNFL in the peripheral region was significantly thicker, whereas the thickness of the GCL+IPL and ONL was significantly thinner in both patient groups compared with that in controls. Conclusions. The results are consistent with degeneration of the outer retina preceding inner retinal changes in RP. OCT image segmentation enables objective evaluation of retinal structural changes in RP, with potential use in the planning of therapeutic interventions and conceivably as an outcome measure. PMID:21948552

Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice

PubMed Central

Sapieha, P; Chen, J; Stahl, A; Seaward, M R; Favazza, T L; Juan, A M; Hatton, C J; Joyal, J-S; Krah, N M; Dennison, R J; Tang, J; Kern, T S; Akula, J D; Smith, L E H

2012-01-01

Objective: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Design: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks–26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. Results: The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. Conclusion: This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM. PMID:23448719

Viral posterior uveitis

PubMed Central

Lee, Joanne H.; Agarwal, Aniruddha; Mahendradas, Padmamalini; Lee, Cecilia S.; Gupta, Vishali; Pavesio, Carlos E.; Agrawal, Rupesh

2017-01-01

The causes of posterior uveitis can be divided into infectious, autoimmune, or masquerade syndromes. Viral infections, a significant cause of sight-threatening ocular diseases in the posterior segment, include human herpesviruses, measles, rubella, and arboviruses such as dengue, West Nile, and chikungunya virus. Viral posterior uveitis may occur as an isolated ocular disease in congenital or acquired infections or as part of a systemic viral illness. Many viruses remain latent in the infected host with a risk of reactivation that depends on various factors, including virulence and host immunity, age, and comorbidities. Although some viral illnesses are self-limiting and have a good visual prognosis, others, such as cytomegalovirus retinitis or acute retinal necrosis, may result in serious complications and profound vision loss. Since some of these infections may respond well to antiviral therapy, it is important to work up all cases of posterior uveitis to rule out an infectious etiology. We review the clinical features, diagnostic tools, treatment regimens, and long-term outcomes for each of these viral posterior uveitides. PMID:28012878

Predicted molecular signaling guiding photoreceptor cell migration following transplantation into damaged retina

NASA Astrophysics Data System (ADS)

Unachukwu, Uchenna John; Warren, Alice; Li, Ze; Mishra, Shawn; Zhou, Jing; Sauane, Moira; Lim, Hyungsik; Vazquez, Maribel; Redenti, Stephen

2016-03-01

To replace photoreceptors lost to disease or trauma and restore vision, laboratories around the world are investigating photoreceptor replacement strategies using subretinal transplantation of photoreceptor precursor cells (PPCs) and retinal progenitor cells (RPCs). Significant obstacles to advancement of photoreceptor cell-replacement include low migration rates of transplanted cells into host retina and an absence of data describing chemotactic signaling guiding migration of transplanted cells in the damaged retinal microenvironment. To elucidate chemotactic signaling guiding transplanted cell migration, bioinformatics modeling of PPC transplantation into light-damaged retina was performed. The bioinformatics modeling analyzed whole-genome expression data and matched PPC chemotactic cell-surface receptors to cognate ligands expressed in the light-damaged retinal microenvironment. A library of significantly predicted chemotactic ligand-receptor pairs, as well as downstream signaling networks was generated. PPC and RPC migration in microfluidic ligand gradients were analyzed using a highly predicted ligand-receptor pair, SDF-1α - CXCR4, and both PPCs and RPCs exhibited significant chemotaxis. This work present a systems level model and begins to elucidate molecular mechanisms involved in PPC and RPC migration within the damaged retinal microenvironment.

Cytomegalovirus: virological facts for clinicians.

PubMed

Bodaghi, B; Michelson, S

1999-12-01

Human cytomegalovirus (HCMV) is a complex DNA virus encoding more than 200 viral proteins. This highly adapted opportunist agent has developed several ways to evade the immune system. Among all clinical features due to HCMV, retinitis occurs especially in severely immunosuppressed patients, particularly during the end phase of HIV infection. Highly active antiretroviral therapy (HAART) has significantly reduced the incidence of this complication. However, in this HAART era, we observe the emergence of new clinical patterns in patients presenting with cicatricial HCMV retinitis. These patterns could be potentially related to immune mechanisms directed against viral antigens expressed at the surface of retinal cells that are still latently infected without any viral replication. We used a model of human retinal pigment epithelial (RPE) cells to evaluate virus-host interactions in the presence of different cytokines in the eye which play a major role in immunological or infectious conditions. Two different enzymatic pathways seem to be particularly involved during infection. Lack of tryptophan and production of nitric oxide seem to block HCMV replication in RPE cells. We propose a model to explain some of the mechanisms involved during severe immunosuppression and also after immune recovery.

Laser-induced retinal injury thresholds: variation with retinal irradiated area

NASA Astrophysics Data System (ADS)

Lund, David J.; Schulmeister, Karl; Seiser, Bernhard; Edthofer, Florian

2005-04-01

The retinal injury threshold for exposure to a laser source varies as a function of the irradiated area on the retina. Currently accepted guidelines for the safe use of lasers provide that the MPE will increase as the diameter of the irradiated area for retinal diameters between 25 mm and 1700 mm, based on the ED50 data available in the late 1970s. Recent studies by Zuclich and Lund produced data showing that the ED50 for ns-duration exposures at 532 nm and ms duration exposures at 590 nm varied as the square of the diameter of the irradiated area on the retina. This paper will discuss efforts to resolve the disagreement between the new data and the earlier data though an analysis of all accessible data relating the retinal injury threshold to the diameter of the incident beam on the retina and through simulations using computer models of laser-induced injury. The results show that the retinal radiant exposure required to produce retinal injury is a function of both exposure duration and retinal irradiance diameter and that the current guidelines for irradiance diameter dependence do not accurately reflect the variation of the threshold data.

Testing the biocompatibility of a glutathione-containing intra-ocular irrigation solution by using an isolated perfused bovine retina organ culture model - an alternative to animal testing.

PubMed

Januschowski, Kai; Zhour, Ahmad; Lee, Albert; Maddani, Ramin; Mueller, Sebastien; Spitzer, Martin S; Schnichels, Sven; Schultheiss, Maximilian; Doycheva, Deshka; Bartz-Schmidt, Karl-Ulrich; Szurman, Peter

2012-03-01

The effects of a glutathione-containing intra-ocular irrigation solution, BSS Plus©, on retinal function and on the survival of ganglion cells in whole-mount retinal explants were studied. Evidence is provided that the perfused ex vivo bovine retina can serve as an alternative to in vivo animal testing. Isolated bovine retinas were prepared and perfused with an oxygen-saturated standard irrigation solution, and an electroretinogram was recorded to assess retinal function. After stable b-waves were detected, the isolated retinas were perfused with BSS Plus for 45 minutes. To investigate the effects of BSS Plus on photoreceptor function, 1mM aspartate was added to the irrigation solution in order to obtain a-waves, and the ERG trace was monitored for 75 minutes. For histological analysis, isolated whole retinal mounts were stored for 24 hours at 4°C, in the dark. The percentages of cell death in the retinal ganglion cell layer and in the outer and inner nuclear layers were estimated by using an ethidium homodimer-1 stain and the TUNEL assay. General swelling of the retina was examined with high-resolution optical coherence tomography. During perfusion with BSS Plus, no significant changes in a-wave and b-wave amplitudes were recorded. Retinas stored for 24 hours in BSS Plus showed a statistically significant smaller percentage (52.6%, standard deviation [SD] = 16.1%) of cell death in the retinal ganglion cell layer compared to the control group (69.6%, SD = 3.9, p = 0.0031). BSS Plus did not seem to affect short-term retinal function, and had a beneficial effect on the survival of retinal ganglion cells. This method for analysing the isolated perfused retina represents a valuable alternative for testing substances for their retinal biocompatibility and toxicity. 2012 FRAME.

Use of the multifocal electroretinogram (mfERG) for assessing the response of 670 nm light emitting diodes (LED) photoillumination in an animal model with laser retinal injuries

NASA Astrophysics Data System (ADS)

DiCarlo, Cheryl D.; Brown, Jeremiah; Grado, Andres; Sankovich, James; Zwick, Harry; Lund, David J.; Stuck, Bruce E.

2004-07-01

There is no uniformly accepted objective method to diagnose the functional extent of retinal damage following laser eye injury and there is no uniform therapy for laser retinal injury. J.T. Eells, et al, reported the use of Light Emitting Diodes (LED) photoillumination (670 nm) for methanol-induced retinal toxicity in rats. The findings indicated a preservation of retinal architecture, as determined by histopathology and a partial functional recovery of photoreceptors, as determined by electroretinogram (ERG), in the LED exposed methanol-intoxicated rats. The purpose of this study is to use multifocal electroretinography (mfERG) to evaluate recovery of retinal function following treatment with LED photoillumination in a cynomolgus monkey laser retinal injury model. Control and LED array (670 nm) illuminated animals received macular Argon laser lesions (514 nm, 130 mW, 100 ms). LED array exposure was accomplished for 4 days for a total dose of 4 J/cm2 per day. Baseline and post-laser exposure mfERGs were performed. mfERG results for five animals post-laser injury but prior to treatment (Day 0) showed increased implicit times and P1 waveform amplitudes when compared to a combined laboratory normal and each animal's baseline normal values. In general, preliminary mfERG results of our first five subjects recorded using both the 103-hexagon and 509-hexagon patterns indicate a more rapid functional recovery in the LED illuminated animal as compared to the control by the end of the fourth day post-exposure. Research is continuing to determine if this difference in functional return is seen in additional subjects and if statistical significance exists.

Early light deprivation effects on human cone-driven retinal function.

PubMed

Esposito Veneruso, Paolo; Ziccardi, Lucia; Magli, Giulia; Parisi, Vincenzo; Falsini, Benedetto; Magli, Adriano

2017-03-01

To assess whether the early light deprivation induced by congenital cataract may influence the cone-driven retinal function in humans. Forty-one patients affected by congenital cataract (CC) who had undergone uncomplicated cataract extraction surgery and intraocular lens implant, and 14 healthy subjects (HS) were enrolled. All patients underwent complete ophthalmological and orthoptic evaluations and best-corrected visual acuity (BCVA) measurement; light-adapted full-field electroretinograms (ERG) and photopic negative responses (PhNR) were recorded to obtain a reliable measurement of the outer/inner retinal function and of the retinal ganglion cells' function respectively. Mean values of light-adapted ERG a- and b-wave and PhNR amplitude of CC eyes were significantly reduced and photopic ERG b-wave implicit time mean values were significantly delayed when compared to HS ones. When studying photopic ERG mean amplitudes at 5 ms, significant differences were found when comparing CC and control eyes. In CC eyes, statistically significant correlations were found between a- and b- wave amplitudes and PhNR amplitudes. No significant correlations were found between ERG parameters and BCVA, as well as between the age of CC patients at surgery and the time elapsed from lens extraction. No significant differences were found when functional parameters of bilateral and unilateral congenital cataract (uCC) eyes were compared, however uCC eyes showed significant differences when compared with contralateral healthy eyes. We found a significant impairment of cone-driven retinal responses in patients with a history of congenital cataract. These changes might result from the long-lasting effects of early light deprivation on the cone retinal pathways. Our findings support the relevance of retinal involvement in deficits induced by early light deprivation. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Parenteral Lipid Dose Restriction With Soy Oil, Not Fish Oil, Preserves Retinal Function in Neonatal Piglets.

PubMed

Lansing, Marihan; Sauvé, Yves; Dimopoulos, Ioannis; Field, Catherine J; Suh, Miyoung; Wizzard, Pamela; Goruk, Susan; Lim, David; Muto, Mitsuru; Wales, Paul; Turner, Justine

2018-03-13

A dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (AA) is critical for neonatal retinal development. Both are absent/minimal in parenteral nutrition (PN) using soy-oil emulsions ([SO] Intralipid®) traditionally used for neonatal intestinal failure. In contrast, fish-oil emulsions ([FO] Omegaven®) are enriched in DHA/AA. The aim of this study was to compare retinal function and fatty acid content in neonatal piglets fed PN with SO or FO. Two-5-day-old piglets were randomly allocated to SO (n = 4) or FO (n = 4), provided at equivalent doses (5g/kg/d). After 14 days of PN, retinal function was assessed by electroretinography and retinas were harvested for fatty acid content analysis. Sow-fed piglets served as a reference (REF). Light flash-elicited stoppage of cone and rod dark-currents (a-waves) and the ensuing postsynaptic activation of cone and rod ON bipolar cells (b-waves) were comparable between SO and REF. Responses recorded from FO were subnormal (P <0.001) when compared with both SO and REF. Retinal DHA content was similar in both groups (FO, 14.59% vs SO, 12.22%; P = 0.32); while AA was lower in FO (FO, 6.01% vs SO, 8.21%; P = .001). Paradoxically, FO containing more DHA and AA did not preserve retinal function when compared with the same low dose of SO. This may be due to the reduced AA enrichment in the retina with FO treatment. Further investigation into the ideal amounts of DHA and AA for optimal neonatal retinal function is required. © 2018 American Society for Parenteral and Enteral Nutrition.

Development and Implementation of an Objective, Non-invasive, Behaviorally Relevant Metric for Laser Eye Injury

DTIC Science & Technology

2005-09-01

34Assessment of local retinal function in patients with retinitis pigmentosa using the multi-focal ERG technique.," Vision Research, vol. 38, pp. 163-179... pigmentosa , and retinal detachment10. mfERG response characteristics have been shown to vary depending on the part of the retina that is affected by a...expanding. Thus, the potential for laser eye injury and retinal damage is increasing. Sensitive and accurate methods to evaluate and follow laser retinal

Construction of a plasmid for human brain-derived neurotrophic factor and its effect on retinal pigment epithelial cell viability

PubMed Central

Yan, Bo-jing; Wu, Zhi-zhong; Chong, Wei-hua; Li, Gen-lin

2016-01-01

Several studies have investigated the protective functions of brain-derived neurotrophic factor (BDNF) in retinitis pigmentosa. However, a BDNF-based therapy for retinitis pigmentosa is not yet available. To develop an efficient treatment for fundus disease, an eukaryotic expression plasmid was generated and used to transfect human 293T cells to assess the expression and bioactivity of BDNF on acute retinal pigment epithelial-19 (ARPE-19) cells, a human retinal epithelial cell line. After 96 hours of co-culture in a Transwell chamber, ARPE-19 cells exposed to BDNF secreted by 293T cells were more viable than ARPE-19 cells not exposed to secreted BDNF. Western blot assay showed that Bax levels were downregulated and that Bcl-2 levels were upregulated in human ARPE-19 cells exposed to BDNF. Furthermore, 293T cells transfected with the BDNF gene steadily secreted the protein. The powerful anti-apoptotic function of this BDNF may be useful for the treatment of retinitis pigmentosa and other retinal degenerative diseases. PMID:28197196

Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease.

PubMed

Kolko, Miriam; Vosborg, Fia; Henriksen, Ulrik L; Hasan-Olive, Md Mahdi; Diget, Elisabeth Holm; Vohra, Rupali; Gurubaran, Iswariya Raja Sridevi; Gjedde, Albert; Mariga, Shelton Tendai; Skytt, Dorte M; Utheim, Tor Paaske; Storm-Mathisen, Jon; Bergersen, Linda H

2016-06-01

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion

PubMed Central

Becker, Silke; Eastlake, Karen; Jayaram, Hari; Jones, Megan F.; Brown, Robert A.; McLellan, Gillian J.; Charteris, David G.; Khaw, Peng T.

2016-01-01

Human Müller glia with stem cell characteristics (hMGSCs) have been shown to improve retinal function upon transplantation into rat models of retinal ganglion cell (RGC) depletion. However, their translational potential may depend upon successful engraftment and improvement of retinal function in experimental models with anatomical and functional features resembling those of the human eye. We investigated the effect of allogeneic transplantation of feline Müller glia with the ability to differentiate into cells expressing RGC markers, following ablation of RGCs by N-methyl-d-aspartate (NMDA). Unlike previous observations in the rat, transplantation of hMGSC-derived RGCs into the feline vitreous formed aggregates and elicited a severe inflammatory response without improving visual function. In contrast, allogeneic transplantation of feline MGSC (fMGSC)-derived RGCs into the vitrectomized eye improved the scotopic threshold response (STR) of the electroretinogram (ERG). Despite causing functional improvement, the cells did not attach onto the retina and formed aggregates on peripheral vitreous remnants, suggesting that vitreous may constitute a barrier for cell attachment onto the retina. This was confirmed by observations that cellular scaffolds of compressed collagen and enriched preparations of fMGSC-derived RGCs facilitated cell attachment. Although cells did not migrate into the RGC layer or the optic nerve, they significantly improved the STR and the photopic negative response of the ERG, indicative of increased RGC function. These results suggest that MGSCs have a neuroprotective ability that promotes partial recovery of impaired RGC function and indicate that cell attachment onto the retina may be necessary for transplanted cells to confer neuroprotection to the retina. Significance Müller glia with stem cell characteristics are present in the adult human retina, but they do not have regenerative ability. These cells, however, have potential for development of cell therapies to treat retinal disease. Using a feline model of retinal ganglion cell (RGC) depletion, cell grafting methods to improve RGC function have been developed. Using cellular scaffolds, allogeneic transplantation of Müller glia-derived RGC promoted cell attachment onto the retina and enhanced retinal function, as judged by improvement of the photopic negative and scotopic threshold responses of the electroretinogram. The results suggest that the improvement of RGC function observed may be ascribed to the neuroprotective ability of these cells and indicate that attachment of the transplanted cells onto the retina is required to promote effective neuroprotection. PMID:26718648

Photobiomodulation reduces photoreceptor death and regulates cytoprotection in early states of P23H retinal dystrophy

NASA Astrophysics Data System (ADS)

Kirk, Diana K.; Gopalakrishnan, Sandeep; Schmitt, Heather; Abroe, Betsy; Stoehr, Michele; Dubis, Adam; Carroll, Joseph; Stone, Jonathan; Valter, Krisztina; Eells, Janis

2013-03-01

Irradiation by light in the far-red to near-infrared (NIR) region of the spectrum (photobiomodulation, PBM) has been demonstrated to attenuate the severity of neurodegenerative disease in experimental and clinical studies. The purpose of this study was to test the hypothesis that 670 nm PBM would protect against the loss of retinal function and improve photoreceptor survival in a rodent model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated once per day with a 670 nm LED array (180 sec treatments at 50 mW/cm2; fluence 9 joules/cm2) (Quantum Devices Inc., Barneveld WI) from postnatal day (p) 16-20 or from p10-20. Sham-treated rats were restrained, but not exposed to NIR light. The status of the retina was determined at p22 by assessment of mitochondrial function, oxidative stress and cell death. In a second series of studies, retinal status was assessed at p30 by measuring photoreceptor function by ERG and retinal morphology by Spectral Domain Optical Coherence Tomography (SD-OCT). 670 nm PBM increased retinal mitochondrial cytochrome oxidase activity and upregulated the retina's production of the key mitochondrial antioxidant enzyme, MnSOD. PBM also attenuated photoreceptor cell loss and improved photoreceptor function. PBM protects photoreceptors in the developing P23H retina, by augmenting mitochondrial function and stimulating antioxidant protective pathways. Photobiomodulation may have therapeutic potential, where mitochondrial damage is a step in the death of photoreceptors.

Non-Invasive Cell-Based Therapy for Traumatic Optic Neuropathy

DTIC Science & Technology

2015-06-01

Morphological and Functional Changes in an Animal Model of Retinitis Pigmentosa . Vis Neurosci, 2013: 1-13. Bin Lu, Catherine W. Morgans, Sergey Girman...of human retinal progenitor cells for treatment of retinitis pigmentosa 2013, ARVO, A0106. Benjamin Bakondi; YuChun Tsai; Bin Lu; Sergey...Systemic administration of MSCs significantly preserved retinal ganglion cell survival after TON. (d) Systemic administration of MSCs also promote limited

Non-Invasive Cell-Based Therapy for Traumatic Optic Neuropathy

DTIC Science & Technology

2014-10-01

Functional Changes in an Animal Model of Retinitis Pigmentosa . Vis Neurosci, 2013: 1-13. Bin Lu, Catherine W. Morgans, Sergey Girman, Jing Luo, Jiagang...human retinal progenitor cells for treatment of retinitis pigmentosa 2013, ARVO, A0106. Benjamin Bakondi; YuChun Tsai; Bin Lu; Sergey...degeneration. Pending NEI (R24) Wang (PI) Preclinical program for Treating Retinitis Pigmentosa by Neural Progenitor Cells   18

Non-Invasive Cell-Based Therapy for Traumatic Optic Neuropathy

DTIC Science & Technology

2013-10-01

Morgans, Sergey Girman, Raymond Lund and Shaomei Wang Retinal Morphological and Functional Changes in an Animal Model of Retinitis Pigmentosa . Vis...model was created. 2. Rat MSC and M-Sch were reliable produced for experiments. 3. Systemic administration of MSC significantly preserved retinal ...TON also promote retinal ganglion cell survival. From the first year study, we have shown that systemic administration of MSC can significantly

Protective Effect of Total Flavones from Hippophae rhamnoides L. against Visible Light-Induced Retinal Degeneration in Pigmented Rabbits.

PubMed

Wang, Yong; Huang, Fenghong; Zhao, Liang; Zhang, Di; Wang, Ou; Guo, Xiaoxuan; Lu, Feng; Yang, Xue; Ji, Baoping; Deng, Qianchun

2016-01-13

Sea buckthorn (Hippophae rhamnoides L.) flavones have been used as candidate functional food ingredients because of their bioactivities, such as treating cardiovascular disorders, lowering plasma cholesterol level, and regulating immune function. However, the protective effects of sea buckthorn flavones against retinal degeneration remain unclear to date. This study investigated the protective effects of total flavones from H. rhamnoides (TFH) against visible light-induced retinal damage and explored the related mechanisms in pigmented rabbits. Rabbits were treated with TFH (250 and 500 mg/kg) for 2 weeks pre-illumination and 1 week post-illumination until sacrifice. Retinal function was quantified by performing electroretinography 1 day before and 1, 3, and 7 days after light exposure (18000 lx for 2 h). Retinal degeneration was evaluated by measuring the thickness of the outer nuclear layer (ONL) and performing the TUNEL assay 7 days after light exposure. Enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry were used to explore the antioxidant, anti-inflammatory, and anti-apoptotic mechanisms of TFH during visible light-induced retinal degeneration. Light exposure produced a degenerative effect primarily on the ONL, inner nuclear layer (INL), and ganglion cell layer (GCL). TFH significantly attenuated the destruction of electroretinograms caused by light damage, maintained ONL thickness, and decreased the number of TUNEL-positive cells in the INL and GCL. TFH ameliorated the retinal oxidative stress (GSH-Px, CAT, T-AOC, and MDA), inflammation (IL-1β and IL-6), angiogenesis (VEGF), and apoptosis (Bax, Bcl2, and caspase-3) induced by light exposure. Therefore, TFH exhibited protective effects against light-induced retinal degeneration by increasing the antioxidant defense mechanisms, suppressing pro-inflammatory and angiogenic cytokines, and inhibiting retinal cell apoptosis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Wenhu, E-mail: wenhu.huang@pfizer.com; Collette, Walter; Twamley, Michelle

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 mildmore » 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.« less

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

NASA Astrophysics Data System (ADS)

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.

Efficacy and Safety of Human Retinal Progenitor Cells

PubMed Central

Semo, Ma'ayan; Haamedi, Nasrin; Stevanato, Lara; Carter, David; Brooke, Gary; Young, Michael; Coffey, Peter; Sinden, John; Patel, Sara; Vugler, Anthony

2016-01-01

Purpose We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. Methods Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. Results The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and βIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. Conclusions Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. Translational Relevance Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies. PMID:27486556

Improvement of retinal functions after ischemia with L-arginine and its derivatives.

PubMed

Liu, S X; Chiou, G C; Varma, R S

1995-01-01

Retinal ischemia was created by occlusion of rat central retinal artery for 30 minutes. The loss of retinal function was indicated by the loss of b-wave of electroretinogram. The recovery of retinal function after reperfusion of central retinal artery was observed with the gradual recovery of b-wave amplitude to approximately 20% of original b-wave amplitude. When L-arginine (RVC-579) was administered at the time of retina ischemia, the b-wave amplitudes recovered up to 64% of original height and were significantly higher than corresponding controls at 120, 180, and 240 min after ischemia. When the derivative of L-arginine, N alpha-benzoyl-L-arginine ethyl ester (RVC-578), was administered, the b-wave recovery was significantly higher than corresponding controls at 90, 120, 180, and 240 min after ischemia; the recovery reached 51% of the original b-wave value. These results indicate that the L-arginine and its lipophilic derivatives could be used for the treatment of ischemic retinopathy. Since L-arginine is a natural amino acid, it is not expected to produce major side effects, if any, and could pave the way for the development of a safer drug to be used in the clinics. Compounds which increase the formation of NO in vivo, dilate blood vessels. Both L-arginine and RVC-578 can be placed in this category. They may improve effects of retinal ischemia by increasing NO production.

Structural and functional changes associated with normal and abnormal fundus autofluorescence in patients with retinitis pigmentosa.

PubMed

Greenstein, Vivienne C; Duncker, Tobias; Holopigian, Karen; Carr, Ronald E; Greenberg, Jonathan P; Tsang, Stephen H; Hood, Donald C

2012-02-01

To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa. Twenty-one retinitis pigmentosa patients (21 eyes) with rings/arcs and 21 normal individuals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral-domain optical coherence tomography. The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial complex and outer segment plus retinal pigment epithelial complex layers were measured. Results were compared with measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence. Disruption/loss of the inner outer segment junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in eight eyes. For 19 eyes, outer segment plus and receptor plus RPE complex thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across, and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8, and 17.0 ± 2.4 dB, respectively. Structural and functional changes can occur inside the hyperfluorescent ring/arc in retinitis pigmentosa.

Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury.

PubMed

Tong, Nianting; Zhang, Zhenzhen; Zhang, Wei; Qiu, Yating; Gong, Yuanyuan; Yin, Lili; Qiu, Qinghua; Wu, Xingwei

2013-01-01

Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R) injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG) just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB) extravasation was determined to assess blood-retinal barrier (BRB) disruption and the structure of tight junctions (TJ) was examined by transmission electron microscopy. Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1) and occludin protein expression and decreased VEGF/PEDF ratio. Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses.

PubMed

Heitmar, R; Varma, C; De, P; Lau, Y C; Blann, A D

2016-11-01

To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease. Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index. Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p < 0.05). Arterial reaction time was linked to serum creatinine (p = 0.036) and eGFR (p = 0.039); venous reaction time was linked to creatinine clearance (p = 0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p < 0.001 and p = 0.003, respectively) and the dilatation amplitude (p = 0.038 and p = 0.048, respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p = 0.004) and dilatation amplitude (p = 0.017), vWf was linked to the maximum constriction response (p = 0.016), and creatinine clearance to the baseline diameter fluctuation (p = 0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p = 0.022). Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses.

Cone dysfunctions in retinitis pigmentosa with retinal nerve fiber layer thickening

PubMed Central

Sobacı, Güngör; Özge, Gökhan; Gündoğan, Fatih Ç

2012-01-01

Purpose To investigate whether or not thicker retinal nerve fiber layer (RNFL) in retinitis pigmentosa (RP) patients relates to functional abnormalities of the photoreceptors. Methods Optical coherence tomography-based RNFL thickness was measured by Stratus-3™ (Zeiss, Basel, Switzerland) optical coherence tomography and electroretinogram (ERG) recordings made using the RETI-port® system (Roland, Wiesbaden, Germany) in 27 patients with retinitis pigmentosa and in 30 healthy subjects. Results Photopic ERG b-wave amplitude, cone ERG b-wave latency, 30 Hz flicker amplitude, and 30 Hz flicker latency had significant correlations to the RNFL-temporal (r = −0.55, P = 0.004, r = 0.68, P = 0.001, r = −0.65, P = 0.001, and r = −0.52, P = 0.007, respectively). Eyes with thicker RNFL (ten eyes) differed significantly from those with thinner RNFL (eight eyes) regarding cone ERG b-wave latency values only (P = 0.001). Conclusion Thicker RNFL in patients with retinitis pigmentosa may be associated with functional abnormality of the cone system. PMID:22536039

Cone dysfunctions in retinitis pigmentosa with retinal nerve fiber layer thickening.

PubMed

Sobacı, Güngör; Ozge, Gökhan; Gündoğan, Fatih Ç

2012-01-01

To investigate whether or not thicker retinal nerve fiber layer (RNFL) in retinitis pigmentosa (RP) patients relates to functional abnormalities of the photoreceptors. Optical coherence tomography-based RNFL thickness was measured by Stratus-3™ (Zeiss, Basel, Switzerland) optical coherence tomography and electroretinogram (ERG) recordings made using the RETI-port(®) system (Roland, Wiesbaden, Germany) in 27 patients with retinitis pigmentosa and in 30 healthy subjects. Photopic ERG b-wave amplitude, cone ERG b-wave latency, 30 Hz flicker amplitude, and 30 Hz flicker latency had significant correlations to the RNFL-temporal (r = -0.55, P = 0.004, r = 0.68, P = 0.001, r = -0.65, P = 0.001, and r = -0.52, P = 0.007, respectively). Eyes with thicker RNFL (ten eyes) differed significantly from those with thinner RNFL (eight eyes) regarding cone ERG b-wave latency values only (P = 0.001). Thicker RNFL in patients with retinitis pigmentosa may be associated with functional abnormality of the cone system.

Retinal isomerization in bacteriorhodopsin captured by a femtosecond x-ray laser.

PubMed

Nogly, Przemyslaw; Weinert, Tobias; James, Daniel; Carbajo, Sergio; Ozerov, Dmitry; Furrer, Antonia; Gashi, Dardan; Borin, Veniamin; Skopintsev, Petr; Jaeger, Kathrin; Nass, Karol; Båth, Petra; Bosman, Robert; Koglin, Jason; Seaberg, Matthew; Lane, Thomas; Kekilli, Demet; Brünle, Steffen; Tanaka, Tomoyuki; Wu, Wenting; Milne, Christopher; White, Thomas; Barty, Anton; Weierstall, Uwe; Panneels, Valerie; Nango, Eriko; Iwata, So; Hunter, Mark; Schapiro, Igor; Schertler, Gebhard; Neutze, Richard; Standfuss, Jörg

2018-06-14

Ultrafast isomerization of retinal is the primary step in photoresponsive biological functions including vision in humans and ion-transport across bacterial membranes. We studied the sub-picosecond structural dynamics of retinal isomerization in the light-driven proton pump bacteriorhodopsin using an x-ray laser. A series of structural snapshots with near-atomic spatial and temporal resolution in the femtosecond regime show how the excited all- trans retinal samples conformational states within the protein binding pocket prior to passing through a twisted geometry and emerging in the 13 -cis conformation. Our findings suggest ultrafast collective motions of aspartic acid residues and functional water molecules in the proximity of the retinal Schiff base as a key ingredient for this stereo-selective and efficient photochemical reaction. Copyright © 2018, American Association for the Advancement of Science.

Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy.

PubMed

Simmons, Aaron B; Bretz, Colin A; Wang, Haibo; Kunz, Eric; Hajj, Kassem; Kennedy, Carson; Yang, Zhihong; Suwanmanee, Thipparat; Kafri, Tal; Hartnett, M Elizabeth

2018-05-05

Inhibition of vascular endothelial growth factor (VEGF) in retinopathy of prematurity (ROP) raises concerns for premature infants because VEGF is essential for retinovascular development as well as neuronal and glial health. This study tested the hypothesis that endothelial cell-specific knockdown of VEGF receptor 2 (VEGFR2), or downstream STAT3, would inhibit VEGF-induced retinopathy without delaying physiologic retinal vascular development. We developed an endothelial cell-specific lentiviral vector that delivered shRNAs to VEGFR2 or STAT3 and a green fluorescent protein reporter under control of the VE-cadherin promoter. The specificity and efficacy of the lentiviral vector-driven shRNAs were validated in vitro and in vivo. In the rat oxygen-induced retinopathy model highly representative of human ROP, the effects of endothelial cell knockdown of VEGFR2 or STAT3 were determined on intravitreal neovascularization (IVNV), physiologic retinal vascular development [assessed as area of peripheral avascular/total retina (AVA)], retinal structure, and retinal function. Targeted knockdown of VEGFR2 or STAT3 specifically in retinal endothelial cells by subretinal injection of lentiviral vectors into postnatal day 8 rat pup eyes efficiently inhibited IVNV, and knockdown of VEGFR2 also reduced AVA and increased retinal thickness without altering retinal function. Taken together, our results support specific knockdown of VEGFR2 in retinal endothelial cells as a novel therapeutic method to treat retinopathy.

BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment

PubMed Central

Hsu, Ying; Kim, Gunhee; Zhang, Qihong; Datta, Poppy; Seo, Seongjin

2017-01-01

Genetic mutations disrupting the structure and function of primary cilia cause various inherited retinal diseases in humans. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic ciliopathy characterized by retinal degeneration, obesity, postaxial polydactyly, intellectual disability, and genital and renal abnormalities. To gain insight into the mechanisms of retinal degeneration in BBS, we developed a congenital knockout mouse of Bbs8, as well as conditional mouse models in which function of the BBSome (a protein complex that mediates ciliary trafficking) can be temporally inactivated or restored. We demonstrate that BBS mutant mice have defects in retinal outer segment morphogenesis. We further demonstrate that removal of Bbs8 in adult mice affects photoreceptor function and disrupts the structural integrity of the outer segment. Notably, using a mouse model in which a gene trap inhibiting Bbs8 gene expression can be removed by an inducible FLP recombinase, we show that when BBS8 is restored in immature retinas with malformed outer segments, outer segment extension can resume normally and malformed outer segment discs are displaced distally by normal outer segment structures. Over time, the retinas of the rescued mice become morphologically and functionally normal, indicating that there is a window of plasticity when initial retinal outer segment morphogenesis defects can be ameliorated. PMID:29049287

VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases.

PubMed

Le, Yun-Zheng

2017-10-01

Müller glia (MG) are major retinal supporting cells that participate in retinal metabolism, function, maintenance, and protection. During the pathogenesis of diabetic retinopathy (DR), a neurovascular disease and a leading cause of blindness, MG modulate vascular function and neuronal integrity by regulating the production of angiogenic and trophic factors. In this article, I will (1) briefly summarize our work on delineating the role and mechanism of MG-modulated vascular function through the production of vascular endothelial growth factor (VEGF) and on investigating VEGF signaling-mediated MG viability and neural protection in diabetic animal models, (2) explore the relationship among VEGF and neurotrophins in protecting Müller cells in in vitro models of diabetes and hypoxia and its potential implication to neuroprotection in DR and hypoxic retinal diseases, and (3) discuss the relevance of our work to the effectiveness and safety of long-term anti-VEGF therapies, a widely used strategy to combat DR, diabetic macular edema, neovascular age-related macular degeneration, retinopathy of prematurity, and other hypoxic retinal vascular disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

High-Resolution Opto-Electronic Retinal Prosthesis: Physical Limitations and Design

NASA Astrophysics Data System (ADS)

Palanker, D.; Vankov, A.; Huie, P.; Butterwick, A.; Chan, I.; Marmor, M. F.; Blumenkranz, M. S.

Electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa (RP). However, current retinal implants provide very low resolution (just a few electrodes), whereas many more pixels would be required for a functional restoration of sight.

Fast and automatic algorithm for optic disc extraction in retinal images using principle-component-analysis-based preprocessing and curvelet transform.

PubMed

Shahbeig, Saleh; Pourghassem, Hossein

2013-01-01

Optic disc or optic nerve (ON) head extraction in retinal images has widespread applications in retinal disease diagnosis and human identification in biometric systems. This paper introduces a fast and automatic algorithm for detecting and extracting the ON region accurately from the retinal images without the use of the blood-vessel information. In this algorithm, to compensate for the destructive changes of the illumination and also enhance the contrast of the retinal images, we estimate the illumination of background and apply an adaptive correction function on the curvelet transform coefficients of retinal images. In other words, we eliminate the fault factors and pave the way to extract the ON region exactly. Then, we detect the ON region from retinal images using the morphology operators based on geodesic conversions, by applying a proper adaptive correction function on the reconstructed image's curvelet transform coefficients and a novel powerful criterion. Finally, using a local thresholding on the detected area of the retinal images, we extract the ON region. The proposed algorithm is evaluated on available images of DRIVE and STARE databases. The experimental results indicate that the proposed algorithm obtains an accuracy rate of 100% and 97.53% for the ON extractions on DRIVE and STARE databases, respectively.

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

PubMed Central

Weinl, Christine; Riehle, Heidemarie; Park, Dongjeong; Stritt, Christine; Beck, Susanne; Huber, Gesine; Wolburg, Hartwig; Olson, Eric N.; Seeliger, Mathias W.; Adams, Ralf H.; Nordheim, Alfred

2013-01-01

Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases. PMID:23563308

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae.

PubMed

Weinl, Christine; Riehle, Heidemarie; Park, Dongjeong; Stritt, Christine; Beck, Susanne; Huber, Gesine; Wolburg, Hartwig; Olson, Eric N; Seeliger, Mathias W; Adams, Ralf H; Nordheim, Alfred

2013-05-01

Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.

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

PubMed

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.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CYTOMEGALOVIRUS RETINITIS: A Longitudinal Study.

PubMed

Invernizzi, Alessandro; Agarwal, Aniruddha; Ravera, Vittoria; Oldani, Marta; Staurenghi, Giovanni; Viola, Francesco

2018-01-01

To evaluate the vitreal, retinal, and choroidal features using spectral domain optical coherence tomography (SD-OCT) in eyes affected by cytomegalovirus (CMV) retinitis. Patients diagnosed with either active or inactive CMV retinitis were included in the study. Complete ophthalmic examination, serial color fundus photography, and SD-OCT (with and without enhanced depth imaging function) were performed for all the subjects at baseline and follow-up visits. The SD-OCT images were analyzed by two independent graders to evaluate the structural changes in areas of CMV retinitis. Prevalence data for vitreal, retinal, and choroidal SD-OCT features were collected. Twelve eyes from 9 patients (6 males, mean age: 52.7 ± 10.3 years) were enrolled. Nine eyes were diagnosed with active CMV retinitis at baseline. Active disease SD-OCT characteristic findings included nebulous vitritis (100%), posterior hyaloid thickening (83.3%), epiretinal membrane (100%), and retinal swelling (100%). Two distinct patterns of chorioretinal involvement were observed in active retinitis: 1) full-thickness retinitis (Full thickness retinitis) (n = 7 eyes) with choriocapillaris alterations and retinal pigment epithelial thickening and 2) cavernous retinitis (n = 3 eyes) characterized by inner retinal hyperreflectivity, large empty spaces in outer nuclear layer, and bridges of retinal tissue but retinal pigment epithelium and choriocapillaris sparing. Patients with cavernous retinitis develop retinal detachment during follow-up. Eyes with Full thickness retinitis developed choriocapillaris atrophy and choroidal thinning and retinal scars as the lesions healed. There are two distinct patterns of chorioretinal involvement in CMV retinitis. SD-OCT is a useful tool in the diagnosis, management, and prediction of the outcome of CMV retinitis.

Ocular toxoplasmosis and retinal detachment: five case reports.

PubMed

Kianersi, F; Naderi Beni, A; Ghanbari, H; Fazel, F

2012-10-01

Ocular toxoplasmosis is a potentially blinding cause of posterior uveitis. Retinal detachment is rare complication of ocular toxoplasmosis. To report the clinical course and prognosis of retinal breaks and detachments occurring in patients with ocular toxoplasmosis. This study was a retrospective, non-comparative case series of five patients with ocular toxoplasmosis who had consulted us with retinal detachment. All of the participants had retinal detachment after severe and treatment resistant toxoplasmic retinochoroiditis, leaving one of them with decreased visual acuity to light perception in spite of treatment and final visual acuity was 20/100 or better in four patients. The functional prognosis for the patients with retinal detachment was poor. Careful retinal examination in ocular toxoplasmosis is warranted, especially in patients with severe intraocular inflammation.

Retinitis pigmentosa and allied conditions today: a paradigm of translational research

PubMed Central

2010-01-01

Monogenic human retinal dystrophies are a group of disorders characterized by progressive loss of photoreceptor cells leading to visual handicap. Retinitis pigmentosa is a type of retinal dystrophy where degeneration of rod photoreceptors occurs at the early stages. At present, there are no available effective therapies to maintain or improve vision in patients affected with retinitis pigmentosa, but post-genomic studies are allowing the development of potential therapeutic approaches. This review summarizes current knowledge on genes that have been identified to be responsible for retinitis pigmentosa, the involvement of these genes in the different forms of the disorder, the role of the proteins encoded by these genes in retinal function, the utility of genotyping, and current efforts to develop novel therapies. PMID:20519033

Risk factors for cytomegalovirus retinitis in patients with cytomegalovirus viremia after hematopoietic stem cell transplantation.

PubMed

Jeon, Sohee; Lee, Won Ki; Lee, Yongeun; Lee, Dong Gun; Lee, Jong Wook

2012-09-01

To evaluate the risk factors for cytomegalovirus (CMV) retinitis in patients with CMV viremia after hematopoietic stem cell transplantation (HSCT). Retrospective cohort study. We included all patients with CMV viremia detected by polymerase chain reaction after HSCT between April 2009 and August 2011. Risk factors for CMV retinitis were evaluated in the cohort of 270 patients with CMV viremia, who survived ≥ 12 weeks after HSCT and were screened for CMV retinitis. Retrospective review of clinical records and laboratory results. Survival analysis of patients in the cohort and frequency of CMV retinitis in relation to various factors. Variables analyzed were demographics, human leukocyte antigen (HLA) matched versus mismatched, related versus unrelated donor, preconditioning regimens, delayed engraftment of lymphocyte, presence of acute or chronic graft-versus-host disease, highest CMV DNA level in blood (copies/ml), cumulative period of CMV viremia (weeks), and CMV infection verified by culture or immunohistology in bronchoalveolar lavage or visceral biopsy specimens. Of the 708 patients who underwent HSCT during the study period, 363 (51%) developed CMV viremia after HSCT. Of the 363 patients with CMV viremia, 270 underwent retinal examination for CMV retinitis. We detected CMV retinitis in 15 of 270 patients with CMV viremia. In the univariate analysis, HLA-mismatched HSCT, HSCT from an unrelated donor, engraftment day, peak CMV DNA level, and duration of viremia were associated with the development of CMV retinitis. In the adjusted multivariate analysis, only peak CMV DNA blood levels predicted the development of CMV retinitis (hazard ratio, 25.0; 95% confidence interval, 3.0-210.8). An additional validity analysis by receiver operating characteristic area under curve suggested that a cutoff of 7.64 × 10(4) copies/mL best predicted the development of CMV retinitis by CMV DNA levels in blood. The development of CMV retinitis should be carefully monitored in patients with a significant viral load, which is represented by a peak CMV DNA level >7.64 × 10(4) copies/ml and a long duration of CMV viremia, especially when patients received HSCT from an unrelated or HLA-mismatched donor and showed delayed lymphocyte engraftment. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Normal central retinal function and structure preserved in retinitis pigmentosa.

PubMed

Jacobson, Samuel G; Roman, Alejandro J; Aleman, Tomas S; Sumaroka, Alexander; Herrera, Waldo; Windsor, Elizabeth A M; Atkinson, Lori A; Schwartz, Sharon B; Steinberg, Janet D; Cideciyan, Artur V

2010-02-01

To determine whether normal function and structure, as recently found in forms of Usher syndrome, also occur in a population of patients with nonsyndromic retinitis pigmentosa (RP). Patients with simplex, multiplex, or autosomal recessive RP (n = 238; ages 9-82 years) were studied with static chromatic perimetry. A subset was evaluated with optical coherence tomography (OCT). Co-localized visual sensitivity and photoreceptor nuclear layer thickness were measured across the central retina to establish the relationship of function and structure. Comparisons were made to patients with Usher syndrome (n = 83, ages 10-69 years). Cross-sectional psychophysical data identified patients with RP who had normal rod- and cone-mediated function in the central retina. There were two other patterns with greater dysfunction, and longitudinal data confirmed that progression can occur from normal rod and cone function to cone-only central islands. The retinal extent of normal laminar architecture by OCT corresponded to the extent of normal visual function in patients with RP. Central retinal preservation of normal function and structure did not show a relationship with age or retained peripheral function. Usher syndrome results were like those in nonsyndromic RP. Regional disease variation is a well-known finding in RP. Unexpected was the observation that patients with presumed recessive RP can have regions with functionally and structurally normal retina. Such patients will require special consideration in future clinical trials of either focal or systemic treatment. Whether there is a common molecular mechanism shared by forms of RP with normal regions of retina warrants further study.

Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats☆

PubMed Central

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

Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats.

PubMed

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.

Duration of spiral aftereffect as a function of retinal size, retinal place, and hemiretinal transfer.

DOT National Transportation Integrated Search

1964-01-01

This experiment has shown that, although both rods and cones mediate the spiral aftereffect, cone areas give a larger response. Increasing size of the retinal image results in longer durations of SAE but rods are more affected by this increase than a...

Personality and Total Health Through Life Project Eye Substudy: Methodology and Baseline Retinal Features.

PubMed

Wijngaarden, Peter Van; Keel, Stuart; Hodgson, Lauren A B; Kumar, Dinesh K; Aliahmad, Behzad; Paim, Cistiane C; Kiely, Kim M; Cherbuin, Nicolas; Anstey, Kaarin J; Dirani, Mohamed

2017-01-01

To describe the methodology and present the retinal grading findings of an older sample of australians with well-defined indices of neurocognitive function in the Personality and total Health (PATH) through life project. A cross-sectional study. Three hundred twenty-six individuals from the PatH through life project were invited to participate. Participants completed a general questionnaire and 2-field, 45-degree nonmydriatic color digital retinal photography. Photographs were graded for retinal pathology according to established protocols. Two hundred fifty-four (77.9%) subjects, aged 72 to 78 years, agreed to participate in the eye substudy. gradable images of at least 1 eye were acquired in 211 of 254 subjects (83.1%). retinal photographic screening identified 1 or more signs of pathology in 130 of the 174 subjects (74.7%) with gradable images of both eyes. a total of 45 participants (17.7%) had self-reported diabetes and diabetic retinopathy was observed in 22 (48.9%) of these participants. This well-defined sample of older australians provides a unique opportunity to interrogate associations between retinal findings, including retinal vascular geometric parameters, and indices of neurocognitive function. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Estimation of prognosis and prevalence of retinitis pigmentosa and Usher syndrome in Norway.

PubMed

Grøndahl, J

1987-04-01

Retinitis pigmentosa was diagnosed in 101 persons from 53 families. The prognosis for visual function was most favourable for the autosomal dominant group (38 patients from 8 families). The autosomal recessive group (40 patients from 25 families) and the 19 solitary cases were very heterogeneous, with prognosis ranging from favourable to very bad. There was a higher intrafamiliar correlation in the autosomal recessive than in the autosomal dominant group. In 28 patients from 18 families with Usher syndrome, almost all had good visual function until 30 years of age, and few had useful visual function after the age of 50. The age when the patients were registered varied between the different genetic types of retinitis pigmentosa, reflecting differences in prognosis. Therefore, ascertainment probability and prevalence were calculated for each genetic group separately. The prevalence of retinitis pigmentosa in Norway, all genetic groups included, was calculated to be 1/4440, the autosomal dominant type of the disease being the most frequent. The prevalence of Usher syndrome was calculated to be 3.6/100,000. Both retinitis pigmentosa and Usher syndrome were more prevalent in Laps.

A cascade model of information processing and encoding for retinal prosthesis.

PubMed

Pei, Zhi-Jun; Gao, Guan-Xin; Hao, Bo; Qiao, Qing-Li; Ai, Hui-Jian

2016-04-01

Retinal prosthesis offers a potential treatment for individuals suffering from photoreceptor degeneration diseases. Establishing biological retinal models and simulating how the biological retina convert incoming light signal into spike trains that can be properly decoded by the brain is a key issue. Some retinal models have been presented, ranking from structural models inspired by the layered architecture to functional models originated from a set of specific physiological phenomena. However, Most of these focus on stimulus image compression, edge detection and reconstruction, but do not generate spike trains corresponding to visual image. In this study, based on state-of-the-art retinal physiological mechanism, including effective visual information extraction, static nonlinear rectification of biological systems and neurons Poisson coding, a cascade model of the retina including the out plexiform layer for information processing and the inner plexiform layer for information encoding was brought forward, which integrates both anatomic connections and functional computations of retina. Using MATLAB software, spike trains corresponding to stimulus image were numerically computed by four steps: linear spatiotemporal filtering, static nonlinear rectification, radial sampling and then Poisson spike generation. The simulated results suggested that such a cascade model could recreate visual information processing and encoding functionalities of the retina, which is helpful in developing artificial retina for the retinally blind.

A Fine-Scale Functional Logic to Convergence from Retina to Thalamus.

PubMed

Liang, Liang; Fratzl, Alex; Goldey, Glenn; Ramesh, Rohan N; Sugden, Arthur U; Morgan, Josh L; Chen, Chinfei; Andermann, Mark L

2018-05-31

Numerous well-defined classes of retinal ganglion cells innervate the thalamus to guide image-forming vision, yet the rules governing their convergence and divergence remain unknown. Using two-photon calcium imaging in awake mouse thalamus, we observed a functional arrangement of retinal ganglion cell axonal boutons in which coarse-scale retinotopic ordering gives way to fine-scale organization based on shared preferences for other visual features. Specifically, at the ∼6 μm scale, clusters of boutons from different axons often showed similar preferences for either one or multiple features, including axis and direction of motion, spatial frequency, and changes in luminance. Conversely, individual axons could "de-multiplex" information channels by participating in multiple, functionally distinct bouton clusters. Finally, ultrastructural analyses demonstrated that retinal axonal boutons in a local cluster often target the same dendritic domain. These data suggest that functionally specific convergence and divergence of retinal axons may impart diverse, robust, and often novel feature selectivity to visual thalamus. Copyright © 2018 Elsevier Inc. All rights reserved.

Acute retinal ischemia inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production.

PubMed

Hein, Travis W; Ren, Yi; Potts, Luke B; Yuan, Zhaoxu; Kuo, Enoch; Rosa, Robert H; Kuo, Lih

2012-01-03

Because retinal vascular disease is associated with ischemia and increased oxidative stress, the vasodilator function of retinal arterioles was examined after retinal ischemia induced by elevated intraocular pressure (IOP). The role of superoxide anions in the development of vascular dysfunction was assessed. IOP was increased and maintained at 80 to 90 mm Hg for 30, 60, or 90 minutes by infusing saline into the anterior chamber of a porcine eye. The fellow eye with normal IOP (10-20 mm Hg) served as control. In some pigs, superoxide dismutase mimetic TEMPOL (1 mM) or vehicle (saline) was injected intravitreally before IOP elevation. After enucleation, retinal arterioles were isolated and pressurized without flow for functional analysis by recording diameter changes using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production in isolated retinal arterioles. Isolated retinal arterioles developed stable basal tone and the vasodilations to endothelium-dependent nitric oxide (NO)-mediated agonists bradykinin and L-lactate were significantly reduced only by 90 minutes of ischemia. However, vasodilation to endothelium-independent NO donor sodium nitroprusside was unaffected after all time periods of ischemia. DHE staining showed that 90 minutes of ischemia significantly increased superoxide levels in retinal arterioles. Intravitreal injection of membrane-permeable radical scavenger but not vehicle before ischemia prevented elevation of vascular superoxide and preserved bradykinin-induced dilation. Endothelium-dependent NO-mediated dilation of retinal arterioles is impaired by 90 minutes of ischemia induced by elevated IOP. The inhibitory effect appears to be mediated by the alteration of NO signaling via vascular superoxide.

Intraocular Delivery of miR-146 Inhibits Diabetes-Induced Retinal Functional Defects in Diabetic Rat Model.

PubMed

Zhuang, Pei; Muraleedharan, Chithra K; Xu, Shunbin

2017-03-01

Previously, we showed that microRNA-146 (miR-146) is a pivotal negative feedback regulator of multiple nuclear factor kappa-B (NF-κB) activation pathways in retinal endothelial cells (RECs). We hypothesized that miR-146 plays an important role in diabetic retinopathy (DR) by inhibiting diabetes-induced inflammatory response in the retina. The purpose of the current study is to test this hypothesis in vivo. Lentiviruses expressing rno-miR-146a, lenti-miR-146a, and negative control oligonucleotide with scrambled sequence, lenti-miR-neg ctl, were produced. Young male Sprague-Dawley rats were injected with a single dose of streptozotocin ([STZ] 65 mg/kg) to induce diabetes. One week after diabetes, animals were injected with lentivirus intravitreally (4 μl, ∼106 CFU/mL). Three months after diabetes, retinal microvascular leakage was tested by Evans blue assay; retinal function by electroretinogram (ERG). Total RNA and protein lysate were isolated from the retina for quantitative (q)RT-PCR and Western blot analyses. Lenti-miR-146a robustly transduced human retinal endothelial cells (HRECs) and increased the expression of miR-146a in vitro. In vivo, intravitreal injection of lenti-miR-146a increased the expression of miR-146a in the retina, while its key downstream target genes, including CARD10, IRAK1, and TRAF6, were downregulated. Intravitreal delivery of miR-146 inhibited diabetes-induced upregulation of NF-κB downstream gene, Intercellular Adhesion Molecule 1 (ICAM1), as well as microvascular leakage and retinal functional defects. Intravitreal delivery of miR-146 inhibited diabetes-induced NF-κB activation and retinal microvascular and neuronal functional defects in a diabetic rat model.

Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.

PubMed

Wang, Nan-Kai; Tosi, Joaquin; Kasanuki, Jennifer Mie; Chou, Chai Lin; Kong, Jian; Parmalee, Nancy; Wert, Katherine J; Allikmets, Rando; Lai, Chi-Chun; Chien, Chung-Liang; Nagasaki, Takayuki; Lin, Chyuan-Sheng; Tsang, Stephen H

2010-04-27

To study whether C57BL/6J-Tyr/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65/Rpe65 C57BL6 mice. Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell-derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65/Rpe65 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation. RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65/Rpe65 mice transplanted with RPE-like cells showed significant visual recovery during a 7-month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue. ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials.

Evaluation of Retinal Function and Morphology of the Pink-Eyed Royal College of Surgeons (RCS) Rat: A Comparative Study of in Vivo and in Vitro Methods.

PubMed

Rösch, Sarah; Aretzweiler, Christoph; Müller, Frank; Walter, Peter

2017-02-01

To characterize the course of retinal degeneration in the pink-eyed RCS rat in vivo and in vitro. Retinal function of RCS rats at the age of 2 to 100 weeks was determined in vivo using full-field electroretinography (ERG). Retinal morphology was evaluated in vivo using spectral domain Optical Coherence Tomography (sd-OCT) and Fluorescence angiography (FA) as well as postmortem using immunohistochemistry (IH). As a control, retinal function and morphology of non-dystrophic Wistar rats were analyzed. RCS rats showed an extinction of the ERG beginning with the age of 4 weeks. In the OCT, the outer part of the retina (OPR) could be clearly distinguished from the inner part of the retina (IPR) until the age of 8 weeks. However, at this age, it was impossible to determine from OCT images whether the OPR was formed by the outer nuclear layer (ONL) or by cellular debris built in the course of retinal degeneration. In contrast, immunohistochemistry always enabled to differentiate between ONL and debris (RCS 4 weeks of age: OPR mainly formed by ONL; RCS 8 weeks of age: OPR consisted mainly of cell debris, only 1-2 cell rows of photoreceptor somata were left). In general, data obtained in vivo were confirmed by data obtained post mortem. Apart from the problem to differentiate between debris and ONL at the age of 8 weeks in the RCS rat, ERG and OCT are useful methods to evaluate retinal function and structure in vivo and to complement immunohistochemical analysis of the degeneration process.

Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa.

PubMed

Sánchez-Cruz, Alonso; Villarejo-Zori, Beatriz; Marchena, Miguel; Zaldivar-Díez, Josefa; Palomo, Valle; Gil, Carmen; Lizasoain, Ignacio; de la Villa, Pedro; Martínez, Ana; de la Rosa, Enrique J; Hernández-Sánchez, Catalina

2018-04-16

Retinitis pigmentosa (RP) is a group of hereditary retinal neurodegenerative conditions characterized by primary dysfunction and death of photoreceptor cells, resulting in visual loss and, eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of RP, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy. Using the Pde6b rd10/rd10 mouse model of RP, we investigated the effects of daily intraperitoneal administration of VP3.15, a small-molecule heterocyclic GSK-3 inhibitor. Gene expression was analyzed by quantitative PCR and protein expression and phosphorylation by Western blot. Photoreceptor preservation was evaluated by histological analysis and visual function was assessed by electroretinography. In rd10 retinas, increased expression of pro-inflammatory markers and reactive gliosis coincided with the early stages of retinal degeneration. Compared with wild-type controls, GSK-3β expression (mRNA and protein) remained unchanged during the retinal degeneration period. However, levels of GSK-3β Ser9 and its regulator Akt Ser473 were increased in rd10 versus wild-type retinas. In vivo administration of VP3.15 reduced photoreceptor cell loss and preserved visual function. This neuroprotective effect was accompanied by a decrease in the expression of neuroinflammatory markers. These results provide proof of concept of the therapeutic potential of VP3.15 for the treatment of retinal neurodegenerative conditions in general, and RP in particular.

Restoration of vision in blind individuals using bionic devices: a review with a focus on cortical visual prostheses.

PubMed

Lewis, Philip M; Ackland, Helen M; Lowery, Arthur J; Rosenfeld, Jeffrey V

2015-01-21

The field of neurobionics offers hope to patients with sensory and motor impairment. Blindness is a common cause of major sensory loss, with an estimated 39 million people worldwide suffering from total blindness in 2010. Potential treatment options include bionic devices employing electrical stimulation of the visual pathways. Retinal stimulation can restore limited visual perception to patients with retinitis pigmentosa, however loss of retinal ganglion cells precludes this approach. The optic nerve, lateral geniculate nucleus and visual cortex provide alternative stimulation targets, with several research groups actively pursuing a cortically-based device capable of driving several hundred stimulating electrodes. While great progress has been made since the earliest works of Brindley and Dobelle in the 1960s and 1970s, significant clinical, surgical, psychophysical, neurophysiological, and engineering challenges remain to be overcome before a commercially-available cortical implant will be realized. Selection of candidate implant recipients will require assessment of their general, psychological and mental health, and likely responses to visual cortex stimulation. Implant functionality, longevity and safety may be enhanced by careful electrode insertion, optimization of electrical stimulation parameters and modification of immune responses to minimize or prevent the host response to the implanted electrodes. Psychophysical assessment will include mapping the positions of potentially several hundred phosphenes, which may require repetition if electrode performance deteriorates over time. Therefore, techniques for rapid psychophysical assessment are required, as are methods for objectively assessing the quality of life improvements obtained from the implant. These measures must take into account individual differences in image processing, phosphene distribution and rehabilitation programs that may be required to optimize implant functionality. In this review, we detail these and other challenges facing developers of cortical visual prostheses in addition to briefly outlining the epidemiology of blindness, and the history of cortical electrical stimulation in the context of visual prosthetics. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Correlation between fundus autofluorescence and central visual function in chronic central serous chorioretinopathy.

PubMed

Eandi, Chiara M; Piccolino, Felice Cardillo; Alovisi, Camilla; Tridico, Federico; Giacomello, Daniela; Grignolo, Federico M

2015-04-01

To find possible correlations between the morphologic macular changes revealed by fundus autofluorescence (FAF) and the functional parameters such as visual acuity and retinal sensitivity in patients with chronic central serous chorioretinopathy (CSC). Prospective, cross-sectional study. Forty-six eyes (39 consecutive patients) with chronic CSC were studied with FAF and microperimetry (MP). Retinal sensitivity value maps were exactly superimposed over FAF images. The following microperimetric parameters were applied: central 10-degree visual field, 4-2-1 strategy, 61 stimulation spots, white monochromatic background, stimulation time 200 ms, stimulation spot size Goldmann III. A possible relationship between MP and FAF was investigated. Mean best-corrected visual acuity (BCVA) was 20/32 (median 20/25, range 20/20-20/200). BCVA was significantly correlated with FAF findings (Mann-Whitney test; P < .0001). A positive concordance between FAF and MP evaluation was also found (total concordance of 0.720 with a kappa of Cohen of 0.456). The hypo-autofluorescent areas showed decreased retinal sensitivity, while adjacent areas of increased FAF could be associated to both normal and decreased retinal sensitivity. Absolute scotoma, defined as 0 dB retinal sensitivity, corresponded with absence of autofluorescence. Altered FAF in chronic CSC patients has a functional correlation quantified by microperimetry. This study confirms the impact of FAF changes on retinal sensitivity and their value to reflect the functional impairment in chronic CSC. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of the Muscarinic Acetylcholine Receptor Subtype Mediating Cholinergic Vasodilation in Murine Retinal Arterioles

PubMed Central

Sniatecki, Jan J.; Goloborodko, Evgeny; Steege, Andreas; Zavaritskaya, Olga; Vetter, Jan M.; Grus, Franz H.; Patzak, Andreas; Wess, Jürgen; Pfeiffer, Norbert

2011-01-01

Purpose. To identify the muscarinic acetylcholine receptor subtype that mediates cholinergic vasodilation in murine retinal arterioles. Methods. Muscarinic receptor gene expression was determined in murine retinal arterioles using real-time PCR. To assess the functional relevance of muscarinic receptors for mediating vascular responses, retinal vascular preparations from muscarinic receptor–deficient mice were studied in vitro. Changes in luminal arteriole diameter in response to muscarinic and nonmuscarinic vasoactive substances were measured by video microscopy. Results. Only mRNA for the M3 receptor was detected in retinal arterioles. Thus, M3 receptor–deficient mice (M3R−/−) and respective wild-type controls were used for functional studies. Acetylcholine concentration-dependently dilated retinal arterioles from wild-type mice. In contrast, vasodilation to acetylcholine was almost completely abolished in retinal arterioles from M3R−/− mice, whereas responses to the nitric oxide (NO) donor nitroprusside were retained. Carbachol, an acetylcholinesterase-resistant analog of acetylcholine, also evoked dilation in retinal arterioles from wild-type, but not from M3R−/−, mice. Vasodilation responses from wild-type mice to acetylcholine were negligible after incubation with the non–subtype-selective muscarinic receptor blocker atropine or the NO synthase inhibitor Nω-nitro-l-arginine methyl ester, and were even reversed to contraction after endothelial damage with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Conclusions. These findings provide evidence that endothelial M3 receptors mediate cholinergic vasodilation in murine retinal arterioles via activation of NO synthase. PMID:21873683

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy.

PubMed

Wang, Zhongxiao; Liu, Chi-Hsiu; Sun, Ye; Gong, Yan; Favazza, Tara L; Morss, Peyton C; Saba, Nicholas J; Fredrick, Thomas W; He, Xi; Akula, James D; Chen, Jing

2016-10-01

Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies. Lrp5(-/-) mice displayed significantly delayed retinal vascular development, absence of deep layer retinal vessels, leading to increased levels of vascular endothelial growth factor and subsequent pathologic glomeruloid vessels, as well as decreased inner retinal visual function. Lithium treatment in Lrp5(-/-) mice significantly restored the delayed development of retinal vasculature and the intralaminar capillary networks, suppressed formation of pathologic glomeruloid structures, and promoted hyaloid vessel regression. Moreover, lithium treatment partially rescued inner-retinal visual function and increased retinal thickness. These protective effects of lithium were largely mediated through restoration of canonical Wnt signaling in Lrp5(-/-) retina. Lithium treatment also substantially increased vascular tubular formation in LRP5-deficient endothelial cells. These findings suggest that pharmacologic activation of Wnt signaling may help treat ocular pathologies in FEVR and potentially other defective Wnt signaling-related diseases. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Analysis of the chicken retina with an adaptive optics multiphoton microscope.

PubMed

Bueno, Juan M; Giakoumaki, Anastasia; Gualda, Emilio J; Schaeffel, Frank; Artal, Pablo

2011-06-01

The structure and organization of the chicken retina has been investigated with an adaptive optics multiphoton imaging microscope in a backward configuration. Non-stained flat-mounted retinal tissues were imaged at different depths, from the retinal nerve fiber layer to the outer segment, by detecting the intrinsic nonlinear fluorescent signal. From the stacks of images corresponding to the different retinal layers, volume renderings of the entire retina were reconstructed. The density of photoreceptors and ganglion cells layer were directly estimated from the images as a function of the retinal eccentricity. The maximum anatomical resolving power at different retinal eccentricities was also calculated. This technique could be used for a better characterization of retinal alterations during myopia development, and may be useful for visualization of retinal pathologies and intoxication during pharmacological studies.

Analysis of retinal function using chromatic pupillography in retinitis pigmentosa and the relationship to electrically evoked phosphene thresholds.

PubMed

Kelbsch, Carina; Maeda, Fumiatsu; Lisowska, Jolanta; Lisowski, Lukasz; Strasser, Torsten; Stingl, Krunoslav; Wilhelm, Barbara; Wilhelm, Helmut; Peters, Tobias

2017-06-01

To analyse pupil responses to specific chromatic stimuli in patients with advanced retinitis pigmentosa (RP) to ascertain whether chromatic pupillography can be used as an objective marker for residual retinal function. To examine correlations between parameters of the pupil response and the perception threshold of electrically evoked phosphenes. Chromatic pupillography was performed in 40 patients with advanced RP (visual acuity < 0.02 or visual field ≤5°, non-recordable ERGs) and 40 age-matched healthy subjects. Pupil responses to full-field red (605 nm) and blue (420 nm) stimuli of 28 lx corneal illumination were recorded and analysed for two stimulus durations (1 and 4 seconds). The perception threshold of phosphenes to transcorneal electrostimulation was ascertained and correlated to the pupil responses and visual acuity. Patients with RP showed significantly reduced pupil responses to red and blue stimuli compared with the controls. With red stimuli, pupillary escape could be observed; blue stimuli resulted in a well-preserved postillumination pupil response. Phosphene thresholds were significantly increased in patients with RP and correlated with the parameters of the pupil response if all subjects were considered. Within the RP group alone, this relationship was less pronounced and statistically not significant. Chromatic pupillography demonstrated a significant decrease in outer retinal photoreceptor responses but a persisting and disinhibited intrinsic photosensitive retinal ganglion cell function in advanced RP. These phenomena may be useful as an objective marker for the efficacy of any interventional treatment for hereditary retinal diseases as well as for the selection of suitable patients for an electronic retinal implant. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Visual Search in the Detection of Retinal Injury: A Feasibility Study

DTIC Science & Technology

2013-04-01

D, Heyes A. et al. Mobility of people with retinitis pigmentosa as a function of vision and psychological variables. Optometry and Vision Science...AFRL-RH-FS-TR-2013-0019 Visual Search in the Detection of Retinal Injury: A Feasibility Study Thomas Kuyk TASC, Inc. Lei Liu The...Detection of Retinal Injury: A Feasibility Study" 2013 0019 LEON N. McLIN, JR., DR-III, DAF Work Unit Manager 711 HPW/ RHDO POLHAMUS.GARR ETT.D

Vinpocetine modulates metabolic activity and function during retinal ischemia.

PubMed

Nivison-Smith, Lisa; O'Brien, Brendan J; Truong, Mai; Guo, Cindy X; Kalloniatis, Michael; Acosta, Monica L

2015-05-01

Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues. Copyright © 2015 the American Physiological Society.

Retina tissue engineering by conjunctiva mesenchymal stem cells encapsulated in fibrin gel: Hypotheses on novel approach to retinal diseases treatment.

PubMed

Soleimannejad, Mostafa; Ebrahimi-Barough, Somayeh; Nadri, Samad; Riazi-Esfahani, Mohammad; Soleimani, Masoud; Tavangar, Seyed Mohammad; Ai, Jafar

2017-04-01

Retinitis pigmentosa (RP) and age related macular degeneration (AMD) are two retinal diseases that progress by photoreceptor cells death. In retinal transplantation studies, stem and progenitor cells inject into the sub retinal space or vitreous and then these cells can be migrate to the site of retinal degeneration and locate in the host retina and restitute vision. Our hypothesis suggests that using human conjunctiva stem cells (as the source for increasing the number of human stem cells progenitor cells in retina dysfunction diseases) with fibrin gel and also assessing its relating in vitro (cellular and molecular processes) and in vivo (vision tests and pathology) could be a promising strategy for treatment of AMD and RP disorders. In this idea, we describe a novel approach for retina tissue engineering with differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells in fibrin gel with induction medium contain taurine. For assessment of differentiation, immunocytochemistry and real time PCR are used for the expression of Rhodopsin, RPE65, Nestin as differentiated photoreceptor cell markers in 2D and 3D culture. The results show that fibrin gel will offer a proper 3D scaffold for CJMSCs derived photoreceptor cell-like cells. Application of immune-privileged, readily available sources of adult stem cells like human conjunctiva stem cells with fibrin gel would be a promising strategy to increase the number of photoreceptor progenitor cells and promote involuntary angiogenesis needed in retina layer repair and regeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

PubMed Central

Smith, Justine R.; Todd, Shawn; Ashander, Liam M.; Charitou, Theodosia; Ma, Yuefang; Yeh, Steven; Crozier, Ian; Michael, Michael Z.; Appukuttan, Binoy; Williams, Keryn A.; Lynn, David J.; Marsh, Glenn A.

2017-01-01

Purpose Success of Ebola virus (EBOV) as a human pathogen relates at the molecular level primarily to blockade the host cell type I interferon (IFN) antiviral response. Most individuals who survive Ebola virus disease (EVD) develop a chronic disease syndrome: approximately one-quarter of survivors suffer from uveitis, which has been associated with presence of EBOV within the eye. Clinical observations of post-Ebola uveitis indicate involvement of retinal pigment epithelial cells. Methods We inoculated ARPE-19 human retinal pigment epithelial cells with EBOV, and followed course of infection by immunocytochemistry and measurement of titer in culture supernatant. To interrogate transcriptional responses of infected cells, we combined RNA sequencing with in silico pathway, gene ontology, transcription factor binding site, and network analyses. We measured infection-induced changes of selected transcripts by reverse transcription-quantitative polymerase chain reaction. Results Human retinal pigment epithelial cells were permissive to infection with EBOV, and supported viral replication and release of virus in high titer. Unexpectedly, 28% of 560 upregulated transcripts in EBOV-infected cells were type I IFN responsive, indicating a robust type I IFN response. Following EBOV infection, cells continued to express multiple immunomodulatory molecules linked to ocular immune privilege. Conclusions Human retinal pigment epithelial cells may serve as an intraocular reservoir for EBOV, and the molecular response of infected cells may contribute to the persistence of live EBOV within the human eye. Translational Relevance This bedside-to-bench research links ophthalmic findings in survivors of EVD who suffer from uveitis with interactions between retinal pigment epithelial cells and EBOV. PMID:28721309

Postconditioning with inhaled hydrogen promotes survival of retinal ganglion cells in a rat model of retinal ischemia/reperfusion injury.

PubMed

Wang, Ruobing; Wu, Jiangchun; Chen, Zeli; Xia, Fangzhou; Sun, Qinglei; Liu, Lin

2016-02-01

Retinal ischemia/reperfusion (I/R) injury plays a crucial role in the pathophysiology of various ocular diseases. Intraperitoneal injection or ocular instillation with hydrogen (H2)-rich saline was recently shown to be neuroprotective in the retina due to its anti-oxidative and anti-inflammatory effects. Our study aims to explore whether postconditioning with inhaled H2 can protect retinal ganglion cells (RGCs) in a rat model of retinal I/R injury. Retinal I/R injury was performed on the right eyes of rats and was followed by inhalation of 67% H2 mixed with 33% oxygen immediately after ischemia for 1h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining and retrograde labeling with cholera toxin beta (CTB). Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). Potential biomarkers of retinal oxidative stress and inflammatory responses were measured, including the expression of 4-Hydroxynonenalv (4-HNE), interleukin-1 beta (IL1-β) and tumor necrosis factor alpha (TNF-α). HE and CTB tracing showed that the survival rate of RGCs in the H2-treated group was significantly higher than the rate in the I/R group. Rats with H2 inhalation showed better visual function in assessments of FVEP and PLR. Moreover, H2 treatment significantly decreased the number of 4-HNE-stained cells in the ganglion cell layer and inhibited the retinal overexpression of IL1-β and TNF-α that was induced by retinal I/R injury. Our results demonstrate that postconditioning with inhaled high-dose H2 appears to confer neuroprotection against retinal I/R injury via anti-oxidative, anti-inflammatory and anti-apoptosis pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

Analysis of the chicken retina with an adaptive optics multiphoton microscope

PubMed Central

Bueno, Juan M.; Giakoumaki, Anastasia; Gualda, Emilio J.; Schaeffel, Frank; Artal, Pablo

2011-01-01

The structure and organization of the chicken retina has been investigated with an adaptive optics multiphoton imaging microscope in a backward configuration. Non-stained flat-mounted retinal tissues were imaged at different depths, from the retinal nerve fiber layer to the outer segment, by detecting the intrinsic nonlinear fluorescent signal. From the stacks of images corresponding to the different retinal layers, volume renderings of the entire retina were reconstructed. The density of photoreceptors and ganglion cells layer were directly estimated from the images as a function of the retinal eccentricity. The maximum anatomical resolving power at different retinal eccentricities was also calculated. This technique could be used for a better characterization of retinal alterations during myopia development, and may be useful for visualization of retinal pathologies and intoxication during pharmacological studies. PMID:21698025

A Reinterpretation of Cell Transplantation: GFP Transfer From Donor to Host Photoreceptors.

PubMed

Ortin-Martinez, Arturo; Tsai, En Leh Samuel; Nickerson, Philip E; Bergeret, Miriam; Lu, Yao; Smiley, Sheila; Comanita, Lacrimioara; Wallace, Valerie A

2017-04-01

The utilization of fluorescent reporter transgenes to discriminate donor versus host cells has been a mainstay of photoreceptor transplantation research, the assumption being that the presence of reporter+ cells in outer nuclear layer (ONL) of transplant recipients represents the integration of donor photoreceptors. We previously reported that GFP + cells in the ONL of cone-GFP transplanted retinas exhibited rod-like characteristics, raising the possibility that GFP signal in recipient tissue may not be a consequence of donor cell integration. To investigate the basis for this mismatch, we performed a series of transplantations using multiple transgenic donor and recipient models, and assessed cell identity using nuclear architecture, immunocytochemistry, and DNA prelabeling. Our results indicate that GFP + cells in the ONL fail to exhibit hallmark elements of donor cells, including nuclear hetero/euchromatin architecture. Furthermore, GFP signal does not appear to be a consequence of classic donor/host cell fusion or transfating post-transplant, but is most likely due to material exchange between donor and host photoreceptors. This transfer can be mediated by rods and cones, is bidirectional between donor and host cells, requires viable photoreceptors, occurs preferentially at sites of outer limiting membrane disruption and can be detected in second-order retinal neurons and Müller glia. Collectively, these data warrant re-evaluation of the use of lineage tracing fluorescent reporters in transplantation studies involving the retina and other CNS tissues. Furthermore, the reinterpretation of previous functional rescue data, based on material exchange, rather than cell integration, may offer a novel approach to vision rescue. Stem Cells 2017;35:932-939. © 2016 AlphaMed Press.

Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model.

PubMed

Shen, Weiyong; Fruttiger, Marcus; Zhu, Ling; Chung, Sook H; Barnett, Nigel L; Kirk, Joshua K; Lee, SoRa; Coorey, Nathan J; Killingsworth, Murray; Sherman, Larry S; Gillies, Mark C

2012-11-07

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.

Conditional Müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

PubMed Central

Shen, Weiyong; Fruttiger, Marcus; Zhu, Ling; Chung, Sook H.; Barnett, Nigel L.; Kirk, Joshua K.; Lee, SoRa; Coorey, Nathan J.; Killingsworth, Murray; Sherman, Larry S.; Gillies, Mark C.

2014-01-01

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium derived factor. Intravitreal injection of cilliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the central nervous system associated with glial dysfunction. PMID:23136411

Bucky Paper as a Support Membrane in Retinal Cell Transplantation

NASA Technical Reports Server (NTRS)

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

2006-01-01

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

Hydrogen postconditioning promotes survival of rat retinal ganglion cells against ischemia/reperfusion injury through the PI3K/Akt pathway.

PubMed

Wu, Jiangchun; Wang, Ruobing; Yang, Dianxu; Tang, Wenbin; Chen, Zeli; Sun, Qinglei; Liu, Lin; Zang, Rongyu

2018-01-22

Retinal ischemia/reperfusion injury (IRI) plays a crucial role in the pathophysiology of various ocular diseases. Our previous study have shown that postconditioning with inhaled hydrogen (H 2 ) (HPC) can protect retinal ganglion cells (RGCs) in a rat model of retinal IRI. Our further study aims to investigate potential mechanisms underlying HPC-induced protection. Retinal IRI was performed on the right eyes of rats and was followed by inhalation of 67% H 2 mixed with 33% oxygen immediately after ischemia for 1 h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining, retrograde labelling with cholera toxin beta (CTB) and TUNEL staining, respectively. Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). The phosphorylated Akt was analysed by RT-PCR and western blot. The results showed that administration of HPC significantly inhibited the apoptosis of RGCs and protected the visual function. Simultaneously, HPC treatment markedly increased the phosphorylations of Akt. Blockade of PI3K activity by inhibitors (LY294002) dramatically abolished its anti-apoptotic effect and lowered both visual function and Akt phosphorylation levels. Taken together, our results demonstrate that HPC appears to confer neuroprotection against retinal IRI via the PI3K/Akt pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

ApoER2 Function in the Establishment and Maintenance of Retinal Synaptic Connectivity

PubMed Central

Trotter, Justin H.; Klein, Martin; Jinwal, Umesh K.; Abisambra, Jose F.; Dickey, Chad A.; Tharkur, Jeremy; Masiulis, Irene; Ding, Jindong; Locke, Kirstin G.; Rickman, Catherine Bowes; Birch, David G.; Weeber, Edwin J.; Herz, Joachim

2011-01-01

The cellular and molecular mechanisms responsible for the development of inner retinal circuitry are poorly understood. Reelin and apolipoprotein E (apoE), ligands of apoE receptor 2 (ApoER2), are involved in retinal development and degeneration, respectively. Here we describe the function of ApoER2 in the developing and adult retina. ApoER2 expression was highest during postnatal inner retinal synaptic development and was considerably lower in the mature retina. Both during development and in the adult ApoER2 was expressed by A-II amacrine cells. ApoER2 knockout (KO) mice had rod bipolar morphogenic defects, altered A-II amacrine dendritic development, and impaired rod-driven retinal responses. The presence of an intact ApoER2 NPxY motif, necessary for binding disabled-1 (Dab1) and transducing the Reelin signal, was also necessary for development of the rod bipolar pathway while the alternatively-spliced exon19 was not. Mice deficient in another Reelin receptor, very low-density lipoprotein receptor (VLDLR), had normal rod bipolar morphology but altered A-II amacrine dendritic development. VLDLR KO mice also had reductions in oscillatory potentials and delayed synaptic response intervals. Interestingly, age-related reductions in rod and cone function were observed in both ApoER2 and VLDLR KOs. These results support a pivotal role for ApoER2 in the establishment and maintenance of normal retinal synaptic connectivity. PMID:21976526

Probing how initial retinal configuration controls photochemical dynamics in retinal proteins

NASA Astrophysics Data System (ADS)

Wand, A.; Rozin, R.; Eliash, T.; Friedman, N.; Jung, K. H.; Sheves, M.; Ruhman, S.

2013-03-01

The effects of the initial retinal configuration and the active isomerization coordinate on the photochemistry of retinal proteins (RPs) are assessed by comparing photochemical dynamics of two stable retinal ground state configurations (all-trans,15-anti vs. 13-cis,15-syn), within two RPs: Bacteriorhodopsin (BR) and Anabaena Sensory Rhodopsin (ASR). Hyperspectral pump-probe spectroscopy shows that photochemistry starting from 13-cis retinal in both proteins is 3-10 times faster than when started in the all-trans state, suggesting that the hastening is ubiquitous to microbial RPs, regardless of their different biological functions and origin. This may also relate to the known disparity of photochemical rates between microbial RPs and visual pigments. Importance and possible underlying mechanisms are discussed as well.

Inherited Retinal Degenerative Disease Clinical Trial Network

DTIC Science & Technology

2012-10-01

strategies can be designed , tested and adopted as standard care. 2 While repeat evaluation and study of affected patients are vital to rigorously...following document is a summary of our experience and research in testing retinal structure and function in eyes with degenerative retinal diseases...Network PRINCIPAL INVESTIGATOR: Patricia Zilliox, Ph.D. CONTRACTING ORGANIZATION: National Neurovision Research Institute Owings

Involvement of Erythropoietin in Retinal Ischemic Preconditioning

PubMed Central

Dreixler, John C.; Hagevik, Sarah; Hemmert, Jonathan W.; Shaikh, Afzhal R.; Rosenbaum, Daniel M.; Roth, Steven

2009-01-01

Background The purpose of this study was to examine the role of erythropoietin in retinal ischemic preconditioning (IPC). Methods Rats were subjected to retinal ischemia after IPC. Electroretinography assessed functional recovery after ischemia; retinal sections were examined to determine loss of retinal ganglion cells, and Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling was used to assess apoptosis. Levels of downstream mediators were measured in retinal homogenates by Western blotting. To assess the involvement of erythropoietin in IPC, we measured levels of erythropoietin and its receptor (EPO-R) in retinal homogenates following IPC, using Western blotting. To examine erythropoietin’s role in IPC, we studied the impact of blocking erythropoietin via intravitreal injection of soluble EPO-R (sEPO-R) before IPC. Results Erythropoietin levels did not change following IPC, but EPO-R increased. Intravitreal injection of sEPO-R significantly attenuated both the functional and histological neuroprotection produced by IPC in comparison to control injection of denatured sEPO-R. Apoptotic damage after ischemia was enhanced in the sEPO-R treated retinas as indicated by fluorescent Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling. Phosphorylated extracellular-signal-regulated kinase (ERK) and heat shock protein 27 (Hsp27), but not protein kinase B (Akt), upregulated in denatured sEPO-R treated retinae, were attenuated in eyes injected with sEPO-R. Conclusions These results indicate that EPO-R upregulation is a critical component of the functional, histological, and anti-apoptotic protective effect of ischemic preconditioning on ischemia in the retina and that several downstream effectors may be involved in the neuroprotective actions of erythropoietin. PMID:19322943

Clinical application of optical coherence tomography in combination with functional diagnostics: advantages and limitations for diagnosis and assessment of therapy outcome in central serous chorioretinopathy.

PubMed

Schliesser, Joshua A; Gallimore, Gary; Kunjukunju, Nancy; Sabates, Nelson R; Koulen, Peter; Sabates, Felix N

2014-01-01

While identifying functional and structural parameters of the retina in central serous chorioretinopathy (CSCR) patients, this study investigated how an optical coherence tomography (OCT)-based diagnosis can be significantly supplemented with functional diagnostic tools and to what degree the determination of disease severity and therapy outcome can benefit from diagnostics complementary to OCT. CSCR patients were evaluated prospectively with microperimetry (MP) and spectral domain optical coherence tomography (SD-OCT) to determine retinal sensitivity function and retinal thickness as outcome measures along with measures of visual acuity (VA). Patients received clinical care that involved focal laser photocoagulation or pharmacotherapy targeting inflammation and neovascularization. Correlation of clinical parameters with a focus on functional parameters, VA, and mean retinal sensitivity, as well as on the structural parameter mean retinal thickness, showed that functional measures were similar in diagnostic power. A moderate correlation was found between OCT data and the standard functional assessment of VA; however, a strong correlation between OCT and MP data showed that diagnostic measures cannot always be used interchangeably, but that complementary use is of higher clinical value. The study indicates that integrating SD-OCT with MP provides a more complete diagnosis with high clinical relevance for complex, difficult to quantify diseases such as CSCR.

Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish

PubMed Central

Lenkowski, Jenny R.; Raymond, Pamela A.

2014-01-01

Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine. PMID:24412518

Wide-Field Fundus Autofluorescence for Retinitis Pigmentosa and Cone/Cone-Rod Dystrophy.

PubMed

Oishi, Akio; Oishi, Maho; Ogino, Ken; Morooka, Satoshi; Yoshimura, Nagahisa

2016-01-01

Retinitis pigmentosa and cone/cone-rod dystrophy are inherited retinal diseases characterized by the progressive loss of rod and/or cone photoreceptors. To evaluate the status of rod/cone photoreceptors and visual function, visual acuity and visual field tests, electroretinogram, and optical coherence tomography are typically used. In addition to these examinations, fundus autofluorescence (FAF) has recently garnered attention. FAF visualizes the intrinsic fluorescent material in the retina, which is mainly lipofuscin contained within the retinal pigment epithelium. While conventional devices offer limited viewing angles in FAF, the recently developed Optos machine enables recording of wide-field FAF. With wide-field analysis, an association between abnormal FAF areas and visual function was demonstrated in retinitis pigmentosa and cone-rod dystrophy. In addition, the presence of "patchy" hypoautofluorescent areas was found to be correlated with symptom duration. Although physicians should be cautious when interpreting wide-field FAF results because the peripheral parts of the image are magnified significantly, this examination method provides previously unavailable information.

Laminin γ3 plays an important role in retinal lamination, photoreceptor organisation and ganglion cell differentiation.

PubMed

Dorgau, Birthe; Felemban, Majed; Sharpe, Alexander; Bauer, Roman; Hallam, Dean; Steel, David H; Lindsay, Susan; Mellough, Carla; Lako, Majlinda

2018-05-23

Laminins are heterotrimeric glycoproteins of the extracellular matrix. Eleven different laminin chains have been identified in vertebrates. They are ubiquitously expressed in the human body, with a distinct tissue distribution. Laminin expression in neural retina and their functional role during human retinogenesis is still unknown. This study investigated the laminin expression in human developing and adult retina, showing laminin α1, α5, β1, β2 and γ1 to be predominantly expressed in Bruch's membrane and the inner limiting membrane. Laminin-332 and laminin γ3 expression were mainly observed in the neural retina during retinal histogenesis. These expression patterns were largely conserved in pluripotent stem cell-derived retinal organoids. Blocking of laminin γ3 function in retinal organoids resulted in the disruption of laminar organisation and synapse formation, the loss of photoreceptor organisation and retinal ganglion cells. Our data demonstrate a unique temporal and spatial expression for laminins and reveal a novel role for laminin γ3 during human retinogenesis.

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

PubMed Central

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

A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration.

PubMed

Shin, Younghwa; Moiseyev, Gennadiy; Petrukhin, Konstantin; Cioffi, Christopher L; Muthuraman, Parthasarathy; Takahashi, Yusuke; Ma, Jian-Xing

2018-07-01

The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (i.e. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC 50 of 6 μM. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Complement factor h is critical in the maintenance of retinal perfusion.

PubMed

Lundh von Leithner, Peter; Kam, Jaimie Hoh; Bainbridge, James; Catchpole, Ian; Gough, Gerald; Coffey, Peter; Jeffery, Glen

2009-07-01

Vascular pathologies are known to be associated with age-related macular degeneration. Recently, age-related macular degeneration was associated with a single-nucleotide substitution of the complement factor H (CFH) gene, part of the alternative pathway of the complement system, a critical element in the innate immune response. Such polymorphisms are found in more than 50% of cases of age-related macular degeneration. Here we show that the absence of CFH causes an autoimmune response that targets the vascular endothelium of both the inner and outer retinal vascular networks. In CFH-knockout (cfh(-/-)) mice, C3 and C3b, key components of the complement system, are progressively deposited on retinal vessels, which subsequently become restricted and wither, resulting in a reduction of retinal blood supply. This result leads to increased oxygen stress. While such effects are not systemic, these structural changes are mirrored in functional changes with a substantial decline in retinal blood flow dynamics. When the system is challenged functionally by laser-induced choroidal neovascularization, fluorescein leakage was significantly smaller in cfh(-/-) mice compared with controls, likely due to reduced retinal perfusion. These data reveal that in both the presence and absence of exogenous challenge to the innate immune system, CFH is required to maintain normal levels of retinal perfusion. It is likely that C3 and C3b accumulation in the aged CFH-deficient retina is associated with complement-mediated retinal endothelium destruction.

Regenerating reptile retinas: a comparative approach to restoring retinal ganglion cell function.

PubMed

Williams, D L

2017-02-01

Transection or damage to the mammalian optic nerve generally results in loss of retinal ganglion cells by apoptosis. This cell death is seen less in fish or amphibians where retinal ganglion cell survival and axon regeneration leads to recovery of sight. Reptiles lie somewhere in the middle of this spectrum of nerve regeneration, and different species have been reported to have a significant variation in their retinal ganglion cell regenerative capacity. The ornate dragon lizard Ctenophoris ornatus exhibits a profound capacity for regeneration, whereas the Tenerife wall lizard Gallotia galloti has a more variable response to optic nerve damage. Some individuals regain visual activity such as the pupillomotor responses, whereas in others axons fail to regenerate sufficiently. Even in Ctenophoris, although the retinal ganglion cell axons regenerate adequately enough to synapse in the tectum, they do not make long-term topographic connections allowing recovery of complex visually motivated behaviour. The question then centres on where these intraspecies differences originate. Is it variation in the innate ability of retinal ganglion cells from different species to regenerate with functional validity? Or is it variances between different species in the substrate within which the nerves regenerate, the extracellular environment of the damaged nerve or the supporting cells surrounding the regenerating axons? Investigations of retinal ganglion cell regeneration between different species of lower vertebrates in vivo may shed light on these questions. Or perhaps more interesting are in vitro studies comparing axon regeneration of retinal ganglion cells from various species placed on differing substrates.

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

PubMed Central

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

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

NASA Astrophysics Data System (ADS)

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-downs identified KTN1, RAB28, UCHL1, and PSMD14 suggesting that C8ORF37 may have a role in protein homeostasis. Chapter 4 concludes and discusses the impact of generating and characterizing C8orf37 animal models for future studies in understanding photoreceptor function and in the development of therapeutics against retinal degeneration.

Assessment of Rod, Cone, and Intrinsically Photosensitive Retinal Ganglion Cell Contributions to the Canine Chromatic Pupillary Response.

PubMed

Yeh, Connie Y; Koehl, Kristin L; Harman, Christine D; Iwabe, Simone; Guzman, José M; Petersen-Jones, Simon M; Kardon, Randy H; Komáromy, András M

2017-01-01

The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs. Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m2) and bright (400 cd/m2) blue light (for scotopic conditions) or bright red (400 cd/m2) light with 25-cd/m2 blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry. Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas. Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

PubMed Central

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

Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases.

PubMed

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.

Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases

PubMed Central

Ding, Suet Lee Shirley; Kumar, Suresh; Mok, Pooi Ling

2017-01-01

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. PMID:28788088

Application of Photosynthesis to Artificial Sight

DTIC Science & Technology

2001-10-25

to people who suffer from age-related macular degeneration (AMD) or retinitis pigmentosa (RP), diseases that are the leading causes of blindness...related macular degeneration and retinitis pigmentosa . While this work is still in its infancy, it is clear that isolated Photosystem I reaction...insertion of purified Photosystem I (PSI) reaction centers or other photoactive agents into retinal cells where they will restore photoreceptor function

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications.

PubMed

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

T cell responses in experimental viral retinitis: mechanisms, peculiarities and implications for gene therapy with viral vectors.

PubMed

Zinkernagel, Martin S; McMenamin, Paul G; Forrester, John V; Degli-Esposti, Mariapia A

2011-07-01

T lymphocytes play a decisive role in the course and clinical outcome of viral retinal infection. This review focuses on aspects of the adaptive cellular immune response against viral pathogens in the retina. Two distinct models to study adaptive cell mediated immune responses in viral retinitis are presented: (i) experimental retinitis induced by murine cytomegalovirus (MCMV), where the immune system prevents necrotizing damage to the retina and (ii) retinitis induced by the non-cytopathic lymphocytic choriomeningitis virus (LCMV), where the retinal microanatomy is compromised not by the virus, but by the immune response itself. From these studies it is clear that, in the context of viral infections, the cytotoxic T cell response against a pathogen in the retina does not differ from that seen in other organs, and that once such a response has been initiated, clearing of virus from retinal tissue has priority over preservation of retinal architecture and function. Furthermore, implications drawn from these models for gene therapy in retinal diseases are discussed. Copyright © 2011. Published by Elsevier Ltd.

Improved retinal and visual function following panmacular subthreshold diode micropulse laser for retinitis pigmentosa.

PubMed

Luttrull, Jeffrey K

2018-06-01

To examine the effect of subthreshold diode micropulse laser (SDM) on pattern electroretinography (PERG) and visual function in retinitis pigmentosa (RP). The records of all patients (pts) undergoing SDM in a vitreoretinal subspecialty practice were reviewed. Inclusion criteria included the presence of RP evaluated before and after SDM by PERG. As a secondary outcome measure, the results of automated omnifield resolution perimetry (ORP) were also reviewed. All eyes undergoing SDM for RP were eligible study, including 26 eyes of 15 pts; seven male and eight female, aged 16-69 (avg. 47) years. Retinal function by PERG improved by all indices, with significant improvements in the 24° field signal latency measures; the MagD(µV)/ Mag(µV) ratio (P < 0.0001) and the MagD(µV) amplitude (P = 0.0003). ORP significantly improved by all indices (p = 0.02-0.002). Average best-corrected chart visual acuities improved from 0.6 to 0.4 logMAR units (p = 0.02). There were no adverse treatment effects. SDM significantly improved chart visual acuity, mesopic logMAR visual acuity perimetry, and retinal function by PERG in RP without adverse treatment effects. Treatment responses indicate a significant capacity for rescue of dysfunctional retina. These results suggest that early and periodic treatment with SDM might slow disease progression and reduce long-term vision loss.

EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression

PubMed Central

McGuigan, David B.; Heon, Elise; Cideciyan, Artur V.; Ratnapriya, Rinki; Lu, Monica; Sumaroka, Alexander; Roman, Alejandro J.; Batmanabane, Vaishnavi; Garafalo, Alexandra V.; Stone, Edwin M.; Jacobson, Samuel G.

2017-01-01

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. PMID:28704921

Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye.

PubMed

Kim, Jin Young; Park, Raehee; Lee, Jin Hwan J; Shin, Jinyeon; Nickas, Jenna; Kim, Seonhee; Cho, Seo-Hee

2016-11-15

Yap functions as a transcriptional regulator by acting together with sequence-specific DNA binding factors and transcription cofactors to mediate cell proliferation in developing epithelial tissues and tumors. An upstream kinase cascade controls nuclear localization and function in response to partially identified exogenous signals, including cell-to-cell contact. Nevertheless, its role in CNS development is poorly understood. In order to investigate Yap function in developing CNS, we characterized the cellular outcomes after selective Yap gene ablation in developing ocular tissues. When Yap was lost, presumptive retinal pigment epithelium acquired anatomical and molecular characteristics resembling those of the retinal epithelium rather than of RPE, including loss of pigmentation, pseudostratified epithelial morphology and ectopic induction of markers for retinal progenitor cells, like Chx10, and neurons, like β-Tubulin III. In addition, developing retina showed signs of progressive degeneration, including laminar folding, thinning and cell loss, which resulted from multiple defects in cell proliferation and survival, and in junction integrity. Furthermore, Yap-deficient retinal progenitors displayed decreased S-phase cells and altered cell cycle progression. Altogether, our studies not only illustrate the canonical function of Yap in promoting the proliferation of progenitors, but also shed new light on its evolutionarily conserved, instructive role in regional specification, maintenance of junctional integrity and precise regulation of cell proliferation during neuroepithelial development. Copyright © 2016 Elsevier Inc. All rights reserved.

Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger (Edaravone)

PubMed Central

Hara, Hideaki

2017-01-01

Oxidative stress plays a pivotal role in developing and accelerating retinal diseases including age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO). An excess amount of reactive oxygen species (ROS) can lead to functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells (RGCs). Here we demonstrate that edaravone, a free radical scavenger, decreased apoptotic cell death, oxidative damage to DNA and lipids, and angiogenesis through inhibiting JNK and p38 MAPK pathways in AMD, glaucoma, DR, and RVO animal models. These data suggest that the therapeutic strategy for targeting oxidative stress may be important for the treatment of these ocular diseases, and edaravone may be useful for treating retinal diseases associated with oxidative stress. PMID:28194256

Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger (Edaravone).

PubMed

Masuda, Tomomi; Shimazawa, Masamitsu; Hara, Hideaki

2017-01-01

Oxidative stress plays a pivotal role in developing and accelerating retinal diseases including age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO). An excess amount of reactive oxygen species (ROS) can lead to functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells (RGCs). Here we demonstrate that edaravone, a free radical scavenger, decreased apoptotic cell death, oxidative damage to DNA and lipids, and angiogenesis through inhibiting JNK and p38 MAPK pathways in AMD, glaucoma, DR, and RVO animal models. These data suggest that the therapeutic strategy for targeting oxidative stress may be important for the treatment of these ocular diseases, and edaravone may be useful for treating retinal diseases associated with oxidative stress.

Treatment of dry age-related macular degeneration with dobesilate

PubMed Central

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. PMID:22729337

Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype.

PubMed

Schwartz, Sharon B; Aleman, Tomas S; Cideciyan, Artur V; Windsor, Elizabeth A M; Sumaroka, Alexander; Roman, Alejandro J; Rane, Tej; Smilko, Elaine E; Bennett, Jean; Stone, Edwin M; Kimberling, William J; Liu, Xue-Zhong; Jacobson, Samuel G

2005-02-01

To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.

Delayed Administration of Bone Marrow Mesenchymal Stem Cell Conditioned Medium Significantly Improves Outcome After Retinal Ischemia in Rats

PubMed Central

Dreixler, John C.; Poston, Jacqueline N.; Balyasnikova, Irina; Shaikh, Afzhal R.; Tupper, Kelsey Y.; Conway, Sineadh; Boddapati, Venkat; Marcet, Marcus M.; Lesniak, Maciej S.; Roth, Steven

2014-01-01

Purpose. Delayed treatment after ischemia is often unsatisfactory. We hypothesized that injection of bone marrow stem cell (BMSC) conditioned medium after ischemia could rescue ischemic retina, and in this study we characterized the functional and histological outcomes and mechanisms of this neuroprotection. Methods. Retinal ischemia was produced in adult Wistar rats by increasing intraocular pressure for 55 minutes. Conditioned medium (CM) from rat BMSCs or unconditioned medium (uCM) was injected into the vitreous 24 hours after the end of ischemia. Recovery was assessed 7 days after ischemia using electroretinography, at which time we euthanized the animals and then prepared 4-μm-thick paraffin-embedded retinal sections. TUNEL and Western blot were used to identify apoptotic cells and apoptosis-related gene expression 24 hours after injections; that is, 48 hours after ischemia. Protein content in CM versus uCM was studied using tandem mass spectrometry, and bioinformatics methods were used to model protein interactions. Results. Intravitreal injection of CM 24 hours after ischemia significantly improved retinal function and attenuated cell loss in the retinal ganglion cell layer. CM attenuated postischemic apoptosis and apoptosis-related gene expression. By spectral counting, 19 proteins that met stringent identification criteria were increased in the CM compared to uCM; the majority were extracellular matrix proteins that mapped into an interactional network together with other proteins involved in cell growth and adhesion. Conclusions. By restoring retinal function, attenuating apoptosis, and preventing retinal cell loss after ischemia, CM is a robust means of delayed postischemic intervention. We identified some potential candidate proteins for this effect. PMID:24699381

Functional and Morphological Correlations before and after Video-Documented 23-Gauge Pars Plana Vitrectomy with Membrane and ILM Peeling in Patients with Macular Pucker.

PubMed

Mayer, Wolfgang J; Fazekas, Clara; Schumann, Ricarda; Wolf, Armin; Compera, Denise; Kampik, Anselm; Haritoglou, Christos

2015-01-01

Purpose. To assess functional and morphological alterations following video-documented surgery for epiretinal membranes. Methods. Forty-two patients underwent video-documented 23-gauge vitrectomy with peeling of epiretinal (ERM) and inner limiting membrane (ILM). Patient assessment was performed before and 3 and 6 months including best corrected visual acuity (BCVA), slit lamp biomicroscopy, SD-OCT, and central 2° and 18° microperimetry. In addition, all video-documented areas of peeling on the retinal surface were evaluated postoperatively using an additional focal 2° microperimetry. Retinal sensitivity and BCVA were correlated with morphological changes (EZ and ELM) in the foveal region and in regions of membrane peeling. Results. Overall, BCVA increased from 0.6 (±0.2) to 0.2 (±0.2) logMAR after 6 months with an increase in retinal sensitivity (17.9 ± 2.7 dB to 26.8 ± 3.1 dB, p < 0.01). We observed a significant correlation between the integrity of the EZ but not of the ELM and the retinal sensitivity, overall and in peeling areas (p < 0.05). However, no significant correlation between alterations in the area of peeling and overall retinal sensitivity regarding visual acuity gain could be observed after 6 months (p > 0.05). In contrast, overall postoperative retinal sensitivity was significantly decreased in patients with a visual acuity gain lower than 2 lines (p < 0.05) correlating with EZ defects seen in OCT. Conclusions. Mechanical trauma of epiretinal membrane and ILM peeling due to the use of intraocular forceps may affect the outer retinal structure. Nevertheless, these changes seem to have no significant impact on postoperative functional outcome.

A novel imidazopyridine derivative, X22, prevents the retinal ischemia-reperfusion injury via inhibition of MAPKs.

PubMed

Bian, Yang; Ren, Luqing; Wang, Lei; Xu, Shanmei; Tao, Jianjian; Zhang, Xiuhua; Huang, Yi; Qian, Yuanyuan; Zhang, Xin; Song, Zongming; Wu, Wencan; Wang, Yi; Liang, Guang

2015-06-01

Inflammation is a pathological hallmark of ischemia reperfusion (I/R) injury. The present study was conducted to explore the ability of a new anti-inflammatory compound, X22, to attenuate retinal I/R injury via cytokine-inhibitory mechanism. For the in vitro experiment, ARPE-19 cells were pretreated with X22 (5 or 10 μM) or saline for 2 h, followed by stimulation with tert-butyl hydroperoxide (TBHP, 1000 μM) for an indicated amount of time. The expression of inflammatory mediators, cell viability, and cell apoptosis were evaluated. For the in vivo experiment, the rats were randomized to receive treatment with saline or X22 (0.1 μM/kg, 3 μL) before the induction of I/R injury. Histological evaluation, apoptosis of retinal cells, macrophage infiltration, and retina functional changes were further determined. Our data showed that pretreatment with X22 significantly inhibited TBHP-induced inflammatory cytokine expression in ARPE-19 cells. The anti-inflammatory activity of X22 may be associated with its inhibition on MAPKs, rather than NF-κB. Subsequently, our data proved that TBHP induced apoptosis in ARPE-19 cells, while pretreatment of X22 significantly suppressed TBHP-caused ARPE-19 apoptosis. Finally, the in vivo data revealed that X22 administration maintained better inner retinal layer structures, reduced apoptosis of retinal ganglion cell, and improved retinal function in retinal I/R rat models, which were accompanied with a remarkable decrease in retinal macrophage infiltration. These results suggest that the novel compound X22 is a potential agent for the treatment of retinal I/R-related diseases via the MAPKs-targeting anti-inflammatory mechanism and deserves the further development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Concentric retinitis pigmentosa: clinicopathologic correlations.

PubMed

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 or modify photoreceptor degeneration in concentric retinitis pigmentosa.

Accidental human laser retinal injuries from military laser systems

NASA Astrophysics Data System (ADS)

Stuck, Bruce E.; Zwick, Harry; Molchany, Jerome W.; Lund, David J.; Gagliano, Donald A.

1996-04-01

The time course of the ophthalmoscopic and functional consequences of eight human laser accident cases from military laser systems is described. All patients reported subjective vision loss with ophthalmoscopic evidence of retinal alteration ranging from vitreous hemorrhage to retinal burn. Five of the cases involved single or multiple exposures to Q-switched neodymium radiation at close range whereas the other three incidents occur over large ranges. Most exposures were within 5 degrees of the foveola, yet none directly in the foveola. High contrast visual activity improved with time except in the cases with progressive retinal fibrosis between lesion sites or retinal hole formation encroaching the fovea. In one patient the visual acuity recovered from 20/60 at one week to 20/25 in four months with minimal central visual field loss. Most cases showed suppression of high and low spatial frequency contrast sensitivity. Visual field measurements were enlarged relative to ophthalmoscopic lesion size observations. Deep retinal scar formation and retinal traction were evident in two of the three cases with vitreous hemorrhage. In one patient, nerve fiber layer damage to the papillo-macular bundle was clearly evident. Visual performance measured with a pursuit tracking task revealed significant performance loss relative to normal tracking observers even in cases where acuity returned to near normal levels. These functional and performance deficits may reflect secondary effects of parafoveal laser injury.

Design of a high-resolution optoelectronic retinal prosthesis.

PubMed

Palanker, Daniel; Vankov, Alexander; Huie, Phil; Baccus, Stephen

2005-03-01

It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. However, current retinal implants provide very low resolution (just a few electrodes), whereas at least several thousand pixels would be required for functional restoration of sight. This paper presents the design of an optoelectronic retinal prosthetic system with a stimulating pixel density of up to 2500 pix mm(-2) (corresponding geometrically to a maximum visual acuity of 20/80). Requirements on proximity of neural cells to the stimulation electrodes are described as a function of the desired resolution. Two basic geometries of sub-retinal implants providing required proximity are presented: perforated membranes and protruding electrode arrays. To provide for natural eye scanning of the scene, rather than scanning with a head-mounted camera, the system operates similar to 'virtual reality' devices. An image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. The goggles are transparent to visible light, thus allowing for the simultaneous use of remaining natural vision along with prosthetic stimulation. Optical delivery of visual information to the implant allows for real-time image processing adjustable to retinal architecture, as well as flexible control of image processing algorithms and stimulation parameters.

Design of a high-resolution optoelectronic retinal prosthesis

NASA Astrophysics Data System (ADS)

Palanker, Daniel; Vankov, Alexander; Huie, Phil; Baccus, Stephen

2005-03-01

It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. However, current retinal implants provide very low resolution (just a few electrodes), whereas at least several thousand pixels would be required for functional restoration of sight. This paper presents the design of an optoelectronic retinal prosthetic system with a stimulating pixel density of up to 2500 pix mm-2 (corresponding geometrically to a maximum visual acuity of 20/80). Requirements on proximity of neural cells to the stimulation electrodes are described as a function of the desired resolution. Two basic geometries of sub-retinal implants providing required proximity are presented: perforated membranes and protruding electrode arrays. To provide for natural eye scanning of the scene, rather than scanning with a head-mounted camera, the system operates similar to 'virtual reality' devices. An image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. The goggles are transparent to visible light, thus allowing for the simultaneous use of remaining natural vision along with prosthetic stimulation. Optical delivery of visual information to the implant allows for real-time image processing adjustable to retinal architecture, as well as flexible control of image processing algorithms and stimulation parameters.

Retinal vessel enhancement based on the Gaussian function and image fusion

NASA Astrophysics Data System (ADS)

Moraru, Luminita; Obreja, Cristian Dragoş

2017-01-01

The Gaussian function is essential in the construction of the Frangi and COSFIRE (combination of shifted filter responses) filters. The connection of the broken vessels and an accurate extraction of the vascular structure is the main goal of this study. Thus, the outcome of the Frangi and COSFIRE edge detection algorithms are fused using the Dempster-Shafer algorithm with the aim to improve detection and to enhance the retinal vascular structure. For objective results, the average diameters of the retinal vessels provided by Frangi, COSFIRE and Dempster-Shafer fusion algorithms are measured. These experimental values are compared to the ground truth values provided by manually segmented retinal images. We prove the superiority of the fusion algorithm in terms of image quality by using the figure of merit objective metric that correlates the effects of all post-processing techniques.

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy.

PubMed

Tschernutter, M; Schlichtenbrede, F C; Howe, S; Balaggan, K S; Munro, P M; Bainbridge, J W B; Thrasher, A J; Smith, A J; Ali, R R

2005-04-01

The Royal College of Surgeons (RCS) rat is a well-characterized model of autosomal recessive retinitis pigmentosa (RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding , a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus (SFFV) promoter. The vector was subretinally injected into the right eye of 10-day-old RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders.

Therapeutic Potential of Co-enzyme Q10 in Retinal Diseases.

PubMed

Zhang, Xun; Tohari, Ali Mohammad; Marcheggiani, Fabio; Zhou, Xinzhi; Reilly, James; Tiano, Luca; Shu, Xinhua

2017-01-01

Coenzyme Q10 (CoQ10) plays a critical role in mitochondrial oxidative phosphorylation by serving as an electron carrier in the respiratory electron transport chain. CoQ10 also functions as a lipid-soluble antioxidant by protecting lipids, proteins and DNA damaged by oxidative stress. CoQ10 deficiency has been associated with a number of human diseases in which CoQ10 supplementation therapy has been effective in slowing or reversing pathological changes. Oxidative stress is a major contributory factor in the process of retinal degeneration. The related literature was reviewed through searching PubMed using keywords: CoQ10, CoQ10 and oxidative stress, CoQ10 and retinal degeneration. The functions of CoQ10 were summarized and its use in the treatment of age-related macular degeneration and glaucoma highlighted. The therapeutic potential of CoQ10 for other retinal diseases was also discussed. CoQ10 has been applied in different types of neurodegeneration. CoQ10 is detectable in retina and declines with ageing. Early studies showed treatment of CoQ10 improved visual function in patients with age-related macular degeneration. In glaucomatous models, CoQ10 exposure protected ganglion cell death from environmental stress; in glaucoma patients, CoQ10 treatment demonstrated beneficial effects on function of inner retina and enhancement of visual cortical response. Since oxidative stress also plays a critical role in the pathogenesis of diabetic retinopathy and retinitis pigmentosa, CoQ10 is a therapeutic target for both conditions. A wide range of evidence supports a role of CoQ10 in retinal diseases through inhibiting production of reactive oxygen species and protecting neuroretinal cells from oxidative damage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Retinal photography: A window into the cardiovascular-brain link in adolescent bipolar disorder.

PubMed

Naiberg, Melanie R; Hatch, Jessica K; Selkirk, Beth; Fiksenbaum, Lisa; Yang, Victor; Black, Sandra; Kertes, Peter J; Goldstein, Benjamin I

2017-08-15

The burden of cardiovascular disease in bipolar disorder (BD) exceeds what can be explained by traditional cardiovascular risk factors (CVRFs), lifestyle, and/or medications. Moreover, neurocognitive deficits are a core feature of BD, and are also related to CVRFs. We examined retinal vascular photography, a proxy for cerebral microvasculature, in relation to CVRFs, peripheral microvascular function, and neurocognition among BD adolescents. Subjects were 30 adolescents with BD and 32 healthy controls (HC). Retinal photography was conducted using a Topcon TRC 50 DX, Type IA camera, following pupil dilation. Retinal arteriolar and venular caliber was measured, from which the arterio-venular ratio (AVR) was computed. All measures were conducted masked to participant diagnosis. Peripheral arterial tonometry measured endothelial function. Neurocognition was assessed using the Cambridge Neuropsychological Tests Automated Battery. AVR was not significantly different between groups (Cohen's d=0.18, p=0.103). Higher diastolic blood pressure (BP) was associated with lower (worse) AVR in BD (r=-0.441, p=0.015) but not HC (r=-0.192, p=0.293). Similarly, in the BD group only, higher (better) endothelial function was associated with higher AVR (r=0.375, p=0.041). Hierarchical regression models confirmed that, independent of covariates, retinal vascular caliber was significantly associated with diastolic BP and endothelial function in BD. Within the BD group, mood scores were significantly negatively correlated with AVR (β=-0.451, p=0.044). This study's limitations include a small sample size, a cross-sectional study design, and a heterogeneous sample. Retinal photography may offer unique insights regarding the cardiovascular and neurocognitive burden of BD. Larger longitudinal studies are warranted. Copyright © 2017. Published by Elsevier B.V.

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

PubMed

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

2013-02-05

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

Advanced Technologies for Ultrahigh Resolution and Functional Optical Coherence Tomography

DTIC Science & Technology

2008-04-15

photoreceptors in retinitis pigmentosa and related diseases,” Am. J. Ophthalmol. 142, 945- 952, December 2006. 56. A.D. Aguirre, Y. Chen, J.G. Fujimoto, L...1000 patients. These studies provided new insights into retinal pathologies, especially alterations in photoreceptor structure. 1.1.2 Broadband...powers. For applications where light exposure levels are limited by safety considerations, such as retinal imaging, broadband SLD sources provide

Age-Dependent Changes of Monocarboxylate Transporter 8 Availability in the Postnatal Murine Retina

PubMed Central

Henning, Yoshiyuki; Szafranski, Karol

2016-01-01

The thyroid hormones (TH) triiodothyronine (T3) and its prohormone thyroxine (T4) are crucial for retinal development and function, and increasing evidence points at TH dysregulation as a cause for retinal degenerative diseases. Thus, precise regulation of retinal TH supply is required for proper retinal function, but knowledge on these mechanisms is still fragmentary. Several transmembrane transporters have been described as key regulators of TH availability in target tissues of which the monocarboxylate transporter 8 (MCT8), a high affinity transporter for T4 and T3, plays an essential role in the central nervous system. Moreover, in the embryonic chicken retina, MCT8 is highly expressed, but the postnatal availability of MCT8 in the mammalian retina was not reported to date. In the present study, spatiotemporal retinal MCT8 availability was examined in mice of different age. For this purpose, we quantified expression levels of Mct8 via Real-Time Reverse-Transcriptase PCR in mouse eyecups (C57BL/6) of juvenile and adult age groups. Additionally, age-dependent MCT8 protein levels were quantified via Western blotting and localized via immunofluorescence confocal microscopy. While no difference in Mct8 expression levels could be detected between age groups, MCT8 protein levels in juvenile animals were about two times higher than in adult animals based on Western blot analyses. Immunohistochemical analyses showed that MCT8 immunoreactivity in the eyecup was restricted to the retina and the retinal pigment epithelium. In juvenile mice, MCT8 was broadly observed along the apical membrane of the retinal pigment epithelium, tightly surrounding photoreceptor outer segments. Distinct immunopositive staining was also detected in the inner nuclear layer and the ganglion cell layer. However, in adult specimens, immunoreactivity visibly declined in all layers, which was in line with Western blot analyses. Since MCT8 was abundantly present in juvenile and about twofold lower in adult retinae, our findings suggest a pivotal role of MCT8 especially during postnatal maturation. The present study provides novel insights into age-dependent retinal TH supply, which might help to understand different aspects regarding retinal development, function, and disorders. PMID:27616981

Peripheral Refraction, Peripheral Eye Length, and Retinal Shape in Myopia.

PubMed

Verkicharla, Pavan K; Suheimat, Marwan; Schmid, Katrina L; Atchison, David A

2016-09-01

To investigate how peripheral refraction and peripheral eye length are related to retinal shape. Relative peripheral refraction (RPR) and relative peripheral eye length (RPEL) were determined in 36 young adults (M +0.75D to -5.25D) along horizontal and vertical visual field meridians out to ±35° and ±30°, respectively. Retinal shape was determined in terms of vertex radius of curvature Rv, asphericity Q, and equivalent radius of curvature REq using a partial coherence interferometry method involving peripheral eye lengths and model eye raytracing. Second-order polynomial fits were applied to RPR and RPEL as functions of visual field position. Linear regressions were determined for the fits' second order coefficients and for retinal shape estimates as functions of central spherical refraction. Linear regressions investigated relationships of RPR and RPEL with retinal shape estimates. Peripheral refraction, peripheral eye lengths, and retinal shapes were significantly affected by meridian and refraction. More positive (hyperopic) relative peripheral refraction, more negative RPELs, and steeper retinas were found along the horizontal than along the vertical meridian and in myopes than in emmetropes. RPR and RPEL, as represented by their second-order fit coefficients, correlated significantly with retinal shape represented by REq. Effects of meridian and refraction on RPR and RPEL patterns are consistent with effects on retinal shape. Patterns derived from one of these predict the others: more positive (hyperopic) RPR predicts more negative RPEL and steeper retinas, more negative RPEL predicts more positive relative peripheral refraction and steeper retinas, and steeper retinas derived from peripheral eye lengths predict more positive RPR.

A longitudinal study of visual function in carriers of X-linked recessive retinitis pigmentosa.

PubMed

Grover, S; Fishman, G A; Anderson, R J; Lindeman, M

2000-02-01

This study was carried out to evaluate the progression of visual function impairment in carriers of X-linked recessive retinitis pigmentosa. We also assessed the relationship between the retinal findings at presentation and the extent of deterioration. Observational, retrospective, case series. Twenty-seven carriers of X-linked recessive retinitis pigmentosa. Each carrier was clinically categorized into one of four grades (grades 0 through 3) depending on the presence or absence of a tapetal-like retinal reflex and the extent of peripheral pigmentary degeneration. A complete ophthalmologic examination was performed and data for visual acuity, visual field area, and electroretinographic measurements were collected on the most recent visit in both eyes. These were then compared with similar data obtained on their initial visits. A comparison of visual function was carried out between the initial visit and the most recent visit on each carrier. The visual acuity was measured with Snellen's acuity charts. The visual fields to targets V-4-e and II-4-e were planimeterized and used for the analysis. The electroretinographic (ERG) measures used were light-adapted single-flash b-wave amplitudes and 30-Hz red flicker for cone function, dark-adapted maximal b-wave amplitudes, and response to a low intensity blue-flash for rod function. None of the 11 carriers with a tapetal-like reflex only (grade 1) showed any significant change in visual acuity or fields as compared with 3 of 7 (43%) carriers with diffuse peripheral pigmentary findings (grade 3) who showed significant deterioration in visual acuity in at least one eye, and 6 of 7 (86%) who showed a significant decrease in visual field area with at least one target size in at least one eye. By comparison, only 1 of 10 carriers with a grade 1 fundus finding demonstrated a significant decrease in maximal dark-adapted ERG function as compared with 5 of 6 (83%) carriers with grade 3 in response to a single-flash stimulus and with 4 of 5 (80%) carriers in response to a single-flash blue stimulus. For the single-flash photopic response, none of the 10 carriers with grade 1 showed any significant deterioration, whereas 2 of 4 (50%) with grade 3 did show such deterioration. The ERG responses for carriers with grade 2 were in between the extent of decrease in ERG amplitudes of those in carriers with grades 1 and 3. In our cohort of X-linked retinitis pigmentosa carriers, those with only a tapetal-like retinal reflex at presentation had a better prognosis to retain visual function than those with peripheral retinal pigmentation. These data are useful in counseling such carriers as to their visual prognosis.

Increasing Spontaneous Retinal Activity before Eye Opening Accelerates the Development of Geniculate Receptive Fields

PubMed Central

Davis, Zachary W.; Chapman, Barbara

2015-01-01

Visually evoked activity is necessary for the normal development of the visual system. However, little is known about the capacity for patterned spontaneous activity to drive the maturation of receptive fields before visual experience. Retinal waves provide instructive retinotopic information for the anatomical organization of the visual thalamus. To determine whether retinal waves also drive the maturation of functional responses, we increased the frequency of retinal waves pharmacologically in the ferret (Mustela putorius furo) during a period of retinogeniculate development before eye opening. The development of geniculate receptive fields after receiving these increased neural activities was measured using single-unit electrophysiology. We found that increased retinal waves accelerate the developmental reduction of geniculate receptive field sizes. This reduction is due to a decrease in receptive field center size rather than an increase in inhibitory surround strength. This work reveals an instructive role for patterned spontaneous activity in guiding the functional development of neural circuits. SIGNIFICANCE STATEMENT Patterned spontaneous neural activity that occurs during development is known to be necessary for the proper formation of neural circuits. However, it is unknown whether the spontaneous activity alone is sufficient to drive the maturation of the functional properties of neurons. Our work demonstrates for the first time an acceleration in the maturation of neural function as a consequence of driving patterned spontaneous activity during development. This work has implications for our understanding of how neural circuits can be modified actively to improve function prematurely or to recover from injury with guided interventions of patterned neural activity. PMID:26511250

Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment Update

PubMed Central

Lee, Christine; Tu, Hong Anh; Wells, David; Holubowich, Corinne

2017-01-01

Background Retinitis pigmentosa is a group of inherited disorders characterized by the degeneration of the photoreceptors in the retina, resulting in progressive vision loss. The Argus II system is designed to restore partial functional vision in patients with profound vision loss from advanced retinitis pigmentosa. At present, it is the only treatment option approved by Health Canada for this patient population. In June 2016, Health Quality Ontario published a health technology assessment of the Argus II retinal prosthesis system for patients with advanced retinitis pigmentosa. Based on that assessment, the Ontario Health Technology Advisory Committee recommended against publicly funding the Argus II system for this population. It also recommended that Health Quality Ontario re-evaluate the evidence in 1 year. The objective of this report was to examine new evidence published since the 2016 health technology assessment. Methods We completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, and patient preferences related to the Argus II system. We performed a systematic literature search for studies published since the 2016 Argus II health technology assessment. We developed a Markov decision-analytic model to assess the cost-effectiveness of the Argus II system compared with standard care, and we calculated incremental cost-effectiveness ratios over a 20-year time horizon. We also conducted a five-year budget impact analysis. Finally, we interviewed people with retinitis pigmentosa about their lived experience with vision loss, and with the Argus II system. Results Four publications from one multicentre international study were included in the clinical review. Patients showed significant improvements in visual function and functional outcomes with the Argus II system, and these outcomes were sustained up to a 5-year follow-up (moderate quality of evidence). The safety profile was generally acceptable. In the base case economic analysis, the Argus II system was cost-effective compared with standard care if the willingness to pay was more than $97,429 per quality-adjusted life-year. We estimated that funding the Argus II system would cost the province $0.71 to $0.78 million per year over 5 years, assuming 4 implants per year. People with lived experience spoke about the challenges of retinitis pigmentosa, including the gradual but persistent progression of the disease; its impact on their quality of life and their families; and the accessibility challenges they faced. Those who used the Argus II system spoke about its positive impact on their quality of life. Conclusions Based on evidence of moderate quality, the Argus II retinal prosthesis system improved visual function, real-life functional outcomes, and quality of life in patients with advanced retinitis pigmentosa. The Argus II system is expensive, but the cost to publicly fund it would be low, because of the small number of eligible patients. The Argus II system can only enable perception of light/dark and shapes/objects, but these advancements represent important gains for people with retinitis pigmentosa in terms of mobility and quality of life. PMID:29201260

Characterization of macular structure and function in two Swedish families with genetically identified autosomal dominant retinitis pigmentosa

PubMed Central

Abdulridha-Aboud, Wissam; Kjellström, Ulrika; Andréasson, Sten

2016-01-01

Purpose To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions These two families demonstrate the extreme inter- and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype. PMID:27212874

Relating retinal nerve fiber thickness to behavioral sensitivity in patients with glaucoma: application of a linear model.

PubMed

Hood, Donald C

2007-05-01

Glaucoma causes damage to the retinal ganglion cells and their axons, and this damage can be detected with both structural and functional tests. The purpose of this study was to better understand the relationship between a structural measure of retinal nerve fiber layer (RNFL) and the most common functional test, behavioral sensitivity with static automated perimetry (SAP). First, a linear model, previously shown to describe the relationship between local visual evoked potentials and SAP sensitivity, was modified to predict the change in RNFL as measured by optical coherence tomography. Second, previous work by others was shown to be consistent with this model.

Smart, Injury-Triggered Therapy for Ocular Trauma

DTIC Science & Technology

2016-10-01

prognosis due to retinal cell death , scar formation, and lack of functional regeneration. Proliferative vitreoretinopathy (PVR), a form of intraocular...Proteases, Metalloproteinases, Cell death , Gene Therapy 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME...vision has a poor prognosis due to retinal cell death , scar formation, and lack of functional regeneration. Proliferative vitreoretinopathy (PVR), a

Perifoveal function in patients with North Carolina macular dystrophy: the importance of accounting for fixation locus.

PubMed

Seiple, William; Szlyk, Janet P; Paliga, Jennifer; Rabb, Maurice F

2006-04-01

To quantify the extent of visual function losses in patients with North Carolina Macular Dystrophy (NCMD) and to demonstrate the importance of accounting for eccentric fixation when making comparisons with normal data. Five patients with NCMD who were from a single family were examined. Multifocal electroretinograms (mfERGs) and psychophysical assessments of acuity and luminance visual field sensitivities were measured throughout the central retina. Comparisons of responses from equivalent retinal areas were accomplished by shifting normal templates to be centered at the locus of fixation for each patient. Losses of psychophysically measured visual function in patients with NCMD extend to areas adjacent to the locations of visible lesions. The multifocal ERG amplitude was reduced only within the area of visible lesion. Multifocal ERG implicit times were delayed throughout the entire central retinal area assessed. ERG timing is a sensitive assay of retinal function, and our results indicate that NCMD has a widespread effect at the level of the mid and outer retina. The findings also demonstrated that it is necessary to account for fixation locus and to ensure that equivalent retinal areas are compared when testing patients with macular disease who have eccentric fixation.

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

PubMed Central

Fernández-Sánchez, Laura; Rondón, Netxibeth; Esquiva, Gema; Germain, Francisco; de la Villa, Pedro; Cuenca, Nicolás

2015-01-01

Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA)-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss. PMID:26379056

Molecular aspects of eye evolution and development: from the origin of retinal cells to the future of regenerative medicine.

PubMed

Ohuchi, Hideyo

2013-01-01

A central issue of evolutionary developmental biology is how the eye is diverged morphologically and functionally. However, the unifying mechanisms or schemes that govern eye diversification remain unsolved. In this review, I first introduce the concept of evolutionary developmental biology of the eye with a focus on photoreception, the fundamental property of retinal cells. Second, I summarize the early development of vertebrate eyes and the role of a homeobox gene, Lhx1, in subdivision of the retina into 2 domains, the neural retina and retinal pigmented epithelium of the optic primordium. The 2 retinal domains are essential components of the eye as they are found in such prototypic eyes as the extant planarian eye. Finally, I propose the presence of novel retinal cell subtypes with photosensory functions based on our recent work on atypical photopigments (opsins) in vertebrates. Since human diseases are attributable to the aberration of various types of cells due to alterations in gene expression, understanding the precise mechanisms of cellular diversification and unraveling the molecular profiles of cellular subtypes are essential to future regenerative medicine.

Calculation and plotting of retinal nerve fiber paths based on Jansonius et al. 2009/2012 with an R program.

PubMed

Bach, M; Hoffmann, M B

2018-06-01

The data presented in this article are related to the research article entitled "Retinal conduction speed analysis reveals different origins of the P50 and N95 components of the (multifocal) pattern electroretinogram" (Bach et al., 2018) [1]. That analysis required the individual length data of the retinal nerve fibers (from ganglion cell body to optic nerve head, depending on the position of the ganglion cell body). Jansonius et al. (2009, 2012) [2,3] mathematically modeled the path morphology of the human retinal nerve fibers. We here present a working implementation with source code (for the free and open-source programming environment "R") of the Jansonius' formulas, including all errata. One file defines Jansonius et al.'s "phi" function. This function allows quantitative modelling of paths (and any measures derived from them) of the retinal nerve fibers. As a working demonstration, a second file contains a graph which plots samples of nerve fibers. The included R code runs in base R without the need of any additional packages.

New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models.

PubMed

Schur, Rebecca M; Gao, Songqi; Yu, Guanping; Chen, Yu; Maeda, Akiko; Palczewski, Krzysztof; Lu, Zheng-Rong

2018-01-24

No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration. Abca4 -/- Rdh8 -/- mice, an accelerated model of retinal degeneration, were exposed to intense light after prophylactic injections of one of these compounds. Imaging and functional assessments of the retina indicated that these compounds successfully protected photoreceptor cells from degeneration to maintain a full-visual-field response. Furthermore, these compounds demonstrated a strong safety profile in wild-type mice and did not compromise visual function or damage the retina, despite repeated administration. These results indicate that modulating inhibitory GABA signaling can offer prophylactic protection against light-induced retinal degeneration.-Schur, R. M., Gao, S., Yu, G., Chen, Y., Maeda, A., Palczewski, K., Lu, Z.-R. New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models.

In vivo thickness and birefringence determination of the human retinal nerve fiber layer using polarization-sensitive optical coherence tomography.

PubMed

Cense, B; Chen, T C; de Boer, J F

2006-01-01

Thinning of the retinal nerve fiber layer and changes in retinal nerve fiber layer birefringence may both precede clinically detectable glaucomatous vision loss. We present in vivo thickness and depth-resolved birefringence measurements of the human retinal nerve fiber layer (RNFL) by use of polarization-sensitive optical coherence tomography (PS-OCT). Using a fiber-based PS-OCT setup real-time images of the human retina in vivo were recorded, co-registered with retinal video images of the location of PS-OCT scans. PS-OCT scans around the optic nerve head (ONH) of two healthy young volunteers were made using 10 concentric circles of increasing radius. Both the mean retinal nerve fiber layer thickness and mean retinal nerve fiber birefringence for each of 48 sectors on a circle were determined. The retinal nerve fiber layer thickness and birefringence varied as a function of sector around the ONH. Measured double pass phase retardation per unit depth values around the ONH range between 0.10 and 0.35 degrees/microm. The retinal nerve fiber layer becomes thinner with increasing distance from the ONH. In contrast, the birefringence does not vary significantly with increasing distance from the ONH.

Mitochondrial Dysfunction in Retinal Diseases

PubMed Central

Barot, Megha; Gokulgandhi, Mitan R.; Mitra, Ashim K.

2015-01-01

The mitochondrion is a vital intracellular organelle for retinal cell function and survival. There is growing confirmation to support an association between mitochondrial dysfunction and a number of retinal degenerations. Investigations have also unveiled mitochondrial genomic instability as one of the contributing factors for age-related retinal pathophysiology. This review highlights the role of mitochondrial dysfunction originating from oxidative stress in the etiology of retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration (AMD). Moreover, mitochondrial DNA (mtDNA) damage associated with AMD due to susceptibility of mtDNA to oxidative damage and failure of mtDNA repair pathways is also highlighted in this review. The susceptibility of neural retina and retinal pigment epithelium (RPE) mitochondria to oxidative damage with ageing appears to be a major factor in retinal degeneration. It thus appears that the mitochondrion is a weak link in the antioxidant defenses of retinal cells. In addition, failure of mtDNA repair pathways can also specifically contribute towards pathogenesis of AMD. This review will further summarize the prospective role of mitochondria targeting therapeutic agents for the treatment of retinal disease. Mitochondria based drug targeting to diminish oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of various retinal degenerative diseases. PMID:21978133

Mitochondrial dysfunction in retinal diseases.

PubMed

Barot, Megha; Gokulgandhi, Mitan R; Mitra, Ashim K

2011-12-01

The mitochondrion is a vital intracellular organelle for retinal cell function and survival. There is growing confirmation to support an association between mitochondrial dysfunction and a number of retinal degenerations. Investigations have also unveiled mitochondrial genomic instability as one of the contributing factors for age-related retinal pathophysiology. This review highlights the role of mitochondrial dysfunction originating from oxidative stress in the etiology of retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration (AMD). Moreover, mitochondrial DNA (mtDNA) damage associated with AMD due to susceptibility of mtDNA to oxidative damage and failure of mtDNA repair pathways is also highlighted in this review. The susceptibility of neural retina and retinal pigment epithelium (RPE) mitochondria to oxidative damage with ageing appears to be a major factor in retinal degeneration. It thus appears that the mitochondrion is a weak link in the antioxidant defenses of retinal cells. In addition, failure of mtDNA repair pathways can also specifically contribute towards pathogenesis of AMD. This review will further summarize the prospective role of mitochondria targeting therapeutic agents for the treatment of retinal disease. Mitochondria based drug targeting to diminish oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of various retinal degenerative diseases.

Bim is Responsible for the Inherent Sensitivity of the Developing Retinal Vasculature to Hyperoxia

PubMed Central

Wang, Shoujian; Park, SunYoung; Fei, Ping; Sorenson, Christine M.

2010-01-01

Apoptosis plays an important role in development and remodeling of vasculature during organogenesis. Coordinated branching and remodeling of the retinal vascular tree is essential for normal retinal function. Bcl-2 family members, such as bim can not only influence apoptosis, but also cell adhesive and migratory properties essential during vascular development. Here we examined the impact of bim deficiency on postnatal retinal vascularization, as well as retinal neovascularization during oxygen-induced ischemic retinopathy (OIR) and laser-induced choroidal neovascularization. Loss of bim expression was associated with increased retinal vascular density in mature animals. This was mainly attributed to increased numbers of pericytes and endothelial cells. However, the initial spread of the superficial layer of retinal vasculature and, the appearance and density of the tip cells were similar in bim +/+ and bim -/- mice. In addition, hyaloid vessel regression was attenuated in the absence of bim. Furthermore, in the absence of bim retinal vessel obliteration and neovascularization did not occur during OIR. Instead, normal inner retinal vascularization proceeded independent of changes in oxygen levels. In contrast, choroidal neovascularization occurred equally well in bim +/+ and bim -/- mice. Together our data suggest bim expression may be responsible for the inherent sensitivity of the developing retinal vasculature to changes in oxygen levels, and promotes vessel obliteration in response to hyperoxia. PMID:21047504

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PubMed

Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

Contacting co-culture of human retinal microvascular endothelial cells alters barrier function of human embryonic stem cell derived retinal pigment epithelial cells.

PubMed

Skottman, H; Muranen, J; Lähdekorpi, H; Pajula, E; Mäkelä, K; Koivusalo, L; Koistinen, A; Uusitalo, H; Kaarniranta, K; Juuti-Uusitalo, K

2017-10-01

Here we evaluated the effects of human retinal microvascular endothelial cells (hREC) on mature human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells. The hESC-RPE cells (Regea08/017, Regea08/023 or Regea11/013) and hREC (ACBRI 181) were co-cultured on opposite sides of transparent membranes for up to six weeks. Thereafter barrier function, small molecule permeability, localization of RPE and endothelial cell marker proteins, cellular fine structure, and growth factor secretion of were evaluated. After co-culture, the RPE specific CRALBP and endothelial cell specific von Willebrand factor were appropriately localized. In addition, the general morphology, pigmentation, and fine structure of hESC-RPE cells were unaffected. Co-culture increased the barrier function of hESC-RPE cells, detected both with TEER measurements and cumulative permeability of FD4 - although the differences varied among the cell lines. Co-culturing significantly altered VEGF and PEDF secretion, but again the differences were cell line specific. The results of this study showed that co-culture with hREC affects hESC-RPE functionality. In addition, co-culture revealed drastic cell line specific differences, most notably in growth factor secretion. This model has the potential to be used as an in vitro outer blood-retinal barrier model for drug permeability testing. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Visual cycle modulation in neurovascular retinopathy.

PubMed

Akula, James D; Hansen, Ronald M; Tzekov, Radouil; Favazza, Tara L; Vyhovsky, Tanya C; Benador, Ilan Y; Mocko, Julie A; McGee, David; Kubota, Ryo; Fulton, Anne B

2010-08-01

Rats with oxygen-induced retinopathy (OIR) model the pediatric retinal disease retinopathy of prematurity (ROP). Recent findings in OIR rats imply a causal role for the rods in the ROP disease process, although only experimental manipulation of rod function can establish this role conclusively. Accordingly, a visual cycle modulator (VCM) - with no known direct effect on retinal vasculature - was administered to "50/10 model" OIR Sprague-Dawley rats to test the hypotheses that it would 1) alter rod function and 2) consequently alter vascular outcome. Four litters of pups (N=46) were studied. For two weeks, beginning on postnatal day (P) 7, the first and fourth litters were administered 6 mg kg(-1) N-retinylacetamide (the VCM) intraperitoneally; the second and third litters received vehicle (DMSO) alone. Following a longitudinal design, retinal function was assessed by electroretinography (ERG) and the status of the retinal vessels was monitored using computerized fundus photograph analysis. Rod photoreceptor and post-receptor response amplitudes were significantly higher in VCM-treated than in vehicle-treated rats; deactivation of phototransduction was also significantly more rapid. Notably, the arterioles of VCM-treated rats showed significantly greater recovery from OIR. Presuming that the VCM did not directly affect the retinal vessels, a causal role for the neural retina - particularly the rod photoreceptors - in OIR was confirmed. There was no evidence of negative alteration of photoreceptor function consequent to VCM treatment. This finding implicates the rods as a possible therapeutic target in neurovascular diseases such as ROP. Copyright 2010 Elsevier Ltd. All rights reserved.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PubMed Central

Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W.

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects. PMID:28575130

Vision Integrating Strategies in Ophthalmology and Neurochemistry (VISION)

DTIC Science & Technology

2011-02-01

in the above figure. We have already tested this virus in P23H Rhodopsin rat model of retinitis pigmentosa and found that it has a therapeutic...We have established three different mouse models of ocular injury with different injury-initiating mechanisms (i.e. optic nerve crush, retinal ...functionally and structurally rescue photoreceptor cells in rodent models of retinal degeneration. She brings expertise in gene therapy and in cellular

Unilateral retinitis pigmentosa sine pigmento.

PubMed Central

Pearlman, J T; Saxton, J; Hoffman, G

1976-01-01

A patient presented with unilateral findings of night blindness shown by impaired rod function and dark adaptation, constricted visual fields with good central acuity, a barely recordable electro-retinographic b-wave, and a unilaterally impaired electro-oculogram. There were none of the pigmentary changes usually associated with retinitis pigmentosa. The unaffected right eye was normal in all respects. Therefore the case is most probably one of unilateral retinitis pigmentosa sine pigmento. Images PMID:952804

Unilateral retinitis pigmentosa sine pigmento.

PubMed

Pearlman, J T; Saxton, J; Hoffman, G

1976-05-01

A patient presented with unilateral findings of night blindness shown by impaired rod function and dark adaptation, constricted visual fields with good central acuity, a barely recordable electro-retinographic b-wave, and a unilaterally impaired electro-oculogram. There were none of the pigmentary changes usually associated with retinitis pigmentosa. The unaffected right eye was normal in all respects. Therefore the case is most probably one of unilateral retinitis pigmentosa sine pigmento.

Intra-retinal segmentation of optical coherence tomography images using active contours with a dynamic programming initialization and an adaptive weighting strategy

NASA Astrophysics Data System (ADS)

Gholami, Peyman; Roy, Priyanka; Kuppuswamy Parthasarathy, Mohana; Ommani, Abbas; Zelek, John; Lakshminarayanan, Vasudevan

2018-02-01

Retinal layer shape and thickness are one of the main indicators in the diagnosis of ocular diseases. We present an active contour approach to localize intra-retinal boundaries of eight retinal layers from OCT images. The initial locations of the active contour curves are determined using a Viterbi dynamic programming method. The main energy function is a Chan-Vese active contour model without edges. A boundary term is added to the energy function using an adaptive weighting method to help curves converge to the retinal layer edges more precisely, after evolving of curves towards boundaries, in final iterations. A wavelet-based denoising method is used to remove speckle from OCT images while preserving important details and edges. The performance of the proposed method was tested on a set of healthy and diseased eye SD-OCT images. The experimental results, compared between the proposed method and the manual segmentation, which was determined by an optometrist, indicate that our method has obtained an average of 95.29%, 92.78%, 95.86%, 87.93%, 82.67%, and 90.25% respectively, for accuracy, sensitivity, specificity, precision, Jaccard Index, and Dice Similarity Coefficient over all segmented layers. These results justify the robustness of the proposed method in determining the location of different retinal layers.

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

PubMed Central

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing. PMID:26881099

Improving the blind restoration of retinal images by means of point-spread-function estimation assessment

NASA Astrophysics Data System (ADS)

Marrugo, Andrés. G.; Millán, María. S.; Å orel, Michal; Kotera, Jan; Å roubek, Filip

2015-01-01

Retinal images often suffer from blurring which hinders disease diagnosis and progression assessment. The restoration of the images is carried out by means of blind deconvolution, but the success of the restoration depends on the correct estimation of the point-spread-function (PSF) that blurred the image. The restoration can be space-invariant or space-variant. Because a retinal image has regions without texture or sharp edges, the blind PSF estimation may fail. In this paper we propose a strategy for the correct assessment of PSF estimation in retinal images for restoration by means of space-invariant or space-invariant blind deconvolution. Our method is based on a decomposition in Zernike coefficients of the estimated PSFs to identify valid PSFs. This significantly improves the quality of the image restoration revealed by the increased visibility of small details like small blood vessels and by the lack of restoration artifacts.

Nanowire arrays restore vision in blind mice.

PubMed

Tang, Jing; Qin, Nan; Chong, Yan; Diao, Yupu; Yiliguma; Wang, Zhexuan; Xue, Tian; Jiang, Min; Zhang, Jiayi; Zheng, Gengfeng

2018-03-06

The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices.

Micropulsed diode laser therapy: evolution and clinical applications.

PubMed

Sivaprasad, Sobha; Elagouz, Mohammed; McHugh, Dominic; Shona, Olajumoke; Dorin, Giorgio

2010-01-01

Many clinical trials have demonstrated the clinical efficacy of laser photocoagulation in the treatment of retinal vascular diseases, including diabetic retinopathy. There is, however, collateral iatrogenic retinal damage and functional loss after conventional laser treatment. Such side effects may occur even when the treatment is appropriately performed because of morphological damage caused by the visible endpoint, typically a whitening burn. The development of the diode laser with micropulsed emission has allowed subthreshold therapy without a visible burn endpoint. This greatly reduces the risk of structural and functional retinal damage, while retaining the therapeutic efficacy of conventional laser treatment. Studies using subthreshold micropulse laser protocols have reported successful outcomes for diabetic macular edema, central serous chorioretinopathy, macular edema secondary to retinal vein occlusion, and primary open angle glaucoma. The report includes the rationale and basic principles underlying micropulse diode laser therapy, together with a review of its current clinical applications. Copyright © 2010 Elsevier Inc. All rights reserved.

Large Field of View, Modular, Stabilized, Adaptive-Optics-Based Scanning Laser Ophthalmoscope

PubMed Central

Burns, Stephen A.; Tumbar, Remy; Elsner, Ann E.; Ferguson, Daniel; Hammer, Daniel X.

2007-01-01

We describe the design and performance of an adaptive optics retinal imager that is optimized for use during dynamic correction for eye movements. The system incorporates a retinal tracker and stabilizer, a wide field line scan Scanning Laser Ophthalmocsope (SLO), and a high resolution MEMS based adaptive optics SLO. The detection system incorporates selection and positioning of confocal apertures, allowing measurement of images arising from different portions of the double pass retinal point spread function (psf). System performance was excellent. The adaptive optics increased the brightness and contrast for small confocal apertures by more than 2x, and decreased the brightness of images obtained with displaced apertures, confirming the ability of the adaptive optics system to improve the pointspread function. The retinal image was stabilized to within 18 microns 90% of the time. Stabilization was sufficient for cross-correlation techniques to automatically align the images. PMID:17429477

Automated detection of the retinal from OCT spectral domain images of healthy eyes

NASA Astrophysics Data System (ADS)

Giovinco, Gaspare; Savastano, Maria Cristina; Ventre, Salvatore; Tamburrino, Antonello

2015-06-01

Optical coherence tomography (OCT) has become one of the most relevant diagnostic tools for retinal diseases. Besides being a non-invasive technique, one distinguished feature is its unique capability of providing (in vivo) cross-sectional view of the retinal. Specifically, OCT images show the retinal layers. From the clinical point of view, the identification of the retinal layers opens new perspectives to study the correlation between morphological and functional aspects of the retinal tissue. The main contribution of this paper is a new method/algorithm for the automated segmentation of cross-sectional images of the retina of healthy eyes, obtained by means of spectral domain optical coherence tomography (SD-OCT). Specifically, the proposed segmentation algorithm provides the automated detection of different retinal layers. Tests on experimental SD-OCT scans performed by three different instruments/manufacturers have been successfully carried out and compared to a manual segmentation made by an independent ophthalmologist, showing the generality and the effectiveness of the proposed method.

Retinal oxygen extraction in humans

NASA Astrophysics Data System (ADS)

Werkmeister, René M.; Schmidl, Doreen; Aschinger, Gerold; Doblhoff-Dier, Veronika; Palkovits, Stefan; Wirth, Magdalena; Garhöfer, Gerhard; Linsenmeier, Robert A.; Leitgeb, Rainer A.; Schmetterer, Leopold

2015-10-01

Adequate function of the retina is dependent on proper oxygen supply. In humans, the inner retina is oxygenated via the retinal circulation. We present a method to calculate total retinal oxygen extraction based on measurement of total retinal blood flow using dual-beam bidirectional Doppler optical coherence tomography and measurement of oxygen saturation by spectrophotometry. These measurements were done on 8 healthy subjects while breathing ambient room air and 100% oxygen. Total retinal blood flow was 44.3 ± 9.0 μl/min during baseline and decreased to 18.7 ± 4.2 μl/min during 100% oxygen breathing (P < 0.001) resulting in a pronounced decrease in retinal oxygen extraction from 2.33 ± 0.51 μl(O2)/min to 0.88 ± 0.14 μl(O2)/min during breathing of 100% oxygen. The method presented in this paper may have significant potential to study oxygen metabolism in hypoxic retinal diseases such as diabetic retinopathy.

Retinal oxygen extraction in humans

PubMed Central

Werkmeister, René M.; Schmidl, Doreen; Aschinger, Gerold; Doblhoff-Dier, Veronika; Palkovits, Stefan; Wirth, Magdalena; Garhöfer, Gerhard; Linsenmeier, Robert A.; Leitgeb, Rainer A.; Schmetterer, Leopold

2015-01-01

Adequate function of the retina is dependent on proper oxygen supply. In humans, the inner retina is oxygenated via the retinal circulation. We present a method to calculate total retinal oxygen extraction based on measurement of total retinal blood flow using dual-beam bidirectional Doppler optical coherence tomography and measurement of oxygen saturation by spectrophotometry. These measurements were done on 8 healthy subjects while breathing ambient room air and 100% oxygen. Total retinal blood flow was 44.3 ± 9.0 μl/min during baseline and decreased to 18.7 ± 4.2 μl/min during 100% oxygen breathing (P < 0.001) resulting in a pronounced decrease in retinal oxygen extraction from 2.33 ± 0.51 μl(O2)/min to 0.88 ± 0.14 μl(O2)/min during breathing of 100% oxygen. The method presented in this paper may have significant potential to study oxygen metabolism in hypoxic retinal diseases such as diabetic retinopathy. PMID:26503332

[Tanning lamp radiation-induced photochemical retinal damage].

PubMed

Volkov, V V; Kharitonova, N N; Mal'tsev, D S

2014-01-01

On the basis of original clinical research a rare case of bilateral retinal damage due to tanning lamp radiation exposure is presented. Along with significant decrease of visual acuity and light sensitivity of central visual field as well as color vision impairment, bilateral macular dystrophy was found during an ophthalmoscopy and confirmed by optical coherent tomography and fluorescent angiography. Intensive retinoprotective, vascular, and antioxidant therapy was effective and led to functional improvement and stabilization of the pathologic process associated with photochemical retinal damage. A brief review of literature compares mechanisms of retinal damage by either short or long-wave near visible radiation.

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

PubMed

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.

Age-Related Alterations in the Retinal Microvasculature, Microcirculation, and Microstructure.

PubMed

Wei, Yantao; Jiang, Hong; Shi, Yingying; Qu, Dongyi; Gregori, Giovanni; Zheng, Fang; Rundek, Tatjana; Wang, Jianhua

2017-07-01

To characterize age-related alterations in the retinal microcirculation, microvascular network, and microstructure in healthy subjects. Seventy-four healthy subjects aged from 18 to 82 years were recruited and divided into four age groups (G1 with age <35 years, G2 with age 35 ∼ 49 years, G3 with age 50 ∼ 64 years, and G4 with age ≥65 years). Custom ultra-high resolution optical coherence tomography (UHR-OCT) was used to acquire six intraretinal layers of the macula. OCT angiography (OCTA) was used to image the retinal microvascular network. The retinal blood flow velocity (BFV) was measured using a Retinal Function Imager (RFI). Compared to G1, G2 had significant thinning of the retinal nerve fiber layer (RNFL) (P < 0.05), while G3 had thinning of the RNFL and ganglion cell and inner plexiform layer (GCIPL) (P < 0.05), in addition to thickening of the outer plexiform layer (OPL) and photoreceptor layer (PR) (P < 0.05). G4 had loss in retinal vessel density, thinning in RNFL and GCIPL, and decrease in venular BFV, in addition to thickening of the OPL and PR (P < 0.05). Age was negatively related to retinal vessel densities, the inner retinal layers, and venular BFV (P < 0.05). By contrast, age was positively related to OPL and PR (P < 0.05). During aging, decreases in retinal vessel density, inner retinal layer thickness, and venular BFV were evident and impacted each other as observed by simultaneous changes in multiple retinal components.

In Vivo Confocal Intrinsic Optical Signal Identification of Localized Retinal Dysfunction

PubMed Central

Zhang, Qiu-Xiang; Lu, Rong-Wen; Curcio, Christine A.; Yao, Xin-Cheng

2012-01-01

Purpose. The purposes of this study were to investigate the physiological mechanism of stimulus-evoked fast intrinsic optical signals (IOSs) recorded in dynamic confocal imaging of the retina, and to demonstrate the feasibility of in vivo confocal IOS mapping of localized retinal dysfunctions. Methods. A rapid line-scan confocal ophthalmoscope was constructed to achieve in vivo confocal IOS imaging of frog (Rana pipiens) retinas at cellular resolution. In order to investigate the physiological mechanism of confocal IOS, comparative IOS and electroretinography (ERG) measurements were made using normal frog eyes activated by variable-intensity stimuli. A dynamic spatiotemporal filtering algorithm was developed to reject the contamination of hemodynamic changes on fast IOS recording. Laser-injured frog eyes were employed to test the potential of confocal IOS mapping of localized retinal dysfunctions. Results. Comparative IOS and ERG experiments revealed a close correlation between the confocal IOS and retinal ERG, particularly the ERG a-wave, which has been widely used to evaluate photoreceptor function. IOS imaging of laser-injured frog eyes indicated that the confocal IOS could unambiguously detect localized (30 μm) functional lesions in the retina before a morphological abnormality is detectable. Conclusions. The confocal IOS predominantly results from retinal photoreceptors, and can be used to map localized photoreceptor lesion in laser-injured frog eyes. We anticipate that confocal IOS imaging can provide applications in early detection of age-related macular degeneration, retinitis pigmentosa, and other retinal diseases that can cause pathological changes in the photoreceptors. PMID:23150616

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

PubMed Central

Gaub, Benjamin M.; Berry, Michael H.; Holt, Amy E.; Reiner, Andreas; Kienzler, Michael A.; Dolgova, Natalia; Nikonov, Sergei; Aguirre, Gustavo D.; Beltran, William A.; Flannery, John G.; Isacoff, Ehud Y.

2014-01-01

Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second- and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0460). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform light-evoked firing when LiGluR-MAG0460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0460 in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rod-cone dystrophy dog model of blindness, LiGluR-MAG0460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation. PMID:25489083

Activation of Müller cells occurs during retinal degeneration in RCS rats.

PubMed

Zhao, Tong Tao; Tian, Chun Yu; Yin, Zheng Qin

2010-01-01

Müller cells can be activated and included in different functions under many kinds of pathological conditions, however, the status of Müller cells in retinitis pigmentosa are still unknown. Using immunohistochemisty, Western blots and co-culture, we found that Müller cells RCS rats, a classic model of RP, could be activated during the progression of retinal degeneration. After being activated at early stage, Müller cells began to proliferate and hypertrophy, while at later stages, they formed a local 'glial seal' in the subretinal space. As markers of Müller cells activation, the expression of GFAP and ERK increased significantly with progression of retinal degeneration. Co-cultures of normal rat Müller cells and mixed RCS rat retinal cells show that Müller cells significantly increase GFAP and ERK in response to diffusable factors from the degenerting retina, which implies that Müller cells activation is a secondary response to retinal degeneration.

Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects.

PubMed

Lasta, Michael; Palkovits, Stefan; Boltz, Agnes; Schmidl, Doreen; Kaya, Semira; Cherecheanu, Alina Popa; Garhöfer, Gerhard; Schmetterer, Leopold

2012-12-01

An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 ± 3.9; mean ± SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test-retest, short-term as well as day-to-day measurements were calculated.   The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test-retest CV of 3.24 ± 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 ± 3.57%. Short-term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 ± 2.42% and CV in retinal veins: 4.76 ± 3.14%). The day-to-day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 ± 2.87% and CV in retinal veins: 6.18 ± 3.36%). The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required. © 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.

Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration

DTIC Science & Technology

2016-12-01

the biological functions of the 3D printed retina tissue. 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF...cells (hfRPC) as the cell resource for retinal tissue differentiation. We have demonstrated that these 3D - printed hydrogel materials are biocompatible...for retinal cell growth. The hfRPC can be directed toward a specific cell fate within 3D - printed hydrogel and chemically defined induction medium

Retinal Laminar Architecture in Human Retinitis Pigmentosa Caused by Rhodopsin Gene Mutations

PubMed Central

Aleman, Tomas S.; Cideciyan, Artur V.; Sumaroka, Alexander; Windsor, Elizabeth A. M.; Herrera, Waldo; White, D. Alan; Kaushal, Shalesh; Naidu, Anjani; Roman, Alejandro J.; Schwartz, Sharon B.; Stone, Edwin M.; Jacobson, Samuel G.

2008-01-01

Purpose. To determine the underlying retinal micropathology in subclasses of autosomal dominant retinitis pigmentosa (ADRP) caused by rhodopsin (RHO) mutations. Methods. Patients with RHO-ADRP (n = 17, ages 6–73 years), representing class A (R135W and P347L) and class B (P23H, T58R, and G106R) functional phenotypes, were studied with optical coherence tomography (OCT), and colocalized visual thresholds were determined by dark- and light-adapted chromatic perimetry. Autofluorescence imaging was performed with near-infrared light. Retinal histology in hT17M-rhodopsin mice was compared with the human results. Results. Class A patients had only cone-mediated vision. The outer nuclear layer (ONL) thinned with eccentricity and was not detectable within 3 to 4 mm of the fovea. Scotomatous extracentral retina showed loss of ONL, thickening of the inner retina, and demelanization of RPE. Class B patients had superior–inferior asymmetry in function and structure. The superior retina could have normal rod and cone vision, normal lamination (including ONL) and autofluorescence of the RPE melanin; laminopathy was found in the scotomas. With Fourier-domain-OCT, there was apparent inner nuclear layer (INL) thickening in regions with ONL thinning. Retinal regions without ONL had a thick hyporeflective layer that was continuous with the INL from neighboring regions with normal lamination. Transgenic mice had many of the laminar abnormalities found in patients. Conclusions. Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. The results in human class B and the transgenic mice support the following disease sequence: ONL diminution with INL thickening; amalgamation of residual ONL with the thickened INL; and progressive retinal remodeling with eventual thinning. PMID:18385078

CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function.

PubMed

Quinn, Peter M; Alves, C Henrique; Klooster, Jan; Wijnholds, Jan

2018-06-08

The mammalian apical-basal determinant Crumbs homolog-1 (CRB1) plays a crucial role in retinal structure and function by the maintenance of adherens junctions between photoreceptors and Müller glial cells. Patients with mutations in the CRB1 gene develop retinal dystrophies, including early-onset retinitis pigmentosa and Leber congenital amaurosis. Previously, we showed that Crb1 knockout mice developed a slow-progressing retinal phenotype at foci in the inferior retina, whiles specific ablation of Crb2 in immature photoreceptors lead to an early-onset phenotype throughout the retina. Here, we conditionally disrupted one or both alleles of Crb2 in immature photoreceptors, on a genetic background lacking Crb1, and studied the retinal dystrophies thereof. Our data showed that disruption of one allele of Crb2 in immature photoreceptors caused a substantial aggravation of the Crb1 phenotype in the entire inferior retina. The photoreceptor layer showed early-onset progressive thinning limited to the inferior retina while the superior retina maintained intact. Surprisingly, disruption of both alleles of Crb2 in immature photoreceptors further aggravated the phenotype. Throughout the retina, photoreceptor synapses were disrupted and photoreceptor nuclei intermingled with nuclei of the inner nuclear layer. In the superior retina, the ganglion cell layer appeared thicker due to ectopic nuclei of photoreceptors. In conclusion, the data suggest that CRB2 is required to maintain retinal progenitor and photoreceptor cell adhesion and prevent photoreceptor ingression into the immature inner retina. We hypothesise, from these animal models, that decreased levels of CRB2 in immature photoreceptors adjust retinitis pigmentosa due to loss of CRB1 into Leber congenital amaurosis phenotype.

The Rat With Oxygen-Induced Retinopathy Is Myopic With Low Retinal Dopamine

PubMed Central

Zhang, Nan; Favazza, Tara L.; Baglieri, Anna Maria; Benador, Ilan Y.; Noonan, Emily R.; Fulton, Anne B.; Hansen, Ronald M.; Iuvone, P. Michael; Akula, James D.

2013-01-01

Purpose. Dopamine (DA) is a neurotransmitter implicated both in modulating neural retinal signals and in eye growth. Therefore, it may participate in the pathogenesis of the most common clinical sequelae of retinopathy of prematurity (ROP), visual dysfunction and myopia. Paradoxically, in ROP myopia the eye is usually small. The eye of the rat with oxygen-induced retinopathy (OIR) is characterized by retinal dysfunction and short axial length. There have been several investigations of the early maturation of DA in rat retina, but little at older ages, and not in the OIR rat. Therefore, DA, retinal function, and refractive state were investigated in the OIR rat. Methods. In one set of rats, the development of dopaminergic (DAergic) networks was evaluated in retinal cross-sections from rats aged 14 to 120 days using antibodies against tyrosine hydroxylase (TH, the rate-limiting enzyme in the biosynthesis of DA). In another set of rats, retinoscopy was used to evaluate spherical equivalent (SE), electoretinography (ERG) was used to evaluate retinal function, and high-pressure liquid chromatography (HPLC) was used to evaluate retinal contents of DA, its precursor levodopamine (DOPA), and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Results. The normally rapid postnatal ramification of DAergic neurons was disrupted in OIR rats. Retinoscopy revealed that OIR rats were relatively myopic. In the same eyes, ERG confirmed retinal dysfunction in OIR. HPLC of those eyes' retinae confirmed low DA. Regression analysis indicated that DA metabolism (evaluated by the ratio of DOPAC to DA) was an important additional predictor of myopia beyond OIR. Conclusions. The OIR rat is the first known animal model of myopia in which the eye is smaller than normal. Dopamine may modulate, or fail to modulate, neural activity in the OIR eye, and thus contribute to this peculiar myopia. PMID:24168993

The rat with oxygen-induced retinopathy is myopic with low retinal dopamine.

PubMed

Zhang, Nan; Favazza, Tara L; Baglieri, Anna Maria; Benador, Ilan Y; Noonan, Emily R; Fulton, Anne B; Hansen, Ronald M; Iuvone, P Michael; Akula, James D

2013-12-19

Dopamine (DA) is a neurotransmitter implicated both in modulating neural retinal signals and in eye growth. Therefore, it may participate in the pathogenesis of the most common clinical sequelae of retinopathy of prematurity (ROP), visual dysfunction and myopia. Paradoxically, in ROP myopia the eye is usually small. The eye of the rat with oxygen-induced retinopathy (OIR) is characterized by retinal dysfunction and short axial length. There have been several investigations of the early maturation of DA in rat retina, but little at older ages, and not in the OIR rat. Therefore, DA, retinal function, and refractive state were investigated in the OIR rat. In one set of rats, the development of dopaminergic (DAergic) networks was evaluated in retinal cross-sections from rats aged 14 to 120 days using antibodies against tyrosine hydroxylase (TH, the rate-limiting enzyme in the biosynthesis of DA). In another set of rats, retinoscopy was used to evaluate spherical equivalent (SE), electoretinography (ERG) was used to evaluate retinal function, and high-pressure liquid chromatography (HPLC) was used to evaluate retinal contents of DA, its precursor levodopamine (DOPA), and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). The normally rapid postnatal ramification of DAergic neurons was disrupted in OIR rats. Retinoscopy revealed that OIR rats were relatively myopic. In the same eyes, ERG confirmed retinal dysfunction in OIR. HPLC of those eyes' retinae confirmed low DA. Regression analysis indicated that DA metabolism (evaluated by the ratio of DOPAC to DA) was an important additional predictor of myopia beyond OIR. The OIR rat is the first known animal model of myopia in which the eye is smaller than normal. Dopamine may modulate, or fail to modulate, neural activity in the OIR eye, and thus contribute to this peculiar myopia.

Blind source separation in retinal videos

NASA Astrophysics Data System (ADS)

Barriga, Eduardo S.; Truitt, Paul W.; Pattichis, Marios S.; Tüso, Dan; Kwon, Young H.; Kardon, Randy H.; Soliz, Peter

2003-05-01

An optical imaging device of retina function (OID-RF) has been developed to measure changes in blood oxygen saturation due to neural activity resulting from visual stimulation of the photoreceptors in the human retina. The video data that are collected represent a mixture of the functional signal in response to the retinal activation and other signals from undetermined physiological activity. Measured changes in reflectance in response to the visual stimulus are on the order of 0.1% to 1.0% of the total reflected intensity level which makes the functional signal difficult to detect by standard methods since it is masked by the other signals that are present. In this paper, we apply principal component analysis (PCA), blind source separation (BSS), using Extended Spatial Decorrelation (ESD) and independent component analysis (ICA) using the Fast-ICA algorithm to extract the functional signal from the retinal videos. The results revealed that the functional signal in a stimulated retina can be detected through the application of some of these techniques.

In Vivo Imaging of Transgenic Gene Expression in Individual Retinal Progenitors in Chimeric Zebrafish Embryos to Study Cell Nonautonomous Influences.

PubMed

Dudczig, Stefanie; Currie, Peter D; Poggi, Lucia; Jusuf, Patricia R

2017-03-22

The genetic and technical strengths have made the zebrafish vertebrate a key model organism in which the consequences of gene manipulations can be traced in vivo throughout the rapid developmental period. Multiple processes can be studied including cell proliferation, gene expression, cell migration and morphogenesis. Importantly, the generation of chimeras through transplantations can be easily performed, allowing mosaic labeling and tracking of individual cells under the influence of the host environment. For example, by combining functional gene manipulations of the host embryo (e.g., through morpholino microinjection) and live imaging, the effects of extrinsic, cell nonautonomous signals (provided by the genetically modified environment) on individual transplanted donor cells can be assessed. Here we demonstrate how this approach is used to compare the onset of fluorescent transgene expression as a proxy for the timing of cell fate determination in different genetic host environments. In this article, we provide the protocol for microinjecting zebrafish embryos to mark donor cells and to cause gene knockdown in host embryos, a description of the transplantation technique used to generate chimeric embryos, and the protocol for preparing and running in vivo time-lapse confocal imaging of multiple embryos. In particular, performing multiposition imaging is crucial when comparing timing of events such as the onset of gene expression. This requires data collection from multiple control and experimental embryos processed simultaneously. Such an approach can easily be extended for studies of extrinsic influences in any organ or tissue of choice accessible to live imaging, provided that transplantations can be targeted easily according to established embryonic fate maps.

Multifocal and full-field electroretinogram changes associated with color-vision loss in mercury vapor exposure.

PubMed

Ventura, Dora F; Costa, Marcelo T V; Costa, Marcelo F; Berezovsky, Adriana; Salomão, Solange R; Simões, Ana Luíza; Lago, Marcos; Pereira, Luiz H M Canto; Faria, Marcília A M; De Souza, John M; Silveira, Luiz Carlos L

2004-01-01

We evaluated the color vision of mercury-contaminated patients and investigated possible retinal origins of losses using electroretinography. Participants were retired workers from a fluorescent lamp industry diagnosed with mercury contamination (n = 43) and age-matched controls (n = 21). Color discrimination was assessed with the Cambridge Colour Test (CCT). Retinal function was evaluated by using the ISCEV protocol for full-field electroretinography (full-field ERG), as well as by means of multifocal electroretinography (mfERG). Color-vision losses assessed by the CCT consisted of higher color-discrimination thresholds along the protan, deutan, and tritan axes and significantly larger discrimination ellipses in mercury-exposed patients compared to controls. Full-field ERG amplitudes from patients were smaller than those of the controls for the scotopic response b-wave, maximum response, sum of oscillatory potentials (OPs), 30-Hz flicker response, and light-adapted cone response. OP amplitudes measured in patients were smaller than those of controls for O2 and O3. Multifocal ERGs recorded from ten randomly selected patients showed smaller N1-P1 amplitudes and longer latencies throughout the 25-deg central field. Full-field ERGs showed that scotopic, photopic, peripheral, and midperipheral retinal functions were affected, and the mfERGs indicated that central retinal function was also significantly depressed. To our knowledge, this is the first demonstration of retinal involvement in visual losses caused by mercury toxicity.

Cryptochrome 1 in Retinal Cone Photoreceptors Suggests a Novel Functional Role in Mammals

PubMed Central

Nießner, Christine; Denzau, Susanne; Malkemper, Erich Pascal; Gross, Julia Christina; Burda, Hynek; Winklhofer, Michael; Peichl, Leo

2016-01-01

Cryptochromes are a ubiquitous group of blue-light absorbing flavoproteins that in the mammalian retina have an important role in the circadian clock. In birds, cryptochrome 1a (Cry1a), localized in the UV/violet-sensitive S1 cone photoreceptors, is proposed to be the retinal receptor molecule of the light-dependent magnetic compass. The retinal localization of mammalian Cry1, homologue to avian Cry1a, is unknown, and it is open whether mammalian Cry1 is also involved in magnetic field sensing. To constrain the possible role of retinal Cry1, we immunohistochemically analysed 90 mammalian species across 48 families in 16 orders, using an antiserum against the Cry1 C-terminus that in birds labels only the photo-activated conformation. In the Carnivora families Canidae, Mustelidae and Ursidae, and in some Primates, Cry1 was consistently labeled in the outer segment of the shortwave-sensitive S1 cones. This finding would be compatible with a magnetoreceptive function of Cry1 in these taxa. In all other taxa, Cry1 was not detected by the antiserum that likely also in mammals labels the photo-activated conformation, although Western blots showed Cry1 in mouse retinal cell nuclei. We speculate that in the mouse and the other negative-tested mammals Cry1 is involved in circadian functions as a non-light-responsive protein. PMID:26898837

Phospholipase D1 modulates protein kinase C-epsilon in retinal pigment epithelium cells during inflammatory response.

PubMed

Tenconi, Paula E; Giusto, Norma M; Salvador, Gabriela A; Mateos, Melina V

2016-12-01

Inflammation is a key factor in the pathogenesis of several retinal diseases. In view of the essential role of the retinal pigment epithelium in visual function, elucidating the molecular mechanisms elicited by inflammation in this tissue could provide new insights for the treatment of retinal diseases. The aim of the present work was to study protein kinase C signaling and its modulation by phospholipases D in ARPE-19 cells exposed to lipopolysaccharide. This bacterial endotoxin induced protein kinase C-α/βII phosphorylation and protein kinase-ε translocation to the plasma membrane in ARPE-19 cells. Pre-incubation with selective phospholipase D inhibitors demonstrated that protein kinase C-α phosphorylation depends on phospholipase D1 and 2 while protein kinase C-ε activation depends only on phospholipase D1. The inhibition of α and β protein kinase C isoforms with Go 6976 did not modify the reduced mitochondrial function induced by lipopolysaccharide. On the contrary, the inhibition of protein kinase C-α, β and ε with Ro 31-8220 potentiated the decrease in mitochondrial function. Moreover, inhibition of protein kinase C-ε reduced Bcl-2 expression and Akt activation and increased Caspase-3 cleavage in cells treated or not with lipopolysaccharide. Our results demonstrate that through protein kinase C-ε regulation, phospholipase D1 protects retinal pigment epithelium cells from lipopolysaccharide-induced damage. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stanniocalcin-1 Rescued Photoreceptor Degeneration in Two Rat Models of Inherited Retinal Degeneration

PubMed Central

Roddy, Gavin W; Rosa Jr, Robert H; Youn Oh, Joo; Ylostalo, Joni H; Bartosh, Thomas J; Choi, Hosoon; Lee, Ryang Hwa; Yasumura, Douglas; Ahern, Kelly; Nielsen, Gregory; Matthes, Michael T; LaVail, Matthew M; Prockop, Darwin J

2012-01-01

Oxidative stress and photoreceptor apoptosis are prominent features of many forms of retinal degeneration (RD) for which there are currently no effective therapies. We previously observed that mesenchymal stem/stromal cells reduce apoptosis by being activated to secrete stanniocalcin-1 (STC-1), a multifunctional protein that reduces oxidative stress by upregulating mitochondrial uncoupling protein-2 (UCP-2). Therefore, we tested the hypothesis that intravitreal injection of STC-1 can rescue photoreceptors. We first tested STC-1 in the rhodopsin transgenic rat characterized by rapid photoreceptor loss. Intravitreal STC-1 decreased the loss of photoreceptor nuclei and transcripts and resulted in measurable retinal function when none is otherwise present in this rapid degeneration. We then tested STC-1 in the Royal College of Surgeons (RCS) rat characterized by a slower photoreceptor degeneration. Intravitreal STC-1 reduced the number of pyknotic nuclei in photoreceptors, delayed the loss of photoreceptor transcripts, and improved function of rod photoreceptors. Additionally, STC-1 upregulated UCP-2 and decreased levels of two protein adducts generated by reactive oxygen species (ROS). Microarrays from the two models demonstrated that STC-1 upregulated expression of a similar profile of genes for retinal development and function. The results suggested that intravitreal STC-1 is a promising therapy for various forms of RD including retinitis pigmentosa and atrophic age-related macular degeneration (AMD). PMID:22294148

Cryptochrome 1 in Retinal Cone Photoreceptors Suggests a Novel Functional Role in Mammals.

PubMed

Nießner, Christine; Denzau, Susanne; Malkemper, Erich Pascal; Gross, Julia Christina; Burda, Hynek; Winklhofer, Michael; Peichl, Leo

2016-02-22

Cryptochromes are a ubiquitous group of blue-light absorbing flavoproteins that in the mammalian retina have an important role in the circadian clock. In birds, cryptochrome 1a (Cry1a), localized in the UV/violet-sensitive S1 cone photoreceptors, is proposed to be the retinal receptor molecule of the light-dependent magnetic compass. The retinal localization of mammalian Cry1, homologue to avian Cry1a, is unknown, and it is open whether mammalian Cry1 is also involved in magnetic field sensing. To constrain the possible role of retinal Cry1, we immunohistochemically analysed 90 mammalian species across 48 families in 16 orders, using an antiserum against the Cry1 C-terminus that in birds labels only the photo-activated conformation. In the Carnivora families Canidae, Mustelidae and Ursidae, and in some Primates, Cry1 was consistently labeled in the outer segment of the shortwave-sensitive S1 cones. This finding would be compatible with a magnetoreceptive function of Cry1 in these taxa. In all other taxa, Cry1 was not detected by the antiserum that likely also in mammals labels the photo-activated conformation, although Western blots showed Cry1 in mouse retinal cell nuclei. We speculate that in the mouse and the other negative-tested mammals Cry1 is involved in circadian functions as a non-light-responsive protein.

Functional K(ATP) channels in the rat retinal microvasculature: topographical distribution, redox regulation, spermine modulation and diabetic alteration.

PubMed

Ishizaki, Eisuke; Fukumoto, Masanori; Puro, Donald G

2009-05-15

The essential task of the circulatory system is to match blood flow to local metabolic demand. However, much remains to be learned about this process. To better understand how local perfusion is regulated, we focused on the functional organization of the retinal microvasculature, which is particularly well adapted for the local control of perfusion. Here, we assessed the distribution and regulation of functional K(ATP) channels whose activation mediates the hyperpolarization induced by adenosine. Using microvascular complexes freshly isolated from the rat retina, we found a topographical heterogeneity in the distribution of functional K(ATP) channels; capillaries generate most of the K(ATP) current. The initiation of K(ATP)-induced responses in the capillaries supports the concept that the regulation of retinal perfusion is highly decentralized. Additional study revealed that microvascular K(ATP) channels are redox sensitive, with oxidants increasing their activity. Furthermore, the oxidant-mediated activation of these channels is driven by the polyamine spermine, whose catabolism produces oxidants. In addition, our observation that spermine-dependent oxidation occurs predominately in the capillaries accounts for why they generate most of the K(ATP) current detected in retinal microvascular complexes. Here, we also analysed retinal microvessels of streptozotocin-injected rats. We found that soon after the onset of diabetes, an increase in spermine-dependent oxidation at proximal microvascular sites boosts their K(ATP) current and thereby virtually eliminates the topographical heterogeneity of functional K(ATP) channels. We conclude that spermine-dependent oxidation is a previously unrecognized mechanism by which this polyamine modulates ion channels; in addition to a physiological role, spermine-dependent oxidation may also contribute to microvascular dysfunction in the diabetic retina.

Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65.

PubMed

Choi, Elliot H; Suh, Susie; Sander, Christopher L; Hernandez, Christian J Ortiz; Bulman, Elizabeth R; Khadka, Nimesh; Dong, Zhiqian; Shi, Wuxian; Palczewski, Krzysztof; Kiser, Philip D

2018-04-12

RPE65 is the essential trans-cis isomerase of the classical retinoid (visual) cycle. Mutations in RPE65 give rise to severe retinal dystrophies, most of which are associated with loss of protein function and recessive inheritance. The only known exception is a c.1430G>A (D477G) mutation that gives rise to dominant retinitis pigmentosa with delayed onset and choroidal and macular involvement. Position 477 is distant from functionally critical regions of RPE65. Hence, the mechanism of D477G pathogenicity remains unclear, although protein misfolding and aggregation mechanisms have been suggested. We characterized a D477G knock-in mouse model which exhibited mild age-dependent changes in retinal structure and function. Immunoblot analysis of protein extracts from the eyes of the knock-in mice demonstrated the presence of ubiquitinated RPE65 and reduced RPE65 expression. We observed an accumulation of retinyl esters in the knock-in mice as well as a delay in rhodopsin regeneration kinetics and diminished electroretinography responses, indicative of RPE65 functional impairment induced by the D477G mutation in vivo. However, a cell line expressing D477G RPE65 revealed protein expression levels, cellular localization, and retinoid isomerase activity comparable to cells expressing wild-type protein. Structural analysis of an RPE65 chimera suggested that the D477G mutation does not perturb protein folding or tertiary structure. Instead, the mutation generates an aggregation-prone surface that could induce cellular toxicity through abnormal complex formation as suggested by crystal packing analysis. These results indicate that a toxic gain-of-function induced by the D477G RPE65 substitution may play a role in the pathogenesis of this form of dominant retinitis pigmentosa.

Functional Visual Improvement After Cataract Surgery in Eyes With Age-Related Macular Degeneration: Results of the Ophthalmic Surgical Outcomes Data Project.

PubMed

Stock, Michael V; Vollman, David E; Baze, Elizabeth F; Chomsky, Amy S; Daly, Mary K; Lawrence, Mary G

2015-04-01

To determine if cataract surgery on eyes with AMD confers as much functional visual improvement as surgery on eyes without retinal pathology. This is a retrospective analysis of 4924 cataract surgeries from the Veterans Healthcare Administration Ophthalmic Surgical Outcomes Data Project (OSOD). We included cases of eyes with AMD that had both preoperative and postoperative NEI-VFQ-25 questionnaires submitted and compared their outcomes with controls without retinal pathology. We excluded patients with other retinal pathologies (740 patients). The analyses compared changes in visual acuity and overall functional visual improvement and its subscales using t-tests, multivariate logistic regressions, and linear regression modeling. Preoperative and postoperative questionnaires were submitted by 58.3% of AMD and 63.8% of no retinal pathology cases (controls). Analysis of overall score showed that cataract surgery on eyes with AMD led to increased visual function (13.8 ± 2.4 NEI-VFQ units, P < 0.0001); however, increases were significantly less when compared with controls (-6.4 ± 2.9 NEI-VFQ units, P < 0.0001). Preoperative best-corrected visual acuity (preBCVA) in AMD was predictive of postoperative visual function (r = -0.38, P < 0.0001). In controls, postoperative visual function was only weakly associated with preBCVA (r = -0.075, P = 0.0002). Patients with AMD with vision of 20/40 or better had overall outcomes similar to controls (-2.2 ± 4.7 NEI-VFQ units, P = 0.37). Cataract surgery on eyes with AMD offers an increase in functional visual improvement; however, the amount of benefit is associated with the eye's preBCVA. For eyes with preBCVA of 20/40 or greater, the improvement is similar to that of patients without retinal pathology. However, if preBCVA is less than 20/40, the amount of improvement was shown to be significantly less and decreased with decreasing preBCVA.

Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina

PubMed Central

Hambright, Dustin; Park, Kye-Yoon; Brooks, Matthew; McKay, Ron; Swaroop, Anand

2012-01-01

Purpose To examine the potential of NIH-maintained human embryonic stem cell (hESC) lines TE03 and UC06 to differentiate into retinal progenitor cells (hESC-RPCs) using the noggin/Dkk-1/IGF-1/FGF9 protocol. An additional goal is to examine the in vivo dynamics of maturation and retinal integration of subretinal and epiretinal (vitreous space) hESC-RPC grafts without immunosuppression. Methods hESCs were neuralized in vitro with noggin for 2 weeks and expanded to derive neuroepithelial cells (hESC-neural precursors, NPs). Wnt (Integration 1 and wingless) blocking morphogens Dickkopf-1 (Dkk-1) and Insulin-like growth factor 1 (IGF-1) were used to direct NPs to a rostral neural fate, and fibroblast growth factor 9 (FGF9)/fibroblast growth factor-basic (bFGF) were added to bias the differentiation of developing anterior neuroectoderm cells to neural retina (NR) rather than retinal pigment epithelium (RPE). Cells were dissociated and grafted into the subretinal and epiretinal space of young adult (4–6-week-old) mice (C57BL/6J x129/Sv mixed background). Remaining cells were replated for (i) immunocytochemical analysis and (ii) used for quantitative reverse transcription polymerase chain reaction (qRT–PCR) analysis. Mice were sacrificed 3 weeks or 3 months after grafting, and the grafts were examined by histology and immunohistochemistry for survival of hESC-RPCs, presence of mature neuronal and retinal markers, and the dynamics of in vivo maturation and integration into the host retina. Results At the time of grafting, hESC-RPCs exhibited immature neural/neuronal immunophenotypes represented by nestin and neuronal class III β-tubulin, with about half of the cells positive for cell proliferation marker Kiel University -raised antibody number 67 (Ki67), and no recoverin-positive (recoverin [+]) cells. The grafted cells expressed eye field markers paired box 6 (PAX6), retina and anterior neural fold homeobox (RAX), sine oculis homeobox homolog 6 (SIX6), LIM homeobox 2 (LHX2), early NR markers (Ceh-10 homeodomain containing homolog [CHX10], achaete-scute complex homolog 1 [MASH1], mouse atonal homolog 5 [MATH5], neurogenic differentiation 1 [NEUROD1]), and some retinal cell fate markers (brain-specific homeobox/POU domain transcription factor 3B [BRN3B], prospero homeobox 1 [PROX1], and recoverin). The cells in the subretinal grafts matured to predominantly recoverin [+] phenotype by 3 months and survived in a xenogenic environment without immunosuppression as long as the blood–retinal barrier was not breached by the transplantation procedure. The epiretinal grafts survived but did not express markers of mature retinal cells. Retinal integration into the retinal ganglion cell (RGC) layer and the inner nuclear layer (INL) was efficient from the epiretinal but not subretinal grafts. The subretinal grafts showed limited ability to structurally integrate into the host retina and only in cases when NR was damaged during grafting. Only limited synaptogenesis and no tumorigenicity was observed in grafts. Conclusions Our studies show that (i) immunosuppression is not mandatory to xenogenic graft survival in the retina, (ii) the subretinal but not the epiretinal niche can promote maturation of hESC-RPCs to photoreceptors, and (iii) the hESC-RPCs from epiretinal but not subretinal grafts can efficiently integrate into the RGC layer and INL. The latter could be of value for long-lasting neuroprotection of retina in some degenerative conditions and glaucoma. Overall, our results provide new insights into the technical aspects associated with cell-based therapy in the retina. PMID:22539871

Photovoltaic restoration of sight with high visual acuity

PubMed Central

Lorach, Henri; Goetz, Georges; Smith, Richard; Lei, Xin; Mandel, Yossi; Kamins, Theodore; Mathieson, Keith; Huie, Philip; Harris, James; Sher, Alexander; Palanker, Daniel

2015-01-01

Patients with retinal degeneration lose sight due to gradual demise of photoreceptors. Electrical stimulation of the surviving retinal neurons provides an alternative route for delivery of visual information. We demonstrate that subretinal arrays with 70 μm photovoltaic pixels provide highly localized stimulation, with electrical and visual receptive fields of comparable sizes in rat retinal ganglion cells. Similarly to normal vision, retinal response to prosthetic stimulation exhibits flicker fusion at high frequencies, adaptation to static images and non-linear spatial summation. In rats with retinal degeneration, these photovoltaic arrays provide spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in pigmented rats. Ease of implantation of these wireless and modular arrays, combined with their high resolution opens the door to functional restoration of sight. PMID:25915832

Age-Related Alterations in the Retinal Microvasculature, Microcirculation, and Microstructure

PubMed Central

Wei, Yantao; Jiang, Hong; Shi, Yingying; Qu, Dongyi; Gregori, Giovanni; Zheng, Fang; Rundek, Tatjana; Wang, Jianhua

2017-01-01

Purpose To characterize age-related alterations in the retinal microcirculation, microvascular network, and microstructure in healthy subjects. Methods Seventy-four healthy subjects aged from 18 to 82 years were recruited and divided into four age groups (G1 with age <35 years, G2 with age 35 ∼ 49 years, G3 with age 50 ∼ 64 years, and G4 with age ≥65 years). Custom ultra-high resolution optical coherence tomography (UHR-OCT) was used to acquire six intraretinal layers of the macula. OCT angiography (OCTA) was used to image the retinal microvascular network. The retinal blood flow velocity (BFV) was measured using a Retinal Function Imager (RFI). Results Compared to G1, G2 had significant thinning of the retinal nerve fiber layer (RNFL) (P < 0.05), while G3 had thinning of the RNFL and ganglion cell and inner plexiform layer (GCIPL) (P < 0.05), in addition to thickening of the outer plexiform layer (OPL) and photoreceptor layer (PR) (P < 0.05). G4 had loss in retinal vessel density, thinning in RNFL and GCIPL, and decrease in venular BFV, in addition to thickening of the OPL and PR (P < 0.05). Age was negatively related to retinal vessel densities, the inner retinal layers, and venular BFV (P < 0.05). By contrast, age was positively related to OPL and PR (P < 0.05). Conclusions During aging, decreases in retinal vessel density, inner retinal layer thickness, and venular BFV were evident and impacted each other as observed by simultaneous changes in multiple retinal components. PMID:28744554

Central retinal artery occlusion - rethinking retinal survival time.

PubMed

Tobalem, Stephan; Schutz, James S; Chronopoulos, Argyrios

2018-04-18

The critical time from onset of complete occlusion of the central retinal artery (CRA) to functionally significant inner retinal infarction represents a window of opportunity for treatment and also has medical-legal implications, particularly when central retinal artery occlusion (CRAO) complicates therapeutic interventions. Here, we review the evidence for time to infarction from complete CRAO and discuss the implications of our findings. A Medline search was performed using each of the terms "central retinal artery occlusion", "retinal infarction", "retinal ischemia", and "cherry red spot" from 1970 to the present including articles in French and German. All retrieved references as well as their reference lists were screened for relevance. An Internet search using these terms was also performed to look for additional references. We find that the experimental evidence showing that inner retinal infarction occurs after 90-240 min of total CRAO, which is the interval generally accepted in the medical literature and practice guidelines, is flawed in important ways. Moreover, the retinal ganglion cells, supplied by the CRA, are part of the central nervous system which undergoes infarction after non-perfusion of 12-15 min or less. Retinal infarction is most likely to occur after only 12-15 min of complete CRAO. This helps to explain why therapeutic maneuvers for CRAO are often ineffective. Nevertheless, many CRAOs are incomplete and may benefit from therapy after longer intervals. To try to avoid retinal infarcton from inadvertent ocular compression by a headrest during prone anesthesia, the eyes should be checked at intervals of less than 15'.

The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses

PubMed Central

Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L.; Ko, Gladys Y.-P.

2017-01-01

L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4) expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3−/−) mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3−/− mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3−/− mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported. PMID:29259539

Design of a High-resolution Optoelectronic Retinal Prosthesis

NASA Astrophysics Data System (ADS)

Palanker, Daniel

2005-03-01

It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. So far retinal implants have had just a few electrodes, whereas at least several thousand pixels would be required for any functional restoration of sight. We will discuss physical limitations on the number of stimulating electrodes and on delivery of information and power to the retinal implant. Using a model of extracellular stimulation we derive the threshold values of current and voltage as a function of electrode size and distance to the target cell. Electrolysis, tissue heating, and cross-talk between neighboring electrodes depend critically on separation between electrodes and cells, thus strongly limiting the pixels size and spacing. Minimal pixel density required for 20/80 visual acuity (2500 pixels/mm2, pixel size 20 um) cannot be achieved unless the target neurons are within 7 um of the electrodes. At a separation of 50 um, the density drops to 44 pixels/mm2, and at 100 um it is further reduced to 10 pixels/mm2. We will present designs of subretinal implants that provide close proximity of electrodes to cells using migration of retinal cells to target areas. Two basic implant geometries will be described: perforated membranes and protruding electrode arrays. In addition, we will discuss delivery of information to the implant that allows for natural eye scanning of the scene, rather than scanning with a head-mounted camera. It operates similarly to ``virtual reality'' imaging devices where an image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. Optical delivery of visual information to the implant allows for flexible control of the image processing algorithms and stimulation parameters. In summary, we will describe solutions to some of the major problems facing the realization of a functional retinal implant: high pixel density, proximity of electrodes to target cells, natural eye scanning capability, and real-time image processing adjustable to retinal architecture.

The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses.

PubMed

Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L; Ko, Gladys Y-P

2017-01-01

L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Ca v 1.2, Ca v 1.3, and Ca v 1.4) expressed in the retina. While Ca v 1.2 is expressed in all retinal cells including the Müller glia and neurons, Ca v 1.3 and Ca v 1.4 are expressed in the retinal neurons with Ca v 1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Ca v 1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Ca v 1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Ca v 1.3 are not associated with severe vision impairment in humans or in Ca v 1.3-null (Ca v 1.3 -/- ) mice. However, a failure to regulate Ca v 1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Ca v 1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Ca v 1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Ca v 1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Ca v 1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Ca v 1.3 -/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Ca v 1.3 -/- mice retinas. Hence, Ca v 1.3 plays a more prominent role in retinal physiology and function than previously reported.

Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Luqing

Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigmentmore » epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury. - Highlights: • MD2 inhibition reduced retinal damage after I/R induction in mice. • TBHP induced TLR4/MD2 binding via increasing HMGB-1 expression. • TLR4/MD2 initiated inflammatory response via activation of MAPKs and NF-κB. • MD2 could be the therapeutic target for the treatment of retinal I/R.« less

Preparing Fresh Retinal Slices from Adult Zebrafish for Ex Vivo Imaging Experiments.

PubMed

Giarmarco, Michelle M; Cleghorn, Whitney M; Hurley, James B; Brockerhoff, Susan E

2018-05-09

The retina is a complex tissue that initiates and integrates the first steps of vision. Dysfunction of retinal cells is a hallmark of many blinding diseases, and future therapies hinge on fundamental understandings about how different retinal cells function normally. Gaining such information with biochemical methods has proven difficult because contributions of particular cell types are diminished in the retinal cell milieu. Live retinal imaging can provide a view of numerous biological processes on a subcellular level, thanks to a growing number of genetically encoded fluorescent biosensors. However, this technique has thus far been limited to tadpoles and zebrafish larvae, the outermost retinal layers of isolated retinas, or lower resolution imaging of retinas in live animals. Here we present a method for generating live ex vivo retinal slices from adult zebrafish for live imaging via confocal microscopy. This preparation yields transverse slices with all retinal layers and most cell types visible for performing confocal imaging experiments using perfusion. Transgenic zebrafish expressing fluorescent proteins or biosensors in specific retinal cell types or organelles are used to extract single-cell information from an intact retina. Additionally, retinal slices can be loaded with fluorescent indicator dyes, adding to the method's versatility. This protocol was developed for imaging Ca 2+ within zebrafish cone photoreceptors, but with proper markers it could be adapted to measure Ca 2+ or metabolites in Müller cells, bipolar and horizontal cells, microglia, amacrine cells, or retinal ganglion cells. The retinal pigment epithelium is removed from slices so this method is not suitable for studying that cell type. With practice, it is possible to generate serial slices from one animal for multiple experiments. This adaptable technique provides a powerful tool for answering many questions about retinal cell biology, Ca 2+ , and energy homeostasis.

Retinal thinning is uniquely associated with medial temporal lobe atrophy in neurologically normal older adults

PubMed Central

Casaletto, Kaitlin B.; Ward, Michael E.; Baker, Nicholas S.; Bettcher, Brianne M.; Gelfand, Jeffrey M.; Li, Yaqiao; Chen, Robert; Dutt, Shubir; Miller, Bruce; Kramer, Joel H.; Green, Ari J.

2017-01-01

Given the converging pathologic and epidemiologic data indicating a relationship between retinal integrity and neurodegeneration, including Alzheimer’s disease (AD), we aimed to determine if retinal structure correlates with medial temporal lobe (MTL) structure and function in neurologically normal older adults. Spectral-domain optical coherence tomography, verbal and visual memory testing, and 3T-magnetic resonance imaging of the brain were performed in 79 neurologically normal adults enrolled in a healthy aging cohort study. Retinal nerve fiber thinning and reduced total macular and macular ganglion cell volumes were each associated with smaller MTL volumes (ps < 0.04). Notably, these markers of retinal structure were not associated with primary motor cortex or basal ganglia volumes (regions relatively unaffected in AD) (ps > 0.70), or frontal, precuneus, or temporoparietal volumes (regions affected in later AD Braak staging ps > 0.20). Retinal structure was not significantly associated with verbal or visual memory consolidation performances (ps > 0.14). Retinal structure was associated with MTL volumes, but not memory performances, in otherwise neurologically normal older adults. Given that MTL atrophy is a neuropathological hallmark of AD, retinal integrity may be an early marker of ongoing AD-related brain health. PMID:28068565

Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration.

PubMed

Inoue, Yuji; Iriyama, Aya; Ueno, Shuji; Takahashi, Hidenori; Kondo, Mineo; Tamaki, Yasuhiro; Araie, Makoto; Yanagi, Yasuo

2007-08-01

Because there is no effective treatment for this retinal degeneration, potential application of cell-based therapy has attracted considerable attention. Several investigations support that bone marrow mesenchymal stem cells (MSCs) can be used for a broad spectrum of indications. Bone marrow MSCs exert their therapeutic effect in part by secreting trophic factors to promote cell survival. The current study investigates whether bone marrow MSCs secrete factor(s) to promote photoreceptor cell survival and whether subretinal transplantation of bone marrow MSCs promotes photoreceptor survival in a retinal degeneration model using Royal College of Surgeons (RCS) rats. In vitro, using mouse retinal cell culture, it was demonstrated that the conditioned medium of the MSCs delays photoreceptor cell apoptosis, suggesting that the secreted factor(s) from the MSCs promote photoreceptor cell survival. In vivo, the MSCs were injected into the subretinal space of the RCS rats and histological analysis, real-time RT-PCR and electrophysiological analysis demonstrated that the subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function in the RCS rats. These results suggest that MSC is a useful cell source for cell-replacement therapy for some forms of retinal degeneration.

A CNGB1 Frameshift Mutation in Papillon and Phalène Dogs with Progressive Retinal Atrophy

PubMed Central

Ahonen, Saija J.; Arumilli, Meharji; Lohi, Hannes

2013-01-01

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. PMID:24015210

Correspondence between retinotopic cortical mapping and conventional functional and morphological assessment of retinal disease.

PubMed

Ritter, Markus; Hummer, Allan; Ledolter, Anna A; Holder, Graham E; Windischberger, Christian; Schmidt-Erfurth, Ursula M

2018-04-26

The present study describes retinotopic mapping of the primary visual cortex using functional MRI (fMRI) in patients with retinal disease. It addresses the relationship between fMRI data and data obtained by conventional assessment including microperimetry (MP) and structural imaging. Initial testing involved eight patients with central retinal disease (Stargardt disease, STGD) and eight with peripheral retinal disease (retinitis pigmentosa, RP), who were examined using fMRI and MP (Nidek MP-1). All had a secure clinical diagnosis supported by electrophysiological data. fMRI used population-receptive field (pRF) mapping to provide retinotopic data that were then compared with the results of MP, optical coherence tomography and fundus autofluorescence imaging. Full analysis, following assessment of fMRI data reliability criteria, was performed in five patients with STGD and seven patients with RP; unstable fixation was responsible for unreliable pRF measurements in three patients excluded from final analysis. The macular regions in patients with STGD with central visual field defects and outer retinal atrophy (ORA) at the macula correlated well with pRF coverage maps showing reduced density of activated voxels at the occipital pole. Patients with RP exhibited peripheral ORA and concentric visual field defects both on MP and pRF mapping. Anterior V1 voxels, corresponding to peripheral regions, showed no significant activation. Correspondence between MP and pRF mapping was quantified by calculating the simple matching coefficient. Retinotopic maps acquired by fMRI provide a valuable adjunct in the assessment of retinal dysfunction. The addition of microperimetric data to pRF maps allowed better assessment of macular function than MP alone. Unlike MP, pRF mapping provides objective data independent of psychophysical perception from the patient. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

β1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo

PubMed Central

Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah

2014-01-01

Purpose Determine whether Compound 49b treatment ameliorates retinal changes due to the lack of β2-adrenergic receptor signaling. Methods Using retinas from 3-month-old β2-adrenergic receptor-deficient mice, we treated mice with our novel β1-/β2-adrenergic receptor agonist, Compound 49b, to assess the effects of adrenergic agonists acting only on β1-adrenergic receptors due to the absence of β2-adrenergic receptors. Western blotting or enzyme-linked immunosorbent assay (ELISA) analyses were performed for β1- and β2-adrenergic receptors, as well as key insulin resistance proteins, including TNF-α, SOCS3, IRS-1Ser307, and IRTyr960. Analyses were also performed on key anti- and proapoptotic proteins: Akt, Bcl-xL, Bax, and caspase 3. Electroretinogram analyses were conducted to assess functional changes, while histological assessment was conducted for changes in retinal thickness. Results A 2-month treatment of β2-adrenergic receptor-deficient mice with daily eye drops of 1 mM Compound 49b, a novel β1- and β2-adrenergic receptor agonist, reversed the changes in insulin resistance markers (TNF-α and SOCS3) observed in untreated β2-adrenergic receptor-deficient mice, and concomitantly increased morphological integrity (retinal thickness) and functional responses (electroretinogram amplitude). These results suggest that stimulating β1-adrenergic receptors on retinal endothelial cells or Müller cells can compensate for the loss of β2-adrenergic receptor signaling on Müller cells, restore insulin signal transduction, reduce retinal apoptosis, and enhance retinal function. Conclusions Since our previous studies with β1-adrenergic receptor knockout mice confirmed that the reverse also occurs (β2-adrenergic receptor stimulation can compensate for the loss of β1-adrenergic receptor activity), it appears that increased activity in either of these pathways alone is sufficient to block insulin resistance–based retinal cell apoptosis. PMID:24966659

Defining the Catalytic Activity of Nanoceria in the P23H-1 Rat, a Photoreceptor Degeneration Model

PubMed Central

Wong, Lily L.; Pye, Quentin N.; Chen, Lijuan; Seal, Sudipta; McGinnis, James F.

2015-01-01

Purpose Inorganic catalytic nanoceria or cerium oxide nanoparticles (CeNPs) are bona fide antioxidants that possess regenerative radical scavenging activities in vitro. Previously, we demonstrated that CeNPs had neuroprotective and anti-angiogenic properties in rodent retinal degeneration and neovascularization models. However, the cellular mechanisms and duration of the catalytic activity of CeNPs in preventing photoreceptor cell loss are still unknown. In this study, we sought to answer these questions using the P23H-1 rat, an autosomal dominant retinitis pigmentosa (adRP) model. Methods A single dose of either saline or CeNPs was delivered intravitreally into the eyes of P23H-1 rats at 2–3 weeks of age. Retinal functions were examined at 3 to 7 weeks post injection. We quantified retinal proteins by Western blot analyses and counted the number of apoptotic (TUNEL+) profiles in the outer nuclear layer (ONL) of retinal sections. We measured free 8-isoprostanes to quantify lipid peroxidation in retinal tissues. Results We observed increased rod and cone cell functions up to three weeks post injection. Apoptotic cells were reduced by 46%, 56%, 21%, and 24% at 3, 7, 14, 21 days, respectively, after CeNPs injection compared to saline. Additionally, reduction of lipid peroxidation in the retinas of CeNPs-treated vs saline-treated animals was detected 14 days post injection. Conclusions We validated that CeNPs were effective in delaying loss of photoreceptor cell function in an adRP rat model. This represents the fourth rodent retinal disease model that shows delay in disease progression after a single application of CeNPs. We further demonstrated that CeNPs slowed the rate of photoreceptor cell death. We deduced that the catalytic activity of CeNPs in vivo in this rat model to be undiminished for at least 7 days and then declined over the next 14 days after CeNPs administration. PMID:25822196

Regarding the use and misuse of retinal protonated Schiff base photochemistry as a test case for time-dependent density-functional theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valsson, Omar; Filippi, Claudia, E-mail: c.filippi@utwente.nl; Casida, Mark E., E-mail: mark.casida@ujf-grenoble.fr

2015-04-14

The excited-state relaxation of retinal protonated Schiff bases (PSBs) is an important test case for biological applications of time-dependent (TD) density-functional theory (DFT). While well-known shortcomings of approximate TD-DFT might seem discouraging for application to PSB relaxation, progress continues to be made in the development of new functionals and of criteria allowing problematic excitations to be identified within the framework of TD-DFT itself. Furthermore, experimental and theoretical ab initio advances have recently lead to a revised understanding of retinal PSB photochemistry, calling for a reappraisal of the performance of TD-DFT in describing this prototypical photoactive system. Here, we re-investigate themore » performance of functionals in (TD-)DFT calculations in light of these new benchmark results, which we extend to larger PSB models. We focus on the ability of the functionals to describe primarily the early skeletal relaxation of the chromophore and investigate how far along the out-of-plane pathways these functionals are able to describe the subsequent rotation around formal single and double bonds. Conventional global hybrid and range-separated hybrid functionals are investigated as the presence of Hartree-Fock exchange reduces problems with charge-transfer excitations as determined by the Peach-Benfield-Helgaker-Tozer Λ criterion and by comparison with multi-reference perturbation theory results. While we confirm that most functionals cannot render the complex photobehavior of the retinal PSB, do we also observe that LC-BLYP gives the best description of the initial part of the photoreaction.« less

The Argus(®) II Retinal Prosthesis System.

PubMed

Luo, Yvonne Hsu-Lin; da Cruz, Lyndon

2016-01-01

The Argus(®) II Retinal Prosthesis System (Second Sight Medical Products) is the first prosthetic vision device to obtain regulatory approval in both Europe and the USA. As such it has entered the commercial market as a treatment for patients with profound vision loss from end-stage outer retinal disease, predominantly retinitis pigmentosa. To date, over 100 devices have been implanted worldwide, representing the largest group of patients currently treated with visual prostheses. The system works by direct stimulation of the relatively preserved inner retina via epiretinal microelectrodes, thereby replacing the function of the degenerated photoreceptors. Visual information from a glasses-mounted video camera is converted to a pixelated image by an external processor, before being transmitted to the microelectrode array at the macula. Elicited retinal responses are then relayed via the normal optic nerve to the cortex for interpretation. We reviewed the animal and human studies that led to the development of the Argus(®) II device. A sufficiently robust safety profile was demonstrated in the phase I/II clinical trial of 30 patients. Improvement of function in terms of orientation and mobility, target localisation, shape and object recognition, and reading of letters and short unrehearsed words have also been shown. There remains a wide variability in the functional outcomes amongst the patients and the factors contributing to these performance differences are still unclear. Future developments in terms of both software and hardware aimed at improving visual function have been proposed. Further experience in clinical outcomes is being acquired due to increasing implantation. Copyright © 2015. Published by Elsevier Ltd.

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach

PubMed Central

Petersen-Jones, Simon M.; Occelli, Laurence M.; Winkler, Paige A.; Lee, Winston; Sparrow, Janet R.; Tsukikawa, Mai; Boye, Sanford L.; Chiodo, Vince; Capasso, Jenina E.; Becirovic, Elvir; Schön, Christian; Seeliger, Mathias W.; Levin, Alex V.; Hauswirth, William W.

2017-01-01

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials. PMID:29202463

Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma.

PubMed

Mead, Ben; Hill, Lisa J; Blanch, Richard J; Ward, Kelly; Logan, Ann; Berry, Martin; Leadbeater, Wendy; Scheven, Ben A

2016-04-01

Glaucoma is a leading cause of irreversible blindness involving loss of retinal ganglion cells (RGC). Mesenchymal stromal cells (MSC) have shown promise as a paracrine-mediated therapy for compromised neurons. It is, however, unknown whether dental pulp stem cells (DPSC) are effective as a cellular therapy in glaucoma and how their hypothesized influence compares with other more widely researched MSC sources. The present study aimed to compare the efficacy of adipose-derived stem cells, bone marrow-derived MSC (BMSC) and DPSC in preventing the loss of RGC and visual function when transplanted into the vitreous of glaucomatous rodent eyes. Thirty-five days after raised intraocular pressure (IOP) and intravitreal stem cell transplantation, Brn3a(+) RGC numbers, retinal nerve fibre layer thickness (RNFL) and RGC function were evaluated by immunohistochemistry, optical coherence tomography and electroretinography, respectively. Control glaucomatous eyes that were sham-treated with heat-killed DPSC had a significant loss of RGC numbers, RNFL thickness and function compared with intact eyes. BMSC and, to a greater extent, DPSC provided significant protection from RGC loss and RNFL thinning and preserved RGC function. The study supports the use of DPSC as a neuroprotective cellular therapy in retinal degenerative disease such as glaucoma. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Anatomical and functional outcomes of retinectomies in retinal detachments complicated by proliferative vitreoretinopathy.

PubMed

Adhi, Mohammad Idrees; Siyal, Nisar; Aziz, Sumbul

2017-01-01

To study anatomical and functional outcomes of retinectomies in rhegmatogenous retinal detachments complicated by proliferative vitreoretinopathy. This is a retrospective interventional consecutive case series of eyes with rhegmatogenous retinal detachments complicated by advanced proliferative vitreoretinopathy and managed by relaxing retinectomy over a period of seventeen years. Three-port pars plana vitrectomy included core vitrectomy and removal of all epi-retinal membranes. On failure to flatten, retina was cut and excised. Basal vitrectomy and removal of anterior flap of retina then followed. Silicone oil was used as temponade in majority of cases. The dependent variables were anatomical and functional outcomes. The statistical analysis was performed on SPSS 21. Series included 370 eyes of 337 patients. Mean follow up was 39 months. Scleral explant was used in 90(24.39%) cases. Two hundred and nine (56.49%) eyes were operated with trans conjunctival sutureless vitrectomy technique. Procedure was bilateral in 33 patients (09.79%). Retina attached in 311(84.05%) eyes after initial surgery. Final re-attachment after one or more surgeries was achieved in 344(92.97%) eyes. Two hundred and eleven (57.02%) cases achieved visual acuity of 6/60 or better. Relaxing retinectomies have good and encouraging anatomical and functional outcomes. This surgery can be effectively carried out with trans conjunctival sutureless vitrectomy technique.

Pattern of retinal morphological and functional decay in a light-inducible, rhodopsin mutant mouse.

PubMed

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.

Functional Specifications to an Automated Retinal Scanner for Use in Plotting the Vascular Map

DTIC Science & Technology

1988-12-01

available an aid in the early detection and continuing treatment of diabetes . Therefore, it is the distinct wish of the author that this system provide some...choroid, it may be possible to detect diabetes earlier and stem the tide of retinopathy in those patients so afflicted. Additionally, retinal...Subject Terms (continue on reverse i necessary and identify t block number) Retinal Imaging, Automation, Infrared, Diabetic Retinopathy , Field I Group I

Effects of high-level pulse train stimulation on retinal function.

PubMed

Cohen, Ethan D

2009-06-01

We examined how stimulation of the local retina by high-level current pulse trains affected the light-evoked responses of the retinal ganglion cells. The spikes of retinal ganglion cell axons were recorded extracellularly using an in vitro eyecup preparation of the rabbit retina. Epiretinal electrical stimulation was delivered via a 500 microm inner diameter saline-filled, transparent tube positioned over the retinal surface forming the receptive field center. Spot stimuli were presented periodically to the receptive field center during the experiment. Trains of biphasic 1 ms current pulses were delivered to the retina at 50 Hz for 1 min. Pulse train charge densities of 1.3-442 microC/cm(2)/phase were examined. After pulse train stimulation with currents >or=300 microA (133 microC/cm(2)/phase), the ganglion cell's ability to respond to light was depressed and a significant time was required for recovery of the light-evoked response. During train stimulation, the ganglion cell's ability to spike following each current pulse fatigued. The current levels evoking train-evoked depression were suprathreshold to those evoking action potentials. Train-evoked depression was stronger touching the retinal surface, and in some cases impaired ganglion cell function for up to 30 min. This overstimulation could cause a transient refractory period for electrically stimulated perception in the retinal region below the electrode.

Live-cell imaging: new avenues to investigate retinal regeneration

PubMed Central

Lahne, Manuela; Hyde, David R.

2017-01-01

Sensing and responding to our environment requires functional neurons that act in concert. Neuronal cell loss resulting from degenerative diseases cannot be replaced in humans, causing a functional impairment to integrate and/or respond to sensory cues. In contrast, zebrafish (Danio rerio) possess an endogenous capacity to regenerate lost neurons. Here, we will focus on the processes that lead to neuronal regeneration in the zebrafish retina. Dying retinal neurons release a damage signal, tumor necrosis factor α, which induces the resident radial glia, the Müller glia, to reprogram and re-enter the cell cycle. The Müller glia divide asymmetrically to produce a Müller glia that exits the cell cycle and a neuronal progenitor cell. The arising neuronal progenitor cells undergo several rounds of cell divisions before they migrate to the site of damage to differentiate into the neuronal cell types that were lost. Molecular and immunohistochemical studies have predominantly provided insight into the mechanisms that regulate retinal regeneration. However, many processes during retinal regeneration are dynamic and require live-cell imaging to fully discern the underlying mechanisms. Recently, a multiphoton imaging approach of adult zebrafish retinal cultures was developed. We will discuss the use of live-cell imaging, the currently available tools and those that need to be developed to advance our knowledge on major open questions in the field of retinal regeneration. PMID:28966629

Live-cell imaging: new avenues to investigate retinal regeneration.

PubMed

Lahne, Manuela; Hyde, David R

2017-08-01

Sensing and responding to our environment requires functional neurons that act in concert. Neuronal cell loss resulting from degenerative diseases cannot be replaced in humans, causing a functional impairment to integrate and/or respond to sensory cues. In contrast, zebrafish ( Danio rerio ) possess an endogenous capacity to regenerate lost neurons. Here, we will focus on the processes that lead to neuronal regeneration in the zebrafish retina. Dying retinal neurons release a damage signal, tumor necrosis factor α, which induces the resident radial glia, the Müller glia, to reprogram and re-enter the cell cycle. The Müller glia divide asymmetrically to produce a Müller glia that exits the cell cycle and a neuronal progenitor cell. The arising neuronal progenitor cells undergo several rounds of cell divisions before they migrate to the site of damage to differentiate into the neuronal cell types that were lost. Molecular and immunohistochemical studies have predominantly provided insight into the mechanisms that regulate retinal regeneration. However, many processes during retinal regeneration are dynamic and require live-cell imaging to fully discern the underlying mechanisms. Recently, a multiphoton imaging approach of adult zebrafish retinal cultures was developed. We will discuss the use of live-cell imaging, the currently available tools and those that need to be developed to advance our knowledge on major open questions in the field of retinal regeneration.

Spatial resolution, contrast sensitivity, and sensitivity to defocus of chicken retinal ganglion cells in vitro.

PubMed

Diedrich, Erich; Schaeffel, Frank

2009-11-01

The chicken has been extensively studied as an animal model for myopia because its eye growth is tightly controlled by visual experience. It has been found that the retina controls the axial eye growth rates depending on the amount and the sign of defocus imposed in the projected image. Glucagonergic amacrine cells were discovered that appear to encode for the sign of imposed defocus. It is not clear whether the downstream neurons, the retinal ganglion cells, still have access to this information-and whether it ultimately reaches the brain. We have analyzed the spike rates of chicken retinal ganglion cells in vitro using a microelectrode array. For this purpose, we initially defined spatial resolution and contrast sensitivity in vitro. Two classes of chicken retinal ganglions were found, depending on the linearity of their responses with increasing contrast. Responses generally declined with increasing defocus of the visual stimulus. These responses were well predicted by the modulation transfer function for a diffraction-limited defocused optical system, the first Bessel function. Thus, the studied retinal ganglion cells did not distinguish between a loss of contrast at a given spatial frequency due to reduced contrast of the stimulus pattern or because the pattern was presented out of focus. Furthermore, there was no indication that the retinal ganglion cells responded differently to defocus of either sign, at least for the cells that were recorded in this study.

Lens-based wavefront sensorless adaptive optics swept source OCT

NASA Astrophysics Data System (ADS)

Jian, Yifan; Lee, Sujin; Ju, Myeong Jin; Heisler, Morgan; Ding, Weiguang; Zawadzki, Robert J.; Bonora, Stefano; Sarunic, Marinko V.

2016-06-01

Optical coherence tomography (OCT) has revolutionized modern ophthalmology, providing depth resolved images of the retinal layers in a system that is suited to a clinical environment. Although the axial resolution of OCT system, which is a function of the light source bandwidth, is sufficient to resolve retinal features at a micrometer scale, the lateral resolution is dependent on the delivery optics and is limited by ocular aberrations. Through the combination of wavefront sensorless adaptive optics and the use of dual deformable transmissive optical elements, we present a compact lens-based OCT system at an imaging wavelength of 1060 nm for high resolution retinal imaging. We utilized a commercially available variable focal length lens to correct for a wide range of defocus commonly found in patient’s eyes, and a novel multi-actuator adaptive lens for aberration correction to achieve near diffraction limited imaging performance at the retina. With a parallel processing computational platform, high resolution cross-sectional and en face retinal image acquisition and display was performed in real time. In order to demonstrate the system functionality and clinical utility, we present images of the photoreceptor cone mosaic and other retinal layers acquired in vivo from research subjects.

Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa

PubMed Central

Ikeda, Hanako Ohashi; Sasaoka, Norio; Koike, Masaaki; Nakano, Noriko; Muraoka, Yuki; Toda, Yoshinobu; Fuchigami, Tomohiro; Shudo, Toshiyuki; Iwata, Ayana; Hori, Seiji; Yoshimura, Nagahisa; Kakizuka, Akira

2014-01-01

Neuroprotection may prevent or forestall the progression of incurable eye diseases, such as retinitis pigmentosa, one of the major causes of adult blindness. Decreased cellular ATP levels may contribute to the pathology of this eye disease and other neurodegenerative diseases. Here we describe small compounds (Kyoto University Substances, KUSs) that were developed to inhibit the ATPase activity of VCP (valosin-containing protein), the most abundant soluble ATPase in the cell. Surprisingly, KUSs did not significantly impair reported cellular functions of VCP but nonetheless suppressed the VCP-dependent decrease of cellular ATP levels. Moreover, KUSs, as well as exogenous ATP or ATP-producing compounds, e.g. methylpyruvate, suppressed endoplasmic reticulum stress, and demonstrably protected various types of cultured cells from death, including several types of retinal neuronal cells. We then examined their in vivo efficacies in rd10, a mouse model of retinitis pigmentosa. KUSs prevented photoreceptor cell death and preserved visual function. These results reveal an unexpected, crucial role of ATP consumption by VCP in determining cell fate in this pathological context, and point to a promising new neuroprotective strategy for currently incurable retinitis pigmentosa. PMID:25096051

Insulin Sensitivity and Inflammation Mediate the Impact of Fitness on Cerebrovascular Health in Adolescents.

PubMed

Yau, Po Lai; Ross, Naima; Tirsi, Andrew; Arif, Arslan; Ozinci, Zeynep; Convit, Antonio

2017-06-01

To investigate in adolescents the relationships between retinal vessel diameter, physical fitness, insulin sensitivity, and systemic inflammation. We evaluated 157 adolescents, 112 with excessive weight and 45 lean, all without type 2 diabetes mellitus. All received detailed evaluations, including measurements of retinal vessel diameter, insulin sensitivity, levels of inflammation, and physical fitness. Overweight/obese adolescents had significantly narrower retinal arteriolar and wider venular diameters, significantly lower insulin sensitivity, and physical fitness. They also had decreased levels of anti-inflammatory and increased levels of proinflammatory markers as well as an overall higher inflammation balance score. Fitness was associated with larger retinal arteriolar and narrower venular diameters and these relationships were mediated by insulin sensitivity. We demonstrate that inflammation also mediates the relationship between fitness and retinal venular, but not arterial diameter; insulin sensitivity and inflammation balance score jointly mediate this relationship with little overlap in their effects. Increasing fitness and insulin sensitivity and reducing inflammation among adolescents carrying excess weight may improve microvascular integrity. Interventions to improve physical fitness and insulin function and reduce inflammation in adolescents, a group likely to benefit from such interventions, may reduce not only cardiovascular disease in middle age, but also improve cerebrovascular function later in life.

Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina

PubMed Central

Damiani, Devid; Alexander, John J; O'Rourke, Jason R; McManus, Mike; Jadhav, Ashutosh P; Cepko, Constance L; Hauswirth, William W; Harfe, Brian D; Strettoi, Enrica

2009-01-01

MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs and removal of Dicer has been shown to disrupt many developmental processes. In this report, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knockout mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at P16 which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic ERG responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer depleted retinas showed a decrease in several microRNAs. The observation that progressive retinal degeneration occurred upon removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders. PMID:18463241

Low aqueous solubility of 11-cis-retinal limits the rate of pigment formation and dark adaptation in salamander rods.

PubMed

Frederiksen, Rikard; Boyer, Nicholas P; Nickle, Benjamin; Chakrabarti, Kalyan S; Koutalos, Yiannis; Crouch, Rosalie K; Oprian, Daniel; Cornwall, M Carter

2012-06-01

We report experiments designed to test the hypothesis that the aqueous solubility of 11-cis-retinoids plays a significant role in the rate of visual pigment regeneration. Therefore, we have compared the aqueous solubility and the partition coefficients in photoreceptor membranes of native 11-cis-retinal and an analogue retinoid, 11-cis 4-OH retinal, which has a significantly higher solubility in aqueous medium. We have then correlated these parameters with the rates of pigment regeneration and sensitivity recovery that are observed when bleached intact salamander rod photoreceptors are treated with physiological solutions containing these retinoids. We report the following results: (a) 11-cis 4-OH retinal is more soluble in aqueous buffer than 11-cis-retinal. (b) Both 11-cis-retinal and 11-cis 4-OH retinal have extremely high partition coefficients in photoreceptor membranes, though the partition coefficient of 11-cis-retinal is roughly 50-fold greater than that of 11-cis 4-OH retinal. (c) Intact bleached isolated rods treated with solutions containing equimolar amounts of 11-cis-retinal or 11-cis 4-OH retinal form functional visual pigments that promote full recovery of dark current, sensitivity, and response kinetics. However, rods treated with 11-cis 4-OH retinal regenerated on average fivefold faster than rods treated with 11-cis-retinal. (d) Pigment regeneration from recombinant and wild-type opsin in solution is slower when treated with 11-cis 4-OH retinal than with 11-cis-retinal. Based on these observations, we propose a model in which aqueous solubility of cis-retinoids within the photoreceptor cytosol can place a limit on the rate of visual pigment regeneration in vertebrate photoreceptors. We conclude that the cytosolic gap between the plasma membrane and the disk membranes presents a bottleneck for retinoid flux that results in slowed pigment regeneration and dark adaptation in rod photoreceptors.

Lentiviral Expression of Retinal Guanylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness

PubMed Central

Haire, Shannon E; Aleman, Tomas S; Cideciyan, Artur V; Sokal, Izabel; Palczewski, Krzysztof; Jacobson, Samuel G; Semple-Rowland, Susan L

2006-01-01

Background Leber congenital amaurosis (LCA) is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans. Methods and Findings A lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration. Conclusions Blindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness. PMID:16700630

Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis

PubMed Central

Bainbridge, J.W.B.; Mehat, M.S.; Sundaram, V.; Robbie, S.J.; Barker, S.E.; Ripamonti, C.; Georgiadis, A.; Mowat, F.M.; Beattie, S.G.; Gardner, P.J.; Feathers, K.L.; Luong, V.A.; Yzer, S.; Balaggan, K.; Viswanathan, A.; de Ravel, T.J.L.; Casteels, I.; Holder, G.E.; Tyler, N.; Fitzke, F.W.; Weleber, R.G.; Nardini, M.; Moore, A.T.; Thompson, D.A.; Petersen-Jones, S.M.; Michaelides, M.; van den Born, L.I.; Stockman, A.; Smith, A.J.; Rubin, G.; Ali, R.R.

2015-01-01

BACKGROUND Mutations in RPE65 cause Leber’s congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS We performed a phase 1–2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.) PMID:25938638

Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats.

PubMed

Ramirez, Christina J; Minch, Jonathan D; Gay, John M; Lahmers, Sunshine M; Guerra, Dan J; Haldorson, Gary J; Schneider, Terri; Mealey, Katrina L

2011-02-01

Distribution of fluoroquinolones to the retina is normally restricted by ABCG2 at the blood-retinal barrier. As the cat develops a species-specific adverse reaction to photoreactive fluoroquinolones, our goal was to investigate ABCG2 as a candidate gene for fluoroquinolone-induced retinal degeneration and blindness in cats. Feline ABCG2 was sequenced and the consensus amino acid sequence was compared with that of 10 other mammalian species. Expression of ABCG2 in feline retina was assessed by immunoblot. cDNA constructs for feline and human ABCG2 were constructed in a pcDNA3 expression vector and expressed in HEK-293 cells, and ABCG2 expression was analyzed by western blot and immunofluorescence. Mitoxantrone and BODIPY-prazosin efflux measured by flow cytometry and a phototoxicity assay were used to assess feline and human ABCG2 function. Four feline-specific (compared with 10 other mammalian species) amino acid changes in conserved regions of ABCG2 were identified. Expression of ABCG2 on plasma membranes was confirmed in feline retina and in cells transfected with human and feline ABCG2, although some intracellular expression of feline ABCG2 was detected by immunofluorescence. Function of feline ABCG2, compared with human ABCG2, was found to be deficient as determined by flow cytometric measurement of mitoxantrone and BODIPY-prazosin efflux and enrofloxacin-induced phototoxicity assays. Feline-specific amino acid changes in ABCG2 cause a functional defect of the transport protein in cats. This functional defect may be owing, in part, to defective cellular localization of feline ABCG2. Regardless, dysfunction of ABCG2 at the blood-retinal barrier likely results in accumulation of photoreactive fluoroquinolones in feline retina. Exposure of the retina to light would then generate reactive oxygen species that would cause the characteristic retinal degeneration and blindness documented in some cats receiving high doses of some fluoroquinolones. Pharmacological inhibition of ABCG2 in other species might result in retinal damage if fluoroquinolones are concurrently administered.

Retinal microvascular network alterations: potential biomarkers of cerebrovascular and neural diseases.

PubMed

Cabrera DeBuc, Delia; Somfai, Gabor Mark; Koller, Akos

2017-02-01

Increasing evidence suggests that the conditions of retinal microvessels are indicators to a variety of cerebrovascular, neurodegenerative, psychiatric, and developmental diseases. Thus noninvasive visualization of the human retinal microcirculation offers an exceptional opportunity for the investigation of not only the retinal but also cerebral microvasculature. In this review, we show how the conditions of the retinal microvessels could be used to assess the conditions of brain microvessels because the microvascular network of the retina and brain share, in many aspects, standard features in development, morphology, function, and pathophysiology. Recent techniques and imaging modalities, such as optical coherence tomography (OCT), allow more precise visualization of various layers of the retina and its microcirculation, providing a "microscope" to brain microvessels. We also review the potential role of retinal microvessels in the risk identification of cerebrovascular and neurodegenerative diseases. The association between vision problems and cerebrovascular and neurodegenerative diseases, as well as the possible role of retinal microvascular imaging biomarkers in cerebrovascular and neurodegenerative screening, their potentials, and limitations, are also discussed. Copyright © 2017 the American Physiological Society.

Olfactory Dysfunction in Patients With CNGB1-Associated Retinitis Pigmentosa.

PubMed

Charbel Issa, Peter; Reuter, Peggy; Kühlewein, Laura; Birtel, Johannes; Gliem, Martin; Tropitzsch, Anke; Whitcroft, Katherine L; Bolz, Hanno J; Ishihara, Kenji; MacLaren, Robert E; Downes, Susan M; Oishi, Akio; Zrenner, Eberhart; Kohl, Susanne; Hummel, Thomas

2018-05-24

Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1. Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.

New Wrinkles in Retinal Densitometry

PubMed Central

Masella, Benjamin D.; Hunter, Jennifer J.; Williams, David R.

2014-01-01

Purpose. Retinal densitometry provides objective information about retinal function. But, a number of factors, including retinal reflectance changes that are not directly related to photopigment depletion, complicate its interpretation. We explore these factors and suggest a method to minimize their impact. Methods. An adaptive optics scanning light ophthalmoscope (AOSLO) was used to measure changes in photoreceptor reflectance in monkeys before and after photopigment bleaching with 514-nm light. Reflectance measurements at 514 nm and 794 nm were recorded simultaneously. Several methods of normalization to extract the apparent optical density of the photopigment were compared. Results. We identified stimulus-related fluctuations in 794-nm reflectance that are not associated with photopigment absorptance and occur in both rods and cones. These changes had a magnitude approaching those associated directly with pigment depletion, precluding the use of infrared reflectance for normalization. We used a spatial normalization method instead, which avoided the fluctuations in the near infrared, as well as a confocal AOSLO designed to minimize light from layers other than the receptors. However, these methods produced a surprisingly low estimate of the apparent rhodopsin density (animal 1: 0.073 ± 0.006, animal 2: 0.032 ± 0.003). Conclusions. These results confirm earlier observations that changes in photopigment absorption are not the only source of retinal reflectance change during dark adaptation. It appears that the stray light that has historically reduced the apparent density of cone photopigment in retinal densitometry arises predominantly from layers near the photoreceptors themselves. Despite these complications, this method provides a valuable, objective measure of retinal function. PMID:25316726

Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus.

PubMed

Shan, Kun; Liu, Chang; Liu, Bai-Hui; Chen, Xue; Dong, Rui; Liu, Xin; Zhang, Yang-Yang; Liu, Ban; Zhang, Shu-Jie; Wang, Jia-Jian; Zhang, Sheng-Hai; Wu, Ji-Hong; Zhao, Chen; Yan, Biao

2017-10-24

The vascular complications of diabetes mellitus are the major causes of morbidity and mortality among people with diabetes. Circular RNAs are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. In this study, we investigated the role of circular RNA in retinal vascular dysfunction induced by diabetes mellitus. Quantitative polymerase chain reactions, Sanger sequencing, and Northern blots were conducted to detect circular HIPK3 (circHIPK3) expression pattern on diabetes mellitus-related stresses. MTT (3-[4,5-dimethythiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assays, EdU (5-ethynyl-2'-deoxyuridine) incorporation assays, Transwell migration assays, and Matrigel assays were conducted to detect the role of circHIPK3 in retinal endothelial cell function in vitro. Retinal trypsin digestion, vascular permeability assays, and ELISA assays were conducted to detect the role of circHIPK3 in retinal vascular dysfunction in vivo. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were conducted to reveal the mechanism of circHIPK3-mediated retinal vascular dysfunction. circHIPK3 expression was significantly upregulated in diabetic retinas and retinal endothelial cells following stressors related to diabetes mellitus. circHIPK3 silencing or overexpressing circHIPK3 changed retinal endothelial cell viability, proliferation, migration, and tube formation in vitro. circHIPK3 silencing in vivo alleviated retinal vascular dysfunction, as shown by decreased retinal acellular capillaries, vascular leakage, and inflammation. circHIPK3 acted as an endogenous miR-30a-3p sponge to sequester and inhibit miR-30a-3p activity, which led to increased vascular endothelial growth factor-C, FZD4, and WNT2 expression. Ectopic expression of miR-30a-3p mimicked the effect of circHIPK3 silencing on vascular endothelial phenotypes in vivo and in vitro. The circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking miR-30a function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that circular RNA is a potential target to control diabetic proliferative retinopathy. © 2017 American Heart Association, Inc.

Alteration of rod and cone function in children with Usher syndrome.

PubMed

Malm, Eva; Ponjavic, Vesna; Möller, Claes; Kimberling, William J; Stone, Edwin S; Andréasson, Sten

2011-01-01

To evaluate the retinal function, with emphasis on phenotype and rate of progression, in infants and children with different genotypes of Usher syndrome. Fourteen children (2-10 years of age) with retinitis pigmentosa and hearing impairment were examined with full-field electroretinography (ERG) during general anesthesia, ophthalmologic examination, and genetic analysis. Five children were repeatedly examined (follow-up 5-10 years) with full-field ERG under local anesthesia and in 2 children multifocal ERG and optical coherence tomography (OCT) were performed. These results were compared to full-field ERG data from 58 children without retinal eye disorder. Six children were genotyped as Usher 1B, 2A, and 3A. Full-field ERG demonstrated early alterations corresponding to a rod-cone dystrophy in all children. A remaining rod function could be verified in the majority of the children up to 4 years of age. After 4 years of age, there was a further deterioration of the rod function; the progress was severe in Usher types 1 and 2 and moderate in Usher type 3. In all children, the cone function was moderately reduced, in a few cases almost normal. The results from the 58 children without retinal disorder confirm that full-field ERG during general anesthesia is reliable. Multifocal ERG confirmed a preserved central cone function and in OCT there were discrete structural alterations. Full-field ERG during general anesthesia in children with Usher syndrome demonstrates variable phenotypes and different degrees in rate of progression during childhood.

Artemisinin Protects Retinal Neuronal Cells against Oxidative Stress and Restores Rat Retinal Physiological Function from Light Exposed Damage.

PubMed

Yan, Fengxia; Wang, Haitao; Gao, Yang; Xu, Jiangping; Zheng, Wenhua

2017-08-16

Oxidative stress plays a key role in the pathogenesis of age-related macular degeneration (AMD), a leading cause of severe visual loss and blindness in the aging population which lacks any effective treatments currently. In this study, artemisinin, a well-known antimalarial drug was found to suppress hydrogen peroxide (H 2 O 2 )-induced cell death in retinal neuronal RGC-5 cells. Artemisinin, in the therapeutically relevant dosage, concentration-dependently attenuated the accumulation of intracellular reactive oxygen species (ROS), increased mitochondrial membrane potential and decreased cell apoptosis in RGC-5 cells induced by H 2 O 2 . Western blot analysis showed that artemisinin upregulated the phosphorylation of p38 and extracellular signal-regulated kinases1/2 (ERK1/2) and reversed the inhibitory effect of H 2 O 2 on the phosphorylation of these two kinases. Moreover, protective effect of artemisinin was blocked by the p38 kinase inhibitor PD169316 or ERK1/2 kinase pathway inhibitor PD98059, respectively. In contrast, c-Jun N-terminal kinase inhibitor and rapamycin had no effect in the protective effect of artemisinin. Taken together, these results demonstrated that artemisinin promoted the survival of RGC-5 cells from H 2 O 2 toxicity via the activation of the p38 and ERK1/2 pathways. Interestingly, intravitreous injection of artimisinin, concentration-dependently reversed light exposed-damage (a dry AMD animal model) of rat retinal physiological function detected by flash electroretinogram. These results indicate that artemisinin can protect retinal neuronal functions from H 2 O 2 -induced damage in vitro and in vivo and suggest the potential application of artemisinin as a new drug in the treatment of retinal disorders like AMD.

Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis.

PubMed

Lee, Heon-Woo; Chong, Diana C; Ola, Roxana; Dunworth, William P; Meadows, Stryder; Ka, Jun; Kaartinen, Vesa M; Qyang, Yibing; Cleaver, Ondine; Bautch, Victoria L; Eichmann, Anne; Jin, Suk-Won

2017-04-01

Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2 , and Alk3 in mouse retinal vessels. Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of Bmpr2 . Postnatal deletion of Bmpr2 in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of either Alk2 / acvr1 or Alk3 / Bmpr1a caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels. Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels. © 2017 The Authors.

Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein Induced Retinal Angiogenesis

PubMed Central

Lee, Heon-Woo; Chong, Diana C.; Ola, Roxana; Dunworth, William P.; Meadows, Stryder; Ka, Jun; Kaartinen, Vesa M.; Qyang, Yibing; Cleaver, Ondine; Bautch, Victoria L.; Eichmann, Anne; Jin, Suk-Won

2017-01-01

Objective Increasing evidence suggests that Bone Morphogenetic Protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early post-natal angiogenesis by analysis of inducible, endothelial specific deletion of the BMP receptor components Bmpr2, Alk1, Alk2 and Alk3 in mouse retinal vessels. Approach and Results Expression analysis of several BMP ligands showed that pro-angiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of BMP Type 2 receptor (Bmpr2). Postnatal deletion of Bmpr2 in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branchpoints behind the front, leading to attenuated radial expansion. To identify critical BMPR1s associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of three BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for pro-angiogenic BMP signaling in retinal vessels. Conclusions Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential pro-angiogenic cue for retinal vessels. PMID:28232325

Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

PubMed

Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

2016-03-15

Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Diabetes accelerates retinal ganglion cell dysfunction in mice lacking sigma receptor 1.

PubMed

Ha, Yonju; Saul, Alan; Tawfik, Amany; Zorrilla, Eric P; Ganapathy, Vadivel; Smith, Sylvia B

2012-01-01

Sigma receptor 1 (σR1) is a non-opioid transmembrane protein that may act as a molecular chaperone at the endoplasmic reticulum-mitochondrial membrane. Ligands for σR1, such as (+)-pentazocine [(+)-PTZ], confer marked retinal neuroprotection in vivo and in vitro. Recently we analyzed the retinal phenotype of mice lacking σR1 (σR1 KO) and observed normal retinal morphology and function in young mice (5-30 weeks) but diminished negative scotopic threshold responses (nSTRs), retinal ganglion cell (RGC) loss, and disruption of optic nerve axons consistent with inner retinal dysfunction by 1 year. These data led us to test the hypothesis that σR1 may be critical in forestalling chronic retinal stress; diabetes was used as the model of chronic stress. To determine whether σR1 is required for (+)-PTZ neuroprotective effects, primary RGCs isolated from wild-type (WT) and σR1 KO mice were exposed to xanthine-xanthine oxidase (10 µM:2 mU/ml) to induce oxidative stress in the presence or absence of (+)-PTZ. Cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. To assess effects of chronic stress on RGC function, diabetes was induced in 3-week C57BL/6 (WT) and σR1 KO mice, using streptozotocin to yield four groups: WT nondiabetic (WT non-DB), WT diabetic (WT-DB), σR1 KO non-DB, and σR1 KO-DB. After 12 weeks of diabetes, when mice were 15-weeks old, intraocular pressure (IOP) was recorded, electrophysiologic testing was performed (including detection of nSTRs), and the number of RGCs was counted in retinal histological sections. In vitro studies showed that (+)-PTZ could not prevent oxidative stress-induced death of RGCs harvested from σR1 KO mice but afforded robust protection against death of RGCs harvested from WT mice. In the studies of chronic stress induced by diabetes, the IOP measured in the four mouse groups was within the normal range; however, there was a significant increase in the IOP of σR1 KO-DB mice (16 ± 0.5 mmHg) compared to the other groups tested (σR1 KO non-DB, WT non-DB, WT-DB: ~12 ± 0.6 mmHg). Regarding electrophysiologic testing, the nSTRs of σR1 KO non-DB mice were similar to WT non-DB mice at 15 weeks; however, they were significantly lower in σR1 KO-DB mice (5 ± 1 µV) compared to the other groups, including, notably, σR1 KO-nonDB (12±2 µV). As expected, the number of RGCs in σR1 KO non-DB mice was similar to WT non-DB mice at 15 weeks, but under chronic stress of diabetes there were fewer RGCs in retinas of σR1 KO-DB mice. This is the first report showing unequivocally that the neuroprotective effects of (+)-PTZ require σR1. σR1 KO mice show normal retinal structure and function at young ages; however, when subjected to the chronic stress of diabetes, there is an acceleration of retinal functional deficits in σR1 KO mice such that ganglion cell dysfunction is observed at a much earlier age than nondiabetic σR1 KO mice. The data support the hypothesis that σR1 plays a key role in modulating retinal stress and may be an important target for retinal disease.

The Retinitis Pigmentosa Student: Selected Aspects.

ERIC Educational Resources Information Center

Sullivan, Franklin N.

1984-01-01

The characteristic features of RP (retinitis pigmentosa-an untreatable conditions usually resulting in night blindness) are discussed and functioning considerations in the classroom (including the use of protective devices and mobility aids) are noted. Classroom modifications such as darklined paper and black pens are suggested. (CL)

Advancing therapeutic strategies for inherited retinal degeneration: recommendations from the Monaciano Symposium.

PubMed

Thompson, Debra A; Ali, Robin R; Banin, Eyal; Branham, Kari E; Flannery, John G; Gamm, David M; Hauswirth, William W; Heckenlively, John R; Iannaccone, Alessandro; Jayasundera, K Thiran; Khan, Naheed W; Molday, Robert S; Pennesi, Mark E; Reh, Thomas A; Weleber, Richard G; Zacks, David N

2015-02-09

Although rare in the general population, retinal dystrophies occupy a central position in current efforts to develop innovative therapies for blinding diseases. This status derives, in part, from the unique biology, accessibility, and function of the retina, as well as from the synergy between molecular discoveries and transformative advances in functional assessment and retinal imaging. The combination of these factors has fueled remarkable progress in the field, while at the same time creating complex challenges for organizing collective efforts aimed at advancing translational research. The present position paper outlines recent progress in gene therapy and cell therapy for this group of disorders, and presents a set of recommendations for addressing the challenges remaining for the coming decade. It is hoped that the formulation of these recommendations will stimulate discussions among researchers, funding agencies, industry, and policy makers that will accelerate the development of safe and effective treatments for retinal dystrophies and related diseases. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium

PubMed Central

Monaghan, Kevin; McNaughten, Jennifer; McGahon, Mary K.; Kelly, Catriona; Kyle, Daniel; Yong, Phaik Har

2015-01-01

Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4α-phorbol 12,13-didecanoate (4-αPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-αPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4αPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months’ streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the molecular and functional expression of TRPV4 channels in retinal microvascular endothelial cells. These changes may contribute to diabetes induced endothelial dysfunction and retinopathy. PMID:26047504

[Posterior vitrectomy with gas endotamponade and retinal laser therapy in treatment of patients with macular complications of the optic disc pit].

PubMed

Cywiński, Adam; Kałużny, Jakub; Ferda, Daniela; Piwońska-Lobermajer, Anna

2015-01-01

Retrospective evaluation of functional and anatomical treatment outcomes in patients with macular cornplications of optic disc pit. 9 patients (eyes) underwent central posterior vitrectomy in conjunction with posterior vitreous detachment, retinal laser therapy to the optic disc pit area and endotamponade with expansile gas. It was followed by the patient's forced positioning (recommended for a few days especially at night), which ended the treatment protocol. Improved anatomical relationships, accompanied by functional improvement were achieved in each reported case. The resolution of macular lesions was slow, lasting even for several months. Too long delay in performing the surgery (over 5 months since the onset of visual impairment) was associated with the development of retinal complications, mainly macular hole formation, most likely caused by the long-term ischemia. The central posterior vitrectomy combined with posterior vitreous detachment, laser therapy, andd expansile gas tamponade offers good outcomes in patients with retinal complications of optic disc pit. Surgery performed shortly after the onset of visual dysfunction gives the best functional outcomes. Restoration of normal anatomical relationships is a long-term process. In some cases, though, these abnormalities may not resolve completely.

Assessment of Central Visual Function in Patients with Retinitis Pigmentosa.

PubMed

Fujiwara, Kohta; Ikeda, Yasuhiro; Murakami, Yusuke; Tachibana, Takashi; Funatsu, Jun; Koyanagi, Yoshito; Nakatake, Shunji; Yoshida, Noriko; Nakao, Shintaro; Hisatomi, Toshio; Yoshida, Shigeo; Yoshitomi, Takeshi; Ishibashi, Tatsuro; Sonoda, Koh-Hei

2018-05-23

In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.

Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiu, Gui-Zhen; Tian, Wei; Fu, Hai-Tao

Microvascular dysfunction is an important characteristic of diabetic retinopathy. Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes. In this study, we investigated the role of lncRNA-MEG3 in diabetes-related microvascular dysfunction. We show that MEG3 expression level is significantly down-regulated in the retinas of STZ-induced diabetic mice, and endothelial cells upon high glucose and oxidative stress. MEG3 knockdown aggravates retinal vessel dysfunction in vivo, as shown by serious capillary degeneration, and increased microvascular leakage and inflammation. MEG3 knockdown also regulates retinal endothelial cell proliferation, migration, and tube formation in vitro. The role of MEG3 in endothelial cell function is mainlymore » mediated by the activation of PI3k/Akt signaling. MEG3 up-regulation may serve as a therapeutic strategy for treating diabetes-related microvascular complications. - Highlights: • LncRNA-MEG3 level is down-regulated upon diabetic stress. • MEG3 knockdown aggravates retinal vascular dysfunction in vivo. • MEG3 regulates retinal endothelial cell function in vitro. • MEG3 regulates endothelial cell function through PI3k/Akt signaling.« less

The assessment of macular electrophysiology and macular morphology in patients with vitiligo.

PubMed

Aydin, Rukiye; Ozsutcu, Mustafa; Erdur, Sevil Karaman; Dikkaya, Funda; Balevi, Ali; Ozbek, Merve; Senturk, Fevzi

2018-02-01

We aimed to analyze the electrophysiologic function and morphology of macula in vitiligo patients. Seventeen patients with vitiligo and 11 healthy subjects were studied. All participants underwent multifocal electroretinography (mfERG) and spectral domain optical coherence tomography (SD-OCT) evaluations. The mfERG (P1 mfERG responses central and peripheral) and retinal layer segmentation parameters (nine ETDRS subfields) were compared in vitiligo and control groups. The mean P1 response amplitudes were significantly decreased in central and peripheral rings of the fovea in patients with vitiligo compared with controls (p = 0.002 and p = 0.006, respectively). There was a tendency toward a prolonged mean implicit time for both central and peripheral in patients with vitiligo compared to controls, however, with no statistical significance (p = 0.453 and p = 0.05, respectively). There was no statistically significant difference in all retinal layers thickness between two groups. In patients with vitiligo, while photoreceptor segment preserved in SD-OCT, mfERG reduced showing potential decline in central retinal function. This study showed a potential decline in central retinal function in patients with vitiligo even if they have normal fundus appearance and SD-OCT findings.

The evolution of the centrifugal visual system of vertebrates. A cladistic analysis and new hypotheses.

PubMed

Repérant, J; Médina, M; Ward, R; Miceli, D; Kenigfest, N B; Rio, J P; Vesselkin, N P

2007-01-01

In a recent review of the available data concerning the centrifugal visual system (CVS) of vertebrates [Repérant, J., Ward, R., Miceli, D., Rio, J.P., Médina, M., Kenigfest, N.B., Vesselkin, N.P., 2006. The centrifugal visual system of vertebrates: a comparative analysis of its functional anatomical organization, Brain Res. Rev. 52, 1-57], we have shown that this feature of the visual system is not a particularity of birds, but is a permanent component of the vertebrate central nervous system which nevertheless shows considerable morphological and functional variation from one taxonomic group to another. Given these findings, the primary objective of the present article is an attempt to specify the evolutionary significance of this phylogenetic diversity. We begin by drawing up an inventory of this variation under several headings: the intracerebral location of the retinopetal neurons; the mode of intra-retinal arborizations of the centrifugal fibres and the nature of their targets; their neurochemical properties; and the afferent supplies of these neurons. We subsequently discuss these variations, particularly that of the intracerebral location of the retinopetal neurons during development and in adult forms, using the neuromeric terminology and in the framework of cladistic analysis, and seek to interpret them in a phylogenetic context. From this analysis, it becomes evident that the CVS is not a homogeneous entity formed by neurons with a common embryological origin, but rather a collection of at least eight distinct subsystems arising in very different regions of the neuraxis. These are the olfacto-retinal, dorsal thalamo-retinal, ventral thalamo-retinal, pretecto-retinal, tecto-retinal, tegmento-mesencephalo-retinal, dorsal isthmo-retinal and ventral isthmo-retinal systems. The olfacto-retinal system, which is probably absent in Agnatha, appears to be a pleisiomorphic characteristic of all Gnathostomata, while on the other hand the tegmento-mesencephalo-retinal system appears to be present only in Agnatha. Our cladistic analysis also shows that the remaining six subsystems are polyphyletic in origin and have arisen independently on several occasions in different radiations of Gnathostoma. In conclusion, we suggest that, in the course of the palaeontological history of vertebrates, these different retinopetal pathways have been selected on the basis of widely different environmental pressures which remain to be identified.

Electronic approaches to restoration of sight

NASA Astrophysics Data System (ADS)

Goetz, G. A.; Palanker, D. V.

2016-09-01

Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field.

Electronic Approaches to Restoration of Sight

PubMed Central

Goetz, G A; Palanker, D V

2016-01-01

Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex-vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field. PMID:27502748

Automated detection of retinal layers from OCT spectral-domain images of healthy eyes

NASA Astrophysics Data System (ADS)

Giovinco, Gaspare; Savastano, Maria Cristina; Ventre, Salvatore; Tamburrino, Antonello

2015-12-01

Optical coherence tomography (OCT) has become one of the most relevant diagnostic tools for retinal diseases. Besides being a non-invasive technique, one distinguished feature is its unique capability of providing (in vivo) cross-sectional view of the retina. Specifically, OCT images show the retinal layers. From the clinical point of view, the identification of the retinal layers opens new perspectives to study the correlation between morphological and functional aspects of the retinal tissue. The main contribution of this paper is a new method/algorithm for the automated segmentation of cross-sectional images of the retina of healthy eyes, obtained by means of spectral-domain optical coherence tomography (SD-OCT). Specifically, the proposed segmentation algorithm provides the automated detection of different retinal layers. Tests on experimental SD-OCT scans performed by three different instruments/manufacturers have been successfully carried out and compared to a manual segmentation made by an independent ophthalmologist, showing the generality and the effectiveness of the proposed method.

Bull's eye and pigment maculopathy are further retinal manifestations of an abnormal Bruch's membrane in Alport syndrome.

PubMed

Savige, Judy; Wang, Yanyan; Crawford, Andrew; Smith, James; Symons, Andrew; Mack, Heather; Nicholls, Kathy; Wilson, Diane; Colville, Deb

2017-01-01

The retinal features of Alport syndrome include a central and peripheral fleck retinopathy, temporal retinal thinning, and a macular hole. Here we describe further retinal abnormalities. We identified a case of bull's eye maculopathy 20 years previously in a 68-year-old female, and reviewed archived retinal images from our cohort of X-linked (28 males, 28 females) or autosomal recessive (n = 13) Alport syndrome. All individuals had Alport syndrome confirmed on genetic testing or renal biopsy, were examined by an ophthalmologist, and underwent retinal imaging (KOWA non-mydriatic camera, Japan). The index case had the p.Q379X variant in COL4A5 and currently had renal impairment, (eGFR = 45 ml/min/1.73 m 2 ), bilateral hearing loss, and central and peripheral retinopathies. Her maculopathy had deteriorated, and she had a bilateral central visual field loss. Optical coherence tomography (Heidelberg Spectralis) demonstrated a disrupted retinal pigment epithelium and retinal atrophy. We identified a further early bull's eye maculopathy (1/69, 1.4%) from a female with autosomal recessive disease and normal renal function. We also noted a subtle pigment maculopathy associated with an abnormal retinal pigment epithelium in 27 (27/69, 39%) subjects with Alport syndrome, in both males (8/28, 29%) and females (13/28, 46%) with X-linked disease, and in autosomal recessive disease (6/13, 38%). The bull's eye and pigment maculopathies in Alport syndrome result mainly from the damaged Bruch's membrane and overlying retinal pigment epithelium. Bull's eye maculopathy affects vision and patients should undergo regular monitoring for retinal complications.

Biochemical, histological and behavioural aspects of visual function during early development of rainbow trout

USGS Publications Warehouse

Carvalho, Paulo S. M.; Noltie, Douglas B.; Tillitt, D.E.

2004-01-01

Retinal structure and concentration of retinoids involved in phototransduction changed during early development of rainbow trout Oncorhynchus mykiss, correlating with improvements in visual function. A test chamber was used to evaluate the presence of optokinetic or optomotor responses and to assess the functionality of the integrated cellular, physiological and biochemical components of the visual system. The results indicated that in rainbow trout optomotor responses start at 10 days post-hatch, and demonstrated for the first time that increases in acuity, sensitivity to low light as well as in motion detection abilities occur from this stage until exogenous feeding starts. The structure of retinal cells such as cone ellipsoids increased in length as photopic visual acuity improved, and rod densities increased concurrently with improvements in scotopic thresholds (2.2 log10 units). An increase in the concentrations of the chromophore all-trans-retinal correlated with improvements of all behavioural measures of visual function during the same developmental phase. ?? 2004 The Fisheries Society of the British Isles.

A fully organic retinal prosthesis restores vision in a rat model of degenerative blindness

NASA Astrophysics Data System (ADS)

Maya-Vetencourt, José Fernando; Ghezzi, Diego; Antognazza, Maria Rosa; Colombo, Elisabetta; Mete, Maurizio; Feyen, Paul; Desii, Andrea; Buschiazzo, Ambra; di Paolo, Mattia; di Marco, Stefano; Ticconi, Flavia; Emionite, Laura; Shmal, Dmytro; Marini, Cecilia; Donelli, Ilaria; Freddi, Giuliano; Maccarone, Rita; Bisti, Silvia; Sambuceti, Gianmario; Pertile, Grazia; Lanzani, Guglielmo; Benfenati, Fabio

2017-06-01

The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of retinitis pigmentosa. Electrophysiological and behavioural analyses reveal a prosthesis-dependent recovery of light sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.

X‐linked retinoschisis: an update

PubMed Central

Sikkink, Stephen K; Biswas, Susmito; Parry, Neil R A; Stanga, Paulo E; Trump, Dorothy

2007-01-01

X‐linked retinoschisis is the leading cause of macular degeneration in males and leads to splitting within the inner retinal layers leading to visual deterioration. Many missense and protein truncating mutations have now been identified in the causative retinoschisis gene (RS1) which encodes a 224 amino acid secreting retinal protein, retinoschisin. Retinoschisin octamerises is implicated in cell–cell interactions and cell adhesion perhaps by interacting with β2 laminin. Mutations cause loss of retinoschisin function by one of the three mechanisms: by interfering with protein secretion, by preventing its octamerisation or by reducing function in the secreted octamerised protein. The development of retinoschisis mouse models have provided a model system that closely resembles the human disease. Recent reports of RS1 gene transfer to these models and the sustained restoration of some retinal function and morphology suggest gene replacement may be a possible future therapy for patients. PMID:17172462

Emergence of binocular functional properties in a monocular neural circuit

PubMed Central

Ramdya, Pavan; Engert, Florian

2010-01-01

Sensory circuits frequently integrate converging inputs while maintaining precise functional relationships between them. For example, in mammals with stereopsis, neurons at the first stages of binocular visual processing show a close alignment of receptive-field properties for each eye. Still, basic questions about the global wiring mechanisms that enable this functional alignment remain unanswered, including whether the addition of a second retinal input to an otherwise monocular neural circuit is sufficient for the emergence of these binocular properties. We addressed this question by inducing a de novo binocular retinal projection to the larval zebrafish optic tectum and examining recipient neuronal populations using in vivo two-photon calcium imaging. Notably, neurons in rewired tecta were predominantly binocular and showed matching direction selectivity for each eye. We found that a model based on local inhibitory circuitry that computes direction selectivity using the topographic structure of both retinal inputs can account for the emergence of this binocular feature. PMID:19160507

A fully organic retinal prosthesis restores vision in a rat model of degenerative blindness

PubMed Central

Antognazza, Maria Rosa; Colombo, Elisabetta; Mete, Maurizio; Feyen, Paul; Desii, Andrea; Buschiazzo, Ambra; Di Paolo, Mattia; Di Marco, Stefano; Ticconi, Flavia; Emionite, Laura; Shmal, Dmytro; Marini, Cecilia; Donelli, Ilaria; Freddi, Giuliano; Maccarone, Rita; Bisti, Silvia; Sambuceti, Gianmario; Pertile, Grazia; Lanzani, Guglielmo; Benfenati, Fabio

2017-01-01

The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of Retinitis pigmentosa. Electrophysiological and behavioral analyses reveal a prosthesis-dependent recovery of light-sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness. PMID:28250420

Tri-functional cannula for retinal endovascular surgery

DOEpatents

Weiss, Jonathan D [Albuquerque, NM

2010-07-27

A tri-functional cannula combines the functions of tissue Plasminogen Activator (tPA) solution delivery, illumination and venous pressure measurement. The cannula utilizes a tapered hollow-core optical fiber having an inlet for tPA solution, an attached fiber optic splitter configured to receive illumination light from an optical source such and a LED. A window in the cannula transmits the light to and from a central retinal vein. The return light is coupled to an optical detector to measure the pressure within the vein and determine whether an occlusion has been removed.

Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

PubMed Central

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

2016-01-01

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+/Δex41mice. 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. PMID:26813606

Wide-field fundus autofluorescence imaging to evaluate retinal function in patients with retinitis pigmentosa.

PubMed

Ogura, Shuntaro; Yasukawa, Tsutomu; Kato, Aki; Usui, Hideaki; Hirano, Yoshio; Yoshida, Munenori; Ogura, Yuichiro

2014-11-01

To study the correlation between the visual fields (VF) and wide-field fundus autofluorescence (FAF) in patients with retinitis pigmentosa (RP). Retrospective, observational, consecutive case series. Twenty-four eyes of 12 patients diagnosed with RP were enrolled. The VFs measured by Goldmann perimetry and wide-field FAF images were compared for each eye. The relationship between the areas of hypoautofluorescence on the wide-field FAF images and scotoma on Goldmann perimetry were evaluated. The VF and FAF images in the central 60 degrees were trimmed and superimposed to calculate the percentage agreement between the hypoautofluorescence and the scotomas and between the isoautofluorescence and hyperautofluorescence and the remaining VFs. The areas of hypoautofluorescence on the FAF images were correlated significantly (R = 0.86, P < .001) with the areas of the VF defects on Goldmann perimetry. The mean percentage agreement between the hypoautofluorescence and the scotomas was 91.0% ± 7.7% and that of the isoautofluorescence and hyperautofluorescence with the remaining VFs was 84.5% ± 7.4%. The areas of geographic hypoautofluorescence with or without hyperautofluorescent bands reflected the VF defects, while nummular or mottled hypoautofluorescence without VF defects was seen in 7 eyes. These results suggested that wide-field FAF imaging is useful to evaluate the remaining retinal function in patients with RP. Abnormal fundus autofluorescence precedes loss of retinal function and is helpful for monitoring disease progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert

Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinalmore » microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.« less

Relationship between Scanning Laser Polarimetry with Enhanced Corneal Compensation and with Variable Corneal Compensation

PubMed Central

Kim, Kyung Hoon; Choi, Jaewan; Lee, Chang Hwan; Cho, Beom-Jin; Kook, Michael S.

2008-01-01

Purpose To evaluate the structure-function relationships between retinal sensitivity measured by Humphrey visual field analyzer (HVFA) and the retinal nerve fiber layer (RNFL) thickness measured by scanning laser polarimetry (SLP) with variable corneal compensation (VCC) and enhanced corneal compensation (ECC) in glaucomatous and healthy eyes. Methods Fifty-three eyes with an atypical birefringence pattern (ABP) based on SLP-VCC (28 glaucomatous eyes and 25 normal healthy eyes) were enrolled in this cross-sectional study. RNFL thickness was measured by both VCC and ECC techniques, and the visual field was examined by HVFA with 24-2 full-threshold program. The relationships between RNFL measurements in superior and inferior sectors and corresponding retinal mean sensitivity were sought globally and regionally with linear regression analysis in each group. Coefficients of the determination were calculated and compared between VCC and ECC techniques. Results In eyes with ABP, R2 values for the association between SLP parameters and retinal sensitivity were 0.06-0.16 with VCC, whereas they were 0.21-0.48 with ECC. The association of RNFL thickness with retinal sensitivity was significantly better with ECC than with VCC in 5 out of 8 regression models between SLP parameters and HVF parameters (P<0.05). Conclusions The strength of the structure-function association was higher with ECC than with VCC in eyes with ABP, which suggests that the ECC algorithm is a better approach for evaluating the structure-function relationship in eyes with ABP. PMID:18323701

Retinotopic Distribution of Structural and Functional Damages following Bright Light Exposure of Juvenile Rats

PubMed Central

Polosa, Anna; Liu, Wenwen; Lachapelle, Pierre

2016-01-01

In the present study, we aimed at better understanding the short (acute) and long term (chronic) degenerative processes characterizing the juvenile rat model of light-induced retinopathy. Electroretinograms, visual evoked potentials (VEP), retinal histology and western blots were obtained from juvenile albino Sprague-Dawley rats at preselected postnatal ages (from P30 to P400) following exposure to 10,000 lux from P14 to P28. Our results show that while immediately following the cessation of exposure, photoreceptor degeneration was concentrated within a well delineated area of the superior retina (i.e. the photoreceptor hole), with time, this hole continued to expand to form an almost photoreceptor-free region covering most of superior-inferior axis. By the end of the first year of life, only few photoreceptors remained in the far periphery of the superior hemiretina. Interestingly, despite a significant impairment of the outer retinal function, the retinal output (VEP) was maintained in the early phase of this retinopathy. Our findings thus suggest that postnatal exposure to a bright luminous environment triggers a degenerative process that continues to impair the retinal structure and function (mostly at the photoreceptor level) long after the cessation of the exposure regimen (more than 1 year documented herein). Given the slow degenerative process triggered following postnatal bright light exposure, we believe that our model represents an attractive alternative (to other more genetic models) to study the pathophysiology of photoreceptor-induced retinal degeneration as well as therapeutic strategies to counteract it. PMID:26784954

MUW Approach of PS OCT

NASA Astrophysics Data System (ADS)

Hitzenberger, Christoph K.; Pircher, Michael

Polarization sensitive (PS) OCT is a functional extension of OCT that exploits the light's polarization state to generate intrinsic, tissue specific contrast and enables quantitative measurements of tissue parameters. This chapter explains the technique, discusses polarization-changing light-tissue interactions and demonstrates the application of PS-OCT to retinal imaging. Two polarization-changing light-tissue interactions are discussed and their use for retinal diagnostics are demonstrated: (i) birefringence, which is found in fibrous tissues like the retinal nerve fiber layer and can be used for glaucoma diagnostics; and (ii) depolarization, which is observed in the retinal pigment epithelium (RPE) and can be used to segment the RPE and associated lesions like drusen or geographic atrophies in age related macular degeneration.

Retinal vessel caliber among people with acquired immunodeficiency syndrome: relationships with disease-associated factors and mortality.

PubMed

Gangaputra, Sapna; Kalyani, Partho S; Fawzi, Amani A; Van Natta, Mark L; Hubbard, Larry D; Danis, Ronald P; Thorne, Jennifer E; Holland, Gary N

2012-03-01

To evaluate relationships between retinal vessel caliber, AIDS-related factors, and mortality. Longitudinal, observational cohort study. We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Semi-automated evaluation of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, identified independent relationships between indices and various host- and disease-related variables. Included were 1250 participants. Mean follow-up for determination of mortality was 6.1 years. Smaller CRAE was related to increased age (P < .001) and hypertension (P < .001); larger CRAE was related to lower hematocrit (P = .002). Larger CRAE and CRVE were associated with black race (P < .001). Larger CRVE was related to smoking (P = .004); smaller CRVE was related to age (P < .001) and higher mean corpuscular volume (P = .001). We observed the following relationships with AIDS-associated factors: smaller CRAE and larger CRVE with history of highly active antiretroviral therapy (HAART; P < .001); and larger CRAE with lower CD4+ T lymphocyte count (P = .04). We did not identify independent relationships with human immunodeficiency virus RNA blood levels. There was a 12% (95% CI, 2%-21%) increase in mortality risk per quartile of decreasing AVR (P = .02). Variations in retinal vascular caliber are associated with AIDS-specific factors and are markers for increased mortality risk. Relationships are consistent with the hypothesis that the vasculature is altered by known atherogenic effects of chronic HAART or the prolonged inflammatory state associated with AIDS. Copyright © 2012 Elsevier Inc. All rights reserved.

Long-Term Efficacy of GMP Grade Xeno-Free hESC-Derived RPE Cells Following Transplantation

PubMed Central

McGill, Trevor J.; Bohana-Kashtan, Osnat; Stoddard, Jonathan W.; Andrews, Michael D.; Pandit, Neelay; Rosenberg-Belmaker, Lior R.; Wiser, Ofer; Matzrafi, Limor; Banin, Eyal; Reubinoff, Benjamin; Netzer, Nir; Irving, Charles

2017-01-01

Purpose Retinal pigment epithelium (RPE) dysfunction underlies the retinal degenerative process in age-related macular degeneration (AMD), and thus RPE cell replacement provides an optimal treatment target. We characterized longitudinally the efficacy of RPE cells derived under xeno-free conditions from clinical and xeno-free grade human embryonic stem cells (OpRegen) following transplantation into the subretinal space of Royal College of Surgeons (RCS) rats. Methods Postnatal (P) day 20 to 25 RCS rats (n = 242) received a single subretinal injection of 25,000 (low)-, 100,000 (mid)-, or 200,000 (high)-dose xeno-free RPE cells. BSS+ (balanced salt solution) (vehicle) and unoperated eyes served as controls. Optomotor tracking (OKT) behavior was used to quantify functional efficacy. Histology and immunohistochemistry were used to evaluate photoreceptor rescue and transplanted cell survival at 60, 100, 150, and 200 days of age. Results OKT was rescued in a dose-dependent manner. Outer nuclear layer (ONL) was significantly thicker in cell-treated eyes than controls up to P150. Transplanted RPE cells were identified in both the subretinal space and integrated into the host RPE monolayer in animals of all age groups, and often contained internalized photoreceptor outer segments. No pathology was observed. Conclusions OpRegen RPE cells survived, rescued visual function, preserved rod and cone photoreceptors long-term in the RCS rat. Thus, these data support the use of OpRegen RPE cells for the treatment of human RPE cell disorders including AMD. Translational Relevance Our novel xeno-free RPE cells minimize concerns of animal derived contaminants while providing a promising prospective therapy to the diseased retina. PMID:28626601

Multifocal retinitis in New Zealand sheep dogs.

PubMed

Hughes, P L; Dubielzig, R R; Kazacos, K R

1987-01-01

Thirty-nine percent of 1,448 working sheep dogs were affected with varying degrees of multifocal retinal disease on ophthalmoscopic examination. Lesions consisted of localized areas of hyperreflexia in the tapetal fundus, often associated with hyperpigmentation. Severely affected animals had widespread hyperreflexia with retinal vascular attenuation. Only 6% of 125 New Zealand dogs raised in urban environment were similarly affected. Both eyes of 70 dogs from New Zealand were examined histologically. Forty-seven of 70 dogs had ocular inflammatory disease. Ten other dogs had noninflammatory eye disease, and 13 dogs had normal eyes. Histologically, eyes with inflammatory disease were divided into three categories: Dogs 3 years of age or less with active inflammatory disease of the retina, uvea, and vitreous. Four dogs in this group had migrating nematode larvae identified morphologically as genus Toxocara. Diffuse retinitis and retinal atrophy in conjunction with localized retinal necrosis and choroidal fibrosis. Dogs in this category were severely, clinically affected. Chronic, low-grade retinitis with variable retinal atrophy. Most dogs in this category were over 3 years of age, and many were visually functional. The existence of a definable spectrum of morphological changes associated with inflammation, suggests that Toxocara sp. ocular larva migrans may be the cause of a highly prevalent, potentially blinding syndrome of working sheep dogs in New Zealand.

Acute retinal necrosis results in low vision in a young patient with a history of herpes simplex virus encephalitis.

PubMed

Shahi, Sanjeet K

2017-05-01

Acute retinal necrosis (ARN), secondary to herpes simplex encephalitis, is a rare syndrome that can present in healthy individuals, as well as immuno-compromised patients. Most cases are caused by a secondary infection from the herpes virus family, with varicella zoster virus being the leading cause of this syndrome. Potential symptoms include blurry vision, floaters, ocular pain and photophobia. Ocular findings may consist of severe uveitis, retinal vasculitis, retinal necrosis, papillitis and retinal detachment. Clinical manifestations of this disease may include increased intraocular pressure, optic disc oedema, optic neuropathy and sheathed retinal arterioles. A complete work up is essential to rule out cytomegalovirus retinitis, herpes simplex encephalitis, herpes virus, syphilis, posterior uveitis and other conditions. Depending on the severity of the disease, the treatment options consist of anticoagulation therapy, cycloplegia, intravenous acyclovir, systemic steroids, prophylactic laser photocoagulation and pars plana vitrectomy with silicon oil for retinal detachment. An extensive history and clinical examination is crucial in making the correct diagnosis. Also, it is very important to be aware of low vision needs and refer the patients, if expressing any sort of functional issues with completing daily living skills, especially reading. In this article, we report one case of unilateral ARN 20 years after herpetic encephalitis. © 2016 Optometry Australia.

Retinal and visual system: occupational and environmental toxicology.

PubMed

Fox, Donald A

2015-01-01

Occupational chemical exposure often results in sensory systems alterations that occur without other clinical signs or symptoms. Approximately 3000 chemicals are toxic to the retina and central visual system. Their dysfunction can have immediate, long-term, and delayed effects on mental health, physical health, and performance and lead to increased occupational injuries. The aims of this chapter are fourfold. First, provide references on retinal/visual system structure, function, and assessment techniques. Second, discuss the retinal features that make it especially vulnerable to toxic chemicals. Third, review the clinical and corresponding experimental data regarding retinal/visual system deficits produced by occupational toxicants: organic solvents (carbon disulfide, trichloroethylene, tetrachloroethylene, styrene, toluene, and mixtures) and metals (inorganic lead, methyl mercury, and mercury vapor). Fourth, discuss occupational and environmental toxicants as risk factors for late-onset retinal diseases and degeneration. Overall, the toxicants altered color vision, rod- and/or cone-mediated electroretinograms, visual fields, spatial contrast sensitivity, and/or retinal thickness. The findings elucidate the importance of conducting multimodal noninvasive clinical, electrophysiologic, imaging and vision testing to monitor toxicant-exposed workers for possible retinal/visual system alterations. Finally, since the retina is a window into the brain, an increased awareness and understanding of retinal/visual system dysfunction should provide additional insight into acquired neurodegenerative disorders. © 2015 Elsevier B.V. All rights reserved.

Melanopsin Phototransduction Contributes to Light-Evoked Choroidal Expansion and Rod L-Type Calcium Channel Function In Vivo.

PubMed

Berkowitz, Bruce A; Schmidt, Tiffany; Podolsky, Robert H; Roberts, Robin

2016-10-01

In humans, rodents, and pigeons, the dark → light transition signals nonretinal brain tissue to increase choroidal thickness, a major control element of choroidal blood flow, and thus of photoreceptor and retinal pigment epithelium function. However, it is unclear which photopigments in the retina relay the light signal to the brain. Here, we test the hypothesis that melanopsin (Opn4)-regulated phototransduction modulates light-evoked choroidal thickness expansion in mice. Two-month-old C57Bl/6 wild-type (B6), 4- to 5-month-old C57Bl/6/129S6 wild-type (B6 + S6), and 2-month-old melanopsin knockout (Opn4-/-) on a B6 + S6 background were studied. Retinal anatomy was evaluated in vivo by optical coherence tomography and MRI. Choroidal thickness in dark and light were measured by diffusion-weighted MRI. Rod cell L-type calcium channel (LTCC) function in dark and light (manganese-enhanced MRI [MEMRI]) was also measured. Opn4-/- mice did not show the light-evoked expansion of choroidal thickness observed in B6 and B6 + S6 controls. Additionally, Opn4-/- mice had lower than normal rod cell and inner retinal LTCC function in the dark but not in the light. These deficits were not due to structural abnormalities because retinal laminar architecture and thickness, and choroidal thickness in the Opn4-/- mice were similar to controls. First time evidence is provided that melanopsin phototransduction contributes to dark → light control of murine choroidal thickness. The data also highlight a contribution in vivo of melanopsin phototransduction to rod cell and inner retinal depolarization in the dark.

Effects of Retinal Morphology on Contrast Sensitivity and Reading Ability in Neovascular Age-Related Macular Degeneration

PubMed Central

Keane, Pearse A.; Patel, Praveen J.; Ouyang, Yanling; Chen, Fred K.; Ikeji, Felicia; Walsh, Alexander C.; Tufail, Adnan

2010-01-01

Purpose. To investigate the effect of changes in retinal morphology on contrast sensitivity and reading ability in patients with neovascular age-related macular degeneration (AMD) in the Avastin (bevacizumab; Genentech, South San Francisco, CA) for choroidal neovascularization (ABC) Trial. Methods. Contrast sensitivity obtained with Pelli-Robson charts, reading ability assessed with Minnesota Reading charts, and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) obtained by protocol refraction, were recorded. Raw Stratus optical coherence tomography (OCT; Carl Zeiss Meditec, Inc., Dublin, CA) images were analyzed with the publicly available software OCTOR, which allows precise delineation of any retinal compartment of interest. Thickness and volume were calculated for neurosensory retina, subretinal fluid (SRF), subretinal tissue, and pigment epithelium detachment, and the resulting measurements were correlated with each visual function parameter. Results. One hundred twenty-two patients with newly diagnosed neovascular AMD and enrolled in the ABC Trial, were evaluated. Increased subretinal tissue volume correlated with decreased contrast sensitivity (Pearson's correlation coefficient, r = −0.4944, P = 0.001). A modest correlation was detected between SRF volume and contrast sensitivity (r = −0.2562, P = 0.004). Increased retinal thickness at the foveal center also correlated with decreased visual function (ETDRS VA: r = −0.4530, P < 0.001). Conclusions. The strongest correlation detected between the functional parameters assessed and any of the OCT-derived morphologic parameters was that between decreased contrast sensitivity and increased subretinal tissue. In the future, assessment of contrast sensitivity and reading ability, in combination with quantitative subanalysis of retinal compartments, may lead to the identification of parameters relevant to functional improvement and ultimate prognosis in patients with newly diagnosed neovascular AMD (www.controlled-trials.com number, ISRCTN83325075). PMID:20554607

Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats

PubMed Central

Roth, Steven; Dreixler, John C.; Mathew, Biji; Balyasnikova, Irina; Mann, Jacob R.; Boddapati, Venkat; Xue, Lai; Lesniak, Maciej S.

2016-01-01

Purpose We have previously demonstrated the protective effect of bone marrow stem cell (BMSC)-conditioned medium in retinal ischemic injury. We hypothesized here that hypoxic preconditioning of stem cells significantly enhances the neuroprotective effect of the conditioned medium and thereby augments the protective effect in ischemic retina. Methods Rats were subjected to retinal ischemia by increasing intraocular pressure to 130 to 135 mm Hg for 55 minutes. Hypoxic-preconditioned, hypoxic unconditioned, or normoxic medium was injected into the vitreous 24 hours after ischemia ended. Recovery was assessed 7 days after injections by comparing electroretinography measurements, histologic examination, and apoptosis (TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay). To compare proteins secreted into the medium in the groups and the effect of hypoxic exposure, we used rat cytokine arrays. Results Eyes injected with hypoxic BMSC–conditioned medium 24 hours after ischemia demonstrated significantly enhanced return of retinal function, decreased retinal ganglion cell layer loss, and attenuated apoptosis compared to those administered normoxic or hypoxic unconditioned medium. Hypoxic-preconditioned medium had 21 significantly increased protein levels compared to normoxic medium. Conclusions The medium from hypoxic-preconditioned BMSCs robustly restored retinal function and prevented cell loss after ischemia when injected 24 hours after ischemia. The protective effect was even more pronounced than in our previous studies of normoxic conditioned medium. Prosurvival signals triggered by the secretome may play a role in this neuroprotective effect. PMID:27367588

Ultra-wide-field autofluorescence imaging in non-traumatic rhegmatogenous retinal detachment

PubMed Central

Witmer, M T; Cho, M; Favarone, G; Paul Chan, R V; D'Amico, D J; Kiss, S

2012-01-01

Purpose Rhegmatogenous retinal detachment (RRD) affects the function of the retina before and after surgical repair. We investigated ultra-wide-field autofluorescence (UAF) abnormalities in patients with acute RRD to improve our understanding of the functional changes in the retina before and after surgery. Methods In this retrospective study, we present the UAF imaging findings of 16 patients with acute, non-traumatic RRD. Imaging was obtained with the Optos 200 Tx (Optos) in 14 eyes preoperatively and in 12 eyes postoperatively. Twelve eyes had RRDs that involved the macula (group A), whereas four eyes had macula-sparing RRDs (group B). Results All patients (100%) with bullous retinal detachments demonstrated hypofluorescence over the area of retinal detachment. A hyperfluorescent leading edge (HLE) to the retinal detachment was observed preoperatively in 100% of eyes in group A and 75% of eyes in group B. Preoperative UAF through the fovea of group A eyes was normal (30%), hypofluorescent (50%) or hyperfluorescent (20%). In all patients with a HLE preoperatively, the HLE resolved by the 1-month postoperative visit. A residual line of demarcation remained in 8 of the 12 eyes (67%). In group A eyes, postoperative granular autofluorescent changes were present in four of the nine (44%) eyes, and were associated with worse preoperative (P=0.04) and postoperative (P=0.09) visual acuity. Conclusion UAF imaging reveals abnormalities in RRDs that allow excellent demarcation of the extent of the retinal detachment and assist in preoperative characterization of the detachment and postoperative counselling. PMID:22722489

Slow Feature Analysis on Retinal Waves Leads to V1 Complex Cells

PubMed Central

Dähne, Sven; Wilbert, Niko; Wiskott, Laurenz

2014-01-01

The developing visual system of many mammalian species is partially structured and organized even before the onset of vision. Spontaneous neural activity, which spreads in waves across the retina, has been suggested to play a major role in these prenatal structuring processes. Recently, it has been shown that when employing an efficient coding strategy, such as sparse coding, these retinal activity patterns lead to basis functions that resemble optimal stimuli of simple cells in primary visual cortex (V1). Here we present the results of applying a coding strategy that optimizes for temporal slowness, namely Slow Feature Analysis (SFA), to a biologically plausible model of retinal waves. Previously, SFA has been successfully applied to model parts of the visual system, most notably in reproducing a rich set of complex-cell features by training SFA with quasi-natural image sequences. In the present work, we obtain SFA units that share a number of properties with cortical complex-cells by training on simulated retinal waves. The emergence of two distinct properties of the SFA units (phase invariance and orientation tuning) is thoroughly investigated via control experiments and mathematical analysis of the input-output functions found by SFA. The results support the idea that retinal waves share relevant temporal and spatial properties with natural visual input. Hence, retinal waves seem suitable training stimuli to learn invariances and thereby shape the developing early visual system such that it is best prepared for coding input from the natural world. PMID:24810948

Profound re-organization of cell surface proteome in equine retinal pigment epithelial cells in response to in vitro culturing.

PubMed

Szober, Christoph M; Hauck, Stefanie M; Euler, Kerstin N; Fröhlich, Kristina J H; Alge-Priglinger, Claudia; Ueffing, Marius; Deeg, Cornelia A

2012-10-31

The purpose of this study was to characterize the cell surface proteome of native compared to cultured equine retinal pigment epithelium (RPE) cells. The RPE plays an essential role in visual function and represents the outer blood-retinal barrier. We are investigating immunopathomechanisms of equine recurrent uveitis, an autoimmune inflammatory disease in horses leading to breakdown of the outer blood-retinal barrier and influx of autoreactive T-cells into affected horses' vitrei. Cell surface proteins of native and cultured RPE cells from eye-healthy horses were captured by biotinylation, analyzed by high resolution mass spectrometry coupled to liquid chromatography (LC MS/MS), and the most interesting candidates were validated by PCR, immunoblotting and immunocytochemistry. A total of 112 proteins were identified, of which 84% were cell surface membrane proteins. Twenty-three of these proteins were concurrently expressed by both cell states, 28 proteins exclusively by native RPE cells. Among the latter were two RPE markers with highly specialized RPE functions: cellular retinaldehyde-binding protein (CRALBP) and retinal pigment epithelium-specific protein 65kDa (RPE65). Furthermore, 61 proteins were only expressed by cultured RPE cells and absent in native cells. As we believe that initiating events, leading to the breakdown of the outer blood-retinal barrier, take place at the cell surface of RPE cells as a particularly exposed barrier structure, this differential characterization of cell surface proteomes of native and cultured equine RPE cells is a prerequisite for future studies.

Ablation of the Proapoptotic Genes Chop or Ask1 Does Not Prevent or Delay Loss of Visual Function in a P23H Transgenic Mouse Model of Retinitis Pigmentosa

PubMed Central

Adekeye, Adeseye; Haeri, Mohammad; Solessio, Eduardo; Knox, Barry E.

2014-01-01

The P23H mutation in rhodopsin (RhoP23H) is a prevalent cause of autosomal dominant retinitis pigmentosa. We examined the role of the ER stress proteins, Chop and Ask1, in regulating the death of rod photoreceptors in a mouse line harboring the RhoP23H rhodopsin transgene (GHL+). We used knockout mice models to determine whether Chop and Ask1 regulate rod survival or retinal degeneration. Electrophysiological recordings showed similar retinal responses and sensitivities for GHL+, GHL+/Chop−/− and GHL+/Ask1−/− animals between 4–28 weeks, by which time all three mouse lines exhibited severe loss of retinal function. Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals. However, in older mice, a regional protective effect was observed in the central retina of GHL+/Chop−/− and GHL+/Ask1−/−, a region that was severely degenerated in GHL+ mice. Our results show that in the presence of the RhoP23H transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL+ mice. Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression. PMID:24523853

AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.

PubMed

Dinculescu, Astra; Stupay, Rachel M; Deng, Wen-Tao; Dyka, Frank M; Min, Seok-Hong; Boye, Sanford L; Chiodo, Vince A; Abrahan, Carolina E; Zhu, Ping; Li, Qiuhong; Strettoi, Enrica; Novelli, Elena; Nagel-Wolfrum, Kerstin; Wolfrum, Uwe; Smith, W Clay; Hauswirth, William W

2016-01-01

Usher syndrome type III (USH3A) is an autosomal recessive disorder caused by mutations in clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and sensorineural deafness. Efforts to develop therapies for preventing photoreceptor cell loss are hampered by the lack of a retinal phenotype in the existing USH3 mouse models and by conflicting reports regarding the endogenous retinal localization of clarin-1, a transmembrane protein of unknown function. In this study, we used an AAV-based approach to express CLRN1 in the mouse retina in order to determine the pattern of its subcellular localization in different cell types. We found that all major classes of retinal cells express AAV-delivered CLRN1 driven by the ubiquitous, constitutive small chicken β-actin promoter, which has important implications for the design of future USH3 gene therapy studies. Within photoreceptor cells, AAV-expressed CLRN1 is mainly localized at the inner segment region and outer plexiform layer, similar to the endogenous expression of other usher proteins. Subretinal delivery using a full strength viral titer led to significant loss of retinal function as evidenced by ERG analysis, suggesting that there is a critical limit for CLRN1 expression in photoreceptor cells. Taken together, these results suggest that CLRN1 expression is potentially supported by a variety of retinal cells, and the right combination of AAV vector dose, promoter, and delivery method needs to be selected to develop safe therapies for USH3 disorder.

ACUTE ZONAL OCCULT OUTER RETINOPATHY: Structural and Functional Analysis Across the Transition Zone Between Healthy and Diseased Retina.

PubMed

Duncker, Tobias; Lee, Winston; Jiang, Fan; Ramachandran, Rithambara; Hood, Donald C; Tsang, Stephen H; Sparrow, Janet R; Greenstein, Vivienne C

2018-01-01

To assess structure and function across the transition zone (TZ) between relatively healthy and diseased retina in acute zonal occult outer retinopathy. Six patients (6 eyes; age 22-71 years) with acute zonal occult outer retinopathy were studied. Spectral-domain optical coherence tomography, fundus autofluorescence, near-infrared reflectance, color fundus photography, and fundus perimetry were performed and images were registered to each other. The retinal layers of the spectral-domain optical coherence tomography scans were segmented and the thicknesses of two outer retinal layers, that is, the total receptor and outer segment plus layers, and the retinal nerve fiber layer were measured. All eyes showed a TZ on multimodal imaging. On spectral-domain optical coherence tomography, the TZ was in the nasal retina at varying distances from the fovea. For all eyes, it was associated with loss of the ellipsoid zone band, significant thinning of the two outer retinal layers, and in three eyes with thickening of the retinal nerve fiber layer. On fundus autofluorescence, all eyes had a clearly demarcated peripapillary area of abnormal fundus autofluorescence delimited by a border of high autofluorescence; the latter was associated with loss of the ellipsoid zone band and with a change from relatively normal to markedly decreased or nonrecordable visual sensitivity on fundus perimetry. The results of multimodal imaging clarified the TZ in acute zonal occult outer retinopathy. The TZ was outlined by a distinct high autofluorescence border that correlated with loss of the ellipsoid zone band on spectral-domain optical coherence tomography. However, in fundus areas that seemed healthy on fundus autofluorescence, thinning of the outer retinal layers and thickening of the retinal nerve fiber layer were observed near the TZ. The TZ was also characterized by a decrease in visual sensitivity.

Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration

PubMed Central

Wang, Xu; Ma, Wenxin; Gonzalez, Shaimar R.; Kretschmer, Friedrich; Badea, Tudor C.

2017-01-01

Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6brd10) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease. SIGNIFICANCE STATEMENT Photoreceptor degeneration is a cause of irreversible blindness in a number of retinal diseases such as retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Tamoxifen, a selective estrogen receptor modulator approved for the treatment of breast cancer and previously linked to a low incidence of retinal toxicity, was unexpectedly found to exert marked protective effects against photoreceptor degeneration. Structural and functional protective effects were found for an acute model of light-induced photoreceptor injury and for a genetic model for RP. The mechanism of protection involved the modulation of microglial activation and the production of inflammatory cytokines, highlighting the role of inflammatory mechanisms in photoreceptor degeneration. Tamoxifen may be suitable for clinical study as a potential treatment for diseases involving photoreceptor degeneration. PMID:28235894

Barrier properties of cultured retinal pigment epithelium.

PubMed

Rizzolo, Lawrence J

2014-09-01

The principal function of an epithelium is to form a dynamic barrier that regulates movement between body compartments. Each epithelium is specialized with barrier functions that are specific for the tissues it serves. The apical surface commonly faces a lumen, but the retinal pigment epithelium (RPE) appears to be unique by a facing solid tissue, the sensory retina. Nonetheless, there exists a thin (subretinal) space that can become fluid filled during pathology. RPE separates the subretinal space from the blood supply of the outer retina, thereby forming the outer blood-retinal barrier. The intricate interaction between the RPE and sensory retina presents challenges for learning how accurately culture models reflect native behavior. The challenge is heightened by findings that detail the variation of RPE barrier proteins both among species and at different stages of the life cycle. Among the striking differences is the expression of claudin family members. Claudins are the tight junction proteins that regulate ion diffusion across the spaces that lie between the cells of a monolayer. Claudin expression by RPE varies with species and life-stage, which implies functional differences among commonly used animal models. Investigators have turned to transcriptomics to supplement functional studies when comparing native and cultured tissue. The most detailed studies of the outer blood-retinal barrier have focused on human RPE with transcriptome and functional studies reported for human fetal, adult, and stem-cell derived RPE. Copyright © 2014 Elsevier Ltd. All rights reserved.

Combining Zebrafish and Mouse Models to Test the Function of Deubiquitinating Enzyme (Dubs) Genes in Development: Role of USP45 in the Retina.

PubMed

Toulis, Vasileios; Garanto, Alejandro; Marfany, Gemma

2016-01-01

Ubiquitination is a dynamic and reversible posttranslational modification. Much effort has been devoted to characterize the function of ubiquitin pathway genes in the cell context, but much less is known on their functional role in the development and maintenance of organs and tissues in the organism. In fact, several ubiquitin ligases and deubiquitinating enzymes (DUBs) are implicated in human pathological disorders, from cancer to neurodegeneration. The aim of our work is to explore the relevance of DUBs in retinal function in health and disease, particularly since some genes related to the ubiquitin or SUMO pathways cause retinal dystrophies, a group of rare diseases that affect 1:3000 individuals worldwide. We propose zebrafish as an extremely useful and informative genetic model to characterize the function of any particular gene in the retina, and thus complement the expression data from mouse. A preliminary characterization of gene expression in mouse retinas (RT-PCR and in situ hybridization) was performed to select particularly interesting genes, and we later replicated the experiments in zebrafish. As a proof of concept, we selected ups45 to be knocked down by morpholino injection in zebrafish embryos. Morphant phenotypic analysis showed moderate to severe eye morphological defects, with a defective formation of the retinal structures, therefore supporting the relevance of DUBs in the formation and differentiation of the vertebrate retina, and suggesting that genes encoding ubiquitin pathway enzymes are good candidates for causing hereditary retinal dystrophies.

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A treatment

USDA-ARS?s Scientific Manuscript database

We sought to determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received ...

FUNDUS AUTOFLUORESCENCE IN RUBELLA RETINOPATHY: Correlation With Photoreceptor Structure and Function.

PubMed

Bukowska, Danuta M; Wan, Sue Ling; Chew, Avenell L; Chelva, Enid; Tang, Ivy; Mackey, David A; Chen, Fred K

2017-01-01

To illustrate altered fundus autofluorescence in rubella retinopathy and to investigate their relationships with photoreceptor structure and function using multimodal imaging. The authors report four cases of rubella retinopathy aged 8, 33, 42, and 50 years. All patients had dilated clinical fundus examination; wide-field color photography; blue, green, and near-infrared autofluorescence imaging and spectral domain optical coherence tomography. Two patients also underwent microperimetry and adaptive optics imaging. En face optical coherence tomography, cone mosaic, and microperimetry were coregistered with autofluorescence images. The authors explored the structure-function correlation. All four patients had a "salt-and-pepper" appearance on dilated fundus examination and wide-field color photography. There were variable-sized patches of hypoautofluorescence on both blue and near-infrared excitation in all four patients. Wave-guiding cones were visible and retinal sensitivity was intact over these regions. There was no correlation between hypoautofluorescence and regions of attenuated ellipsoid and interdigitation zones. Hyperautofluorescent lesions were also noted and some of these were pseudo-vitelliform lesions. Patchy hypoautofluorescence on near-infrared excitation can be a feature of rubella retinopathy. This may be due to abnormal melanin production or loss of melanin within retinal pigment epithelium cells harboring persistent rubella virus infection. Preservation of the ellipsoid zone, wave-guiding cones, and retinal sensitivity within hypoautofluorescent lesions suggest that these retinal pigment epithelium changes have only mild impact on photoreceptor cell function.

Infrared scanning laser ophthalmoscope imaging of the macula and its correlation with functional loss and structural changes in patients with stargardt disease.

PubMed

Anastasakis, Anastasios; Fishman, Gerald A; Lindeman, Martin; Genead, Mohamed A; Zhou, Wensheng

2011-05-01

To correlate the degree of functional loss with structural changes in patients with Stargardt disease. Eighteen eyes of 10 patients with Stargardt disease were studied. Scanning laser ophthalmoscope infrared images were compared with corresponding spectral-domain optical coherence tomography scans. Additionally, scanning laser ophthalmoscope microperimetry was performed, and results were superimposed on scanning laser ophthalmoscope infrared images and in selected cases on fundus autofluorescence images. Seventeen of 18 eyes showed a distinct hyporeflective foveal and/or perifoveal area with distinct borders on scanning laser ophthalmoscope infrared images, which was less evident on funduscopy and incompletely depicted in fundus autofluorescence images. This hyporeflective zone corresponded to areas of significantly elevated psychophysical thresholds on microperimetry testing, in addition to thinning of the retinal pigment epithelium and disorganization or loss of the photoreceptor cell inner segment-outer segment junction and external-limiting membrane on spectral-domain optical coherence tomography. Scanning laser ophthalmoscope infrared fundus images are useful for depicting retinal structural changes in patients with Stargardt disease. A spectral-domain optical coherence tomography/scanning laser ophthalmoscope microperimetry device allows for a direct correlation of structural abnormalities with functional defects that will likely be applicable for the determination of retinal areas for potential improvement of retinal function in these patients during future clinical trials and for the monitoring of the diseases' natural history.

SLO-infrared imaging of the macula and its correlation with functional loss and structural changes in patients with Stargardt disease

PubMed Central

Anastasakis, Anastasios; Fishman, Gerald A; Lindeman, Martin; Genead, Mohamed A; Zhou, Wensheng

2010-01-01

Purpose To correlate the degree of functional loss with structural changes in patients with Stargardt disease. Methods Eighteen eyes of 10 Stargardt patients were studied. Scanning laser ophthalmoscope (SLO) infrared images were compared to corresponding spectral domain optical coherence tomography (SD-OCT) scans. Additionally, SLO microperimetry was performed and results were superimposed on SLO infrared images and in selected cases on fundus autofluorescence (FAF) images. Results Seventeen of 18 eyes showed a distinct hypo-reflective foveal and/or perifoveal area with distinct borders on SLO-infrared images which was less evident on funduscopy and incompletely depicted in FAF images. This hypo-reflective zone corresponded to areas of significantly elevated psychophysical thresholds on microperimetry testing, in addition to thinning of the retinal pigment epithelium (RPE), disorganization or loss of the photoreceptor cell inner-outer segment (IS-OS) junction and external limiting membrane (ELM) on SD-OCT. Conclusion SLO-infrared fundus images are useful for depicting retinal structural changes in Stargardt patients. An SD-OCT/SLO microperimetry device allows for a direct correlation of structural abnormalities with functional defects that will likely be applicable for the determination of retinal areas for potential improvement of retinal function in these patients during future clinical trials and for the monitoring of the diseases' natural history. PMID:21293320

The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic

PubMed Central

Carroll, Joseph; Dubra, Alfredo; Gardner, Jessica C.; Mizrahi-Meissonnier, Liliana; Cooper, Robert F.; Dubis, Adam M.; Nordgren, Rick; Genead, Mohamed; Connor, Thomas B.; Stepien, Kimberly E.; Sharon, Dror; Hunt, David M.; Banin, Eyal; Hardcastle, Alison J.; Moore, Anthony T.; Williams, David R.; Fishman, Gerald; Neitz, Jay; Neitz, Maureen; Michaelides, Michel

2012-01-01

Purpose. To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations. Methods. Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array. Results. While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with “L/M interchange” mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. Conclusions. The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy. PMID:23139274

Iron homeostasis and toxicity in retinal degeneration.

PubMed

He, Xining; Hahn, Paul; Iacovelli, Jared; Wong, Robert; King, Chih; Bhisitkul, Robert; Massaro-Giordano, Mina; Dunaief, Joshua L

2007-11-01

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels buildup with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich's ataxia, and panthothenate kinase-associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age-matched controls. Over the past 10 years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter-1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron-regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron-induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential.

Endoscopic device for functional imaging of the retina

NASA Astrophysics Data System (ADS)

Barriga, Simon; Lohani, Sweyta; Martell, Bret; Soliz, Peter; Ts'o, Dan

2011-03-01

Non-invasive imaging of retinal function based on the recording of spatially distributed reflectance changes evoked by visual stimuli has to-date been performed primarily using modified commercial fundus cameras. We have constructed a prototype retinal functional imager, using a commercial endoscope (Storz) for the frontend optics, and a low-cost back-end that includes the needed dichroic beam splitter to separate the stimulus path from the imaging path. This device has been tested to demonstrate its performance for the delivery of adequate near infrared (NIR) illumination, intensity of the visual stimulus and reflectance return in the imaging path. The current device was found to be capable of imaging reflectance changes of 0.1%, similar to that observable using the modified commercial fundus camera approach. The visual stimulus (a 505nm spot of 0.5secs) was used with an interrogation illumination of 780nm, and a sequence of imaged captured. At each pixel, the imaged signal was subtracted and normalized by the baseline reflectance, so that the measurement was ΔR/R. The typical retinal activity signal observed had a ΔR/R of 0.3-1.0%. The noise levels were measured when no stimulus was applied and found to vary between +/- 0.05%. Functional imaging has been suggested as a means to provide objective information on retina function that may be a preclinical indicator of ocular diseases, such as age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. The endoscopic approach promises to yield a significantly more economical retinal functional imaging device that would be clinically important.

Photochemical restoration of visual responses in blind mice

PubMed Central

Polosukhina, Aleksandra; Litt, Jeffrey; Tochitsky, Ivan; Nemargut, Joseph; Sychev, Yivgeny; De Kouchkovsky, Ivan; Huang, Tracy; Borges, Katharine; Trauner, Dirk; Van Gelder, Russell N.; Kramer, Richard H.

2012-01-01

Summary Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here we show that, AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance responses in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a new drug strategy for restoring retinal function in degenerative blinding diseases. PMID:22841312

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.

PubMed

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

Tomographic Structural Changes of Retinal Layers after Internal Limiting Membrane Peeling for Macular Hole Surgery.

PubMed

Faria, Mun Yueh; Ferreira, Nuno P; Cristóvao, Diana M; Mano, Sofia; Sousa, David Cordeiro; Monteiro-Grillo, Manuel

2018-01-01

To highlight tomographic structural changes of retinal layers after internal limiting membrane (ILM) peeling in macular hole surgery. Nonrandomized prospective, interventional study in 38 eyes (34 patients) subjected to pars plana vitrectomy and ILM peeling for idiopathic macular hole. Retinal layers were assessed in nasal and temporal regions before and 6 months after surgery using spectral domain optical coherence tomography. Total retinal thickness increased in the nasal region and decreased in the temporal region. The retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) showed thinning on both nasal and temporal sides of the fovea. The thickness of the outer plexiform layer (OPL) increased. The outer nuclear layer (ONL) and outer retinal layers (ORL) increased in thickness after surgery in both nasal and temporal regions. ILM peeling is associated with important alterations in the inner retinal layer architecture, with thinning of the RNFL-GCL-IPL complex and thickening of OPL, ONL, and ORL. These structural alterations can help explain functional outcome and could give indications regarding the extent of ILM peeling, even though peeling seems important for higher rate of hole closure. © 2017 S. Karger AG, Basel.

Retinal Tissue Thickness is Reduced in Diabetic Peripheral Neuropathy.

PubMed

Srinivasan, Sangeetha; Pritchard, Nicola; Vagenas, Dimitrios; Edwards, Katie; Sampson, Geoff P; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

2016-10-01

To investigate the relationship between diabetic peripheral neuropathy (DPN) and retinal tissue thickness. Full retinal thickness in the central retinal, parafoveal, and perifoveal zones and thickness of the ganglion cell complex and retinal nerve fiber layer (RNFL) were assessed in 193 individuals (84 with type 1 diabetes, 67 with type 2 diabetes, and 42 healthy controls) using spectral domain optical coherence tomography. Among those with diabetes, 44 had neuropathy defined using a modified neuropathy disability score recorded on a 0-10 scale. Multiple regression analysis was performed to investigate the relationship between diabetic neuropathy and retinal tissue thickness, adjusted for the presence of diabetic retinopathy (DR), age, sex, duration of diabetes, and HbA 1c levels. In individuals with diabetes, perifoveal thickness was inversely related to the severity of neuropathy (p < 0.05), when adjusted for age, sex, duration of diabetes, and HbA 1c levels. DR was associated with reduced thickness in parafovea (p < 0.01). The RNFL was thinner in individuals with greater degrees of neuropathy (p < 0.04). DPN is associated with structural compromise involving several retinal layers. This compromise may represent a threat to visual integrity and therefore warrants examination of functional correlates.

[Bilateral spontaneously reattached rhegmatogenous retinal detachment. Case report and differential diagnosis with pigmentary retinopathies].

PubMed

García-Guzmán, Jorge Guillermo; Franco-Yáñez, Yasmín; Lima-Gómez, Virgilio

2014-01-01

A dark pigmentation of the ocular fundus presents in degenerative diseases such as retinitis pigmentosa; this disease must be distinguished from others whose evolution is not progressive, in order to estimate the functional prognosis of the patient. To analyze the features which distinguish spontaneously reattached retinal detachment from other causes of ocular fundus pigmentation, in order to be able to identify it even in bilateral cases. A case of a female with chronic visual loss is presented, who was referred for evaluation with the diagnosis of a pigmented retinopathy. Clinical exploration discarded causes as retinitis pigmentosa, retinal inflammatory diseases or trauma. Based on the clinical features, on the topography of pigmentation and in the information provided by electroretinography, a bilateral spontaneous reattachment of rhegmatogenous retinal detachment was diagnosed made. Clinical features of this entity are discussed, as well as the diagnostic approach to distinguish it from other pigment retinopathies. Clinical features of spontaneously reattached retinal detachment allow the explorer to distinguish it from other causes of bilateral pigmentation, despite presenting bilaterally. Since the prognosis of the attached retina is better than that of a degenerative disease, the correct diagnosis makes rehabilitation easier.

Highly efficient retinal metabolism in cones

PubMed Central

Miyazono, Sadaharu; Shimauchi-Matsukawa, Yoshie; Tachibanaki, Shuji; Kawamura, Satoru

2008-01-01

After bleaching of visual pigment in vertebrate photoreceptors, all-trans retinal is reduced to all-trans retinol by retinol dehydrogenases (RDHs). We investigated this reaction in purified carp rods and cones, and we found that the reducing activity toward all-trans retinal in the outer segment (OS) of cones is >30 times higher than that of rods. The high activity of RDHs was attributed to high content of RDH8 in cones. In the inner segment (IS) in both rods and cones, RDH8L2 and RDH13 were found to be the major enzymes among RDH family proteins. We further found a previously undescribed and effective pathway to convert 11-cis retinol to 11-cis retinal in cones: this oxidative conversion did not require NADP+ and instead was coupled with reduction of all-trans retinal to all-trans retinol. The activity was >50 times effective than the oxidizing activity of RDHs that require NADP+. These highly effective reactions of removal of all-trans retinal by RDH8 and production of 11-cis retinal by the coupling reaction are probably the underlying mechanisms that ensure effective visual pigment regeneration in cones that function under much brighter light conditions than rods. PMID:18836074

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal.

PubMed

Quazi, Faraz; Molday, Robert S

2014-04-01

The visual cycle is a series of enzyme-catalyzed reactions which converts all-trans-retinal to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells. Although essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic due to its highly reactive aldehyde group and has to be detoxified by either reduction to retinol or sequestration within retinal-binding proteins. Previous studies have focused on the role of the ATP-binding cassette transporter ABCA4 associated with Stargardt macular degeneration and retinol dehydrogenases (RDH) in the clearance of all-trans-retinal from photoreceptors following photoexcitation. How rod and cone cells prevent the accumulation of 11-cis-retinal in photoreceptor disk membranes in excess of what is required for visual pigment regeneration is not known. Here we show that ABCA4 can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), the Schiff-base conjugate of 11-cis-retinal and PE, from the lumen to the cytoplasmic leaflet of disk membranes. This transport function together with chemical isomerization to its all-trans isomer and reduction to all-trans-retinol by RDH can prevent the accumulation of excess 11-cis-retinal and its Schiff-base conjugate and the formation of toxic bisretinoid compounds as found in ABCA4-deficient mice and individuals with Stargardt macular degeneration. This segment of the visual cycle in which excess 11-cis-retinal is converted to all-trans-retinol provides a rationale for the unusually high content of PE and its long-chain unsaturated docosahexaenoyl group in photoreceptor membranes and adds insight into the molecular mechanisms responsible for Stargardt macular degeneration.

Optical coherence tomography-guided retinal prosthesis design: model of degenerated retinal curvature and thickness for patient-specific devices.

PubMed

Opie, Nicholas L; Ayton, Lauren N; Apollo, Nicholas V; Ganesan, Kumaravelu; Guymer, Robyn H; Luu, Chi D

2014-06-01

Retinitis pigmentosa affects over 1.5 million people worldwide and is a leading cause of vision loss and blindness. While retinal prostheses have shown some success in restoring basic levels of vision, only generic, "one-size-fits-all" devices are currently being implanted. In this study, we used optical coherence tomography scans of the degenerated retina from 88 patients with retinitis pigmentosa to generate models of retinal thickness and curvature for the design of customized implants. We found the average retinal thickness at the fovea to be 152.9 ± 61.3 μm, increasing to a maximum retinal thickness of 250.9 ± 57.5 μm at a nasal eccentricity of 5°. These measures could be used to assist the development of custom-made penetrating electrodes to enhance and optimize epiretinal prostheses. From the retinal thickness measurements, we determined that the optimal length of penetrating electrodes to selectively stimulate retinal ganglion cell bodies and interneuron axons in the ganglion cell layer should be 30-100 μm, and to preferentially stimulate interneurons in the inner nuclear layer, electrodes should be 100-200 μm long. Electrodes greater than 200 μm long had the potential to penetrate through the retina into the choroid, which could cause devastating complications to the eye and should be avoided. The two- and three-dimensional models of retinal thickness developed in this study can be used to design patient-specific epiretinal implants that will help with safety and to optimize the efficacy of neuronal stimulation, ensuring the best functional performance of the device for patients. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

[Clinical electro-ophthalmology at the Max Planck Institute of the Frankfurt University Ophthalmology Clinic 1970-1991].

PubMed

Lorenz, R; Baier, M; Eckl, G; Raile, A

1996-07-01

The survey shows the frequency and distribution of diseases evaluated by electroophthalmological methods. Patients with retinal diseases (51.2%) and those with diseases of the optic nerve (21.8%) were examined most frequently. In a high percentage these investigations lead to a clinically useful assessment: described as confirmation or exclusion of a clinical diagnosis, as establishing a possible differential diagnosis or clearing up formerly unknown aspects of a disease. In cases of hereditary retinal disorders only 11% remained unclear, with presumed optic neuritis only 6%. The importance of electroophthalmological investigations is there ability to assess functional deficits in the visual system especially in somehow more rare retinal and centrally located disorders, functional deficits of unknown origins or in general diseases including the visual system.

Role of the Retinal Vascular Endothelial Cell in Ocular Disease

PubMed Central

Bharadwaj, Arpita S.; Appukuttan, Binoy; Wilmarth, Phillip A.; Pan, Yuzhen; Stempel, Andrew J.; Chipps, Timothy J.; Benedetti, Eric E.; Zamora, David O.; Choi, Dongseok; David, Larry L.; Smith, Justine R.

2012-01-01

Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell. PMID:22982179

Fundus spectroscopy and studies in retinal oximetry using intravitreal illumination

NASA Astrophysics Data System (ADS)

Salyer, David Alan

This dissertation documents the development of a new illumination technique for use in the studies of retinal oximetry and fundus spectroscopy. Intravitreal illumination is a technique where the back of the eye is illuminated trans-sclerally using a scanning monochromator coupled into a fiber optic illuminator. Retinal oximetry is the process of measuring the oxygen saturation of blood contained in retinal vessels by quantitative measurement of the characteristic color shift seen as blood oxygen saturation changes from oxygenated blood (reddish) to deoxygenated blood (bluish). Retinal oximetry was first attempted in 1963 but due to a variety of problems with accuracy and difficulty of measurement, has not matured to the point of clinical acceptability or commercial viability. Accurate retinal oximetry relies in part on an adequate understanding of the spectral reflectance characteristics of the fundus. The use of intravitreal illumination allows new investigations into the spectral reflectance properties of the fundus. The results of much research in fundus reflectance and retinal oximetry is detailed in this document, providing new insight into both of these related fields of study. Intravitreal illumination has been used to study retinal vessel oximetry and fundus reflectometry resulting in several important findings that are presented in this document. Studies on enucleated swine eyes have provided new insight into the bidirectional reflectance distribution function of the fundus. Research on live swine has shown accurate measurement of retinal vessel oxygen saturation and provided the first in vivo spectral transmittance measurement of the sensory retina. A secondary discovery during this research suggests that vitrectomy alters the retinal vasculature, an finding that should spawn new research in its own right.

Fundus Autofluorescence in the Abca4−/− Mouse Model of Stargardt Disease—Correlation With Accumulation of A2E, Retinal Function, and Histology

PubMed Central

Charbel Issa, Peter; Barnard, Alun R.; Singh, Mandeep S.; Carter, Emma; Jiang, Zhichun; Radu, Roxana A.; Schraermeyer, Ulrich; MacLaren, Robert E.

2013-01-01

Purpose. To investigate fundus autofluorescence (AF) characteristics in the Abca4−/− mouse, an animal model for AMD and Stargardt disease, and to correlate findings with functional, structural, and biochemical assessments. Methods. Blue (488 nm) and near-infrared (790 nm) fundus AF images were quantitatively and qualitatively analyzed in pigmented Abca4−/− mice and wild type (WT) controls in vivo. Functional, structural, and biochemical assessments included electroretinography (ERG), light and electron microscopic analysis, and A2E quantification. All assessments were performed across age groups. Results. In Abca4−/− mice, lipofuscin-related 488 nm AF increased early in life with a ceiling effect after 6 months. This increase was first paralleled by an accumulation of typical lipofuscin granules in the retinal pigment epithelium (RPE). Later, lipofuscin and melanin granules decreased in number, whereas melanolipofuscin granules increased. This increase in melanolipofuscin granules paralleled an increase in melanin-related 790 nm AF. Old Abca4−/− mice revealed a flecked fundus AF pattern at both excitation wavelengths. The amount of A2E, a major lipofuscin component, increased 10- to 12-fold in 6- to 9-month-old Abca4−/− mice compared with controls, while 488 nm AF intensity only increased 2-fold. Despite pronounced lipofuscin accumulation in the RPE of Abca4−/− mice, ERG and histology showed a slow age-related thinning of the photoreceptor layer similar to WT controls up to 12 months. Conclusions. Fundus AF can be used to monitor lipofuscin accumulation and melanin-related changes in vivo in mouse models of retinal disease. High RPE lipofuscin may not adversely affect retinal structure or function over prolonged time intervals, and melanin-related changes (melanolipofuscin formation) may occur before the decline in retinal function. PMID:23761084

Five-year safety and performance results from the Argus II Retinal Prosthesis System clinical trial

PubMed Central

da Cruz, Lyndon; Dorn, Jessy D.; Humayun, Mark S.; Dagnelie, Gislin; Handa, James; Barale, Pierre-Olivier; Sahel, José-Alain; Stanga, Paulo E.; Hafezi, Farhad; Safran, Avinoam B.; Salzmann, Joel; Santos, Arturo; Birch, David; Spencer, Rand; Cideciyan, Artur V.; de Juan, Eugene; Duncan, Jacque L.; Eliott, Dean; Fawzi, Amani; Olmos de Koo, Lisa C.; Ho, Allen C.; Brown, Gary; Haller, Julia; Regillo, Carl; Del Priore, Lucian V.; Arditi, Aries; Greenberg, Robert J.

2016-01-01

Purpose The Argus® II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) was developed to restore some vision to patients blind from retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception due to end-stage RP. Design The study is a prospective, multicenter, single-arm, clinical trial. Within-patient controls included the non-implanted fellow eye and patients' native residual vision compared to their vision when using the System. Subjects There were 30 subjects in 10 centers in the U.S. and Europe. Methods The worse-seeing eye of blind patients was implanted with the Argus II System. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by three computer-based, objective tests. Secondary measures included functional vision performance on objectively-scored real-world tasks. Results Twenty-four out of 30 patients remained implanted with functioning Argus II Systems at 5 years post-implant. Only one additional serious adverse event was experienced since the 3-year time point. Patients performed significantly better with the System ON than OFF on all visual function tests and functional vision tasks. Conclusions The five-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. PMID:27453256

Randomized controlled trial of electro-stimulation therapies to modulate retinal blood flow and visual function in retinitis pigmentosa.

PubMed

Bittner, Ava K; Seger, Kenneth; Salveson, Rachel; Kayser, Samantha; Morrison, Natalia; Vargas, Patricia; Mendelsohn, Deborah; Han, Jorge; Bi, Hua; Dagnelie, Gislin; Benavente, Alexandra; Ramella-Roman, Jessica

2018-05-01

We examined changes in visual function and ocular and retinal blood flow (RBF) among retinitis pigmentosa (RP) participants in a randomized controlled trial of electro-stimulation therapies. Twenty-one RP participants were randomized (1:1:1) to transcorneal electrical stimulation (TES) at 6 weekly half-hour sessions, electro-acupuncture or inactive laser acupuncture (sham control) at 10 half-hour sessions over 2 weeks. Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA), quick contrast sensitivity function, Goldmann visual fields, AdaptDx scotopic sensitivity, spectral flow and colour Doppler imaging of the central retinal artery (CRA), and RBF in macular capillaries were measured twice pre-treatment, after 2 TES sessions, within a week and a month after intervention completion. We measured a significant improvement in retrobulbar CRA mean flow velocity for both the TES (p = 0.038) and electro-acupuncture groups (p = 0.001) on average after 2 weeks of treatment when compared to sham controls. Transcorneal electrical simulation (TES) and electro-acupuncture subjects had significant 55% and 34% greater increases, respectively, in RBF in the macular vessels when compared to sham controls (p < 0.001; p = 0.008) within a week of completing six TES sessions or a month after electro-acupuncture. There was a significant difference in the proportion of eyes that had improved visual function when comparing the three intervention groups (p = 0.038): four of seven TES subjects (57%), two of seven electro-acupuncture subjects (29%) and none of the seven control subjects (0%) had a significant visual improvement outside of typical test-retest variability at two consecutive post-treatment visits. Increased blood flow following electro-stimulation therapies is an objective, physiological change that occurred in addition to visual function improvements in some RP patients. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial.

PubMed

da Cruz, Lyndon; Dorn, Jessy D; Humayun, Mark S; Dagnelie, Gislin; Handa, James; Barale, Pierre-Olivier; Sahel, José-Alain; Stanga, Paulo E; Hafezi, Farhad; Safran, Avinoam B; Salzmann, Joel; Santos, Arturo; Birch, David; Spencer, Rand; Cideciyan, Artur V; de Juan, Eugene; Duncan, Jacque L; Eliott, Dean; Fawzi, Amani; Olmos de Koo, Lisa C; Ho, Allen C; Brown, Gary; Haller, Julia; Regillo, Carl; Del Priore, Lucian V; Arditi, Aries; Greenberg, Robert J

2016-10-01

The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. Thirty participants in 10 centers in the United States and Europe. The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Cyclic reconstruction of 4D retinal blood flow with pulse synchronization

NASA Astrophysics Data System (ADS)

Schmoll, Tilman; Lasser, Theo; Leitgeb, Rainer A.

2009-02-01

Doppler OCT systems allow nowadays to visualize quantitative and qualitative angiographic maps of retinal tissue. We equipped the instrument with a pulse oximeter and recorded the pulse synchronously with the resonant Doppler flow data. Recombination of tomograms according to the heart beat cycles yields full volumes for each cycle instant. We believe such multi-dimensional functional information and the ability to monitor dynamic processes over time to open exciting perspectives that ultimately contribute to a better understanding of retinal physiology and patho-physiology in-vivo.

Extracellular matrix components expression in human pluripotent stem cell-derived retinal organoids recapitulates retinogenesis in vivo and reveals an important role for IMPG1 and CD44 in the development of photoreceptors and interphotoreceptor matrix.

PubMed

Felemban, Majed; Dorgau, Birthe; Hunt, Nicola Claire; Hallam, Dean; Zerti, Darin; Bauer, Roman; Ding, Yuchun; Collin, Joseph; Steel, David; Krasnogor, Natalio; Al-Aama, Jumana; Lindsay, Susan; Mellough, Carla; Lako, Majlinda

2018-05-17

The extracellular matrix (ECM) plays an important role in numerous processes including cellular proliferation, differentiation, migration, maturation, adhesion guidance and axonal growth. To date, there has been no detailed analysis of the ECM distribution during retinal ontogenesis in humans and the functional importance of many ECM components is poorly understood. In this study, the expression of key ECM components in adult mouse and monkey retina, developing and adult human retina and retinal organoids derived from human pluripotent stem cells was studied. Our data indicate that basement membrane ECMs (Fibronectin and Collagen IV) were expressed in Bruch's membrane and the inner limiting membrane of the developing human retina, whilst the hyalectins (Versican and Brevican), cluster of differentiation 44 (CD44), photoreceptor-specific ECMs Interphotoreceptor Matrix Proteoglycan 1 (IMPG1) and Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) were detected in the developing interphotoreceptor matrix (IPM). The expression of IMPG1, Versican and Brevican in the developing IPM was conserved between human developing retina and human pluripotent stem cell-derived retinal organoids. Blocking the action of CD44 and IMPG1 in pluripotent stem cell derived retinal organoids affected the development of photoreceptors, their inner/outer segments and connecting cilia and disrupted IPM formation, with IMPG1 having an earlier and more significant impact. Together, our data suggest an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation during human retinogenesis. The expression and the role of many extracellular matrix (ECM) components during human retinal development is not fully understood. In this study, expression of key ECM components (Collagen IV, Fibronectin, Brevican, Versican, IMPG1 and IMPG2) was investigated during human retinal ontogenesis. Collagen IV and Fibronectin were expressed in Bruch's membrane; whereas Brevican, Versican, IMPG1 & IMPG2 in the developing interphotoreceptor matrix (IPM). Retinal organoids were successfully generated from pluripotent stem cells. The expression of ECM components was examined in the retinal organoids and found to recapitulate human retinal development in vivo. Using functional blocking experiments, we were able to highlight an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation. Copyright © 2018 Acta Materialia Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Chen; Tao, Zui; Xue, Langyue

In lower-order vertebrates, Müller glia exhibit characteristics of retinal progenitor cells, while in higher vertebrates, such as mammals, the regenerative capacity of Müller glia is limited. Recently, we reported that Lin28b promoted the trans-differentiation of Müller cells to rod photoreceptor and bipolar cells in the retina of retinitis pigmentosa rat model, whereas it is unclear whether Lin28b can stimulate the reprogramming of Müller glia in vitro for transplantation into a damaged retina. In the present study, Long-Evens rat Müller glia were infected with Adeno-Lin28b or Adeno-GFP. Over-expression of Lin28b in isolated rat Müller glia resulted in the suppression of GFAP expression,more » enhancement of cell proliferation and a significant increase of the expression of retinal progenitor markers 5 days after infection. Moreover, Lin28b caused a significant reduction of the Let-7 family of microRNAs. Following sub-retinal space transplantation, Müller glia-derived retinal progenitors improved b-wave amplification of 30d Royal College of Surgeons retinitis pigmentosa model (RCS-P+) rats, as detected by electroretinography (ERG) recordings. Taken together, these data suggest that the up-regulation of Lin28b expression facilitated the reprogramming of Müller cells toward characteristics of retinal progenitors. - Highlights: • Lin28b reprograms Müller glia to retinal progenitors. • Let-7 micrRNAs are suppressed by Lin28b. • Transplantation of reprogrammed Müller glia restores retinal function.« less

Methane rescues retinal ganglion cells and limits retinal mitochondrial dysfunction following optic nerve crush.

PubMed

Wang, Ruobing; Sun, Qinglei; Xia, Fangzhou; Chen, Zeli; Wu, Jiangchun; Zhang, Yuelu; Xu, Jiajun; Liu, Lin

2017-06-01

Secondary degeneration is a common event in traumatic central nervous system disorders, which involves neuronal apoptosis and mitochondrial dysfunction. Exogenous methane exerts the therapeutic effects in many organ injury. Our study aims to investigate the potential neuroprotection of methane in a rat model of optic nerve crush (ONC). Adult male Sprague-Dawley rats were subjected to ONC and administrated intraperitoneally with methane-saturated or normal saline (10 ml/kg) once per day for one week after ONC. The retinal ganglion cells (RGCs) density was assessed by hematoxylin and eosin staining and Fluoro-Gold retrogradely labeling. Visual function was evaluated by flash visual evoked potentials (FVEP). The retinal apoptosis was measured by terminal-deoxy-transferase-mediated dUTP nick end labeling (TUNEL) assay and the expression of apoptosis-related factors, such as phosphorylated Bcl-2-associated death promoter (pBAD), phosphorylated glycogen synthase kinase-3β (pGSK-3β), Bcl-2 associated X protein (Bax) and Bcl-2 extra large (Bcl-xL). Retinal mitochondrial function was assessed by the mRNA expressions of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), the mitochondrial DNA (mtDNA) copy number, citrate synthase activity and ATP content. Methane treatment significantly improved the RGC loss and visual dysfunction following ONC. As expected, methane also remarkably inhibited the retinal neural apoptosis, such as the fewer TUNEL-positive cells in ganglion cell layer, accompanied by the up-regulations of anti-apoptotic factors (pGSK-3β, pBAD, Bcl-xL) and the down-regulation of pro-apoptotic factor (Bax). Furthermore, methane treatment suppressed up-regulations of critical mitochondrial components (PGC-1α, NRF1 and TFAM) mRNA and mtDNA copy number, as well as improved the reduction of functional mitochondria markers, including citrate synthase activity and ATP content, in retinas with ONC. Taken together, methane treatment promotes RGC survival and limits retinal mitochondrial dysfunction against ONC insult. Methane can be a potential neuroprotective agent for traumatic and glaucomatous neurodegeneration. Copyright © 2017. Published by Elsevier Ltd.

Why choroid vessels appear dark in clinical OCT images

NASA Astrophysics Data System (ADS)

Kirby, Mitchell A.; Li, Chenxi; Choi, Woo June; Gregori, Giovanni; Rosenfeld, Philip; Wang, Ruikang

2018-02-01

With the onset of clinically available spectral domain (SD-OCT) and swept source (SS-OCT) systems, clinicians are now easily able to recognize sub retinal microstructure and vascularization in the choroidal and scleral regions. As the bloodrich choroid supplies nutrients to the upper retinal layers, the ability to monitor choroid function accurately is of vital importance for clinical assessment of retinal health. However, the physical appearance of the choroid blood vessels (darker under a healthy Retinal Pigmented Epithelium (RPE) compared to regions displaying an RPE atrophic lesion) has led to confusion within the OCT ophthalmic community. The differences in appearance between each region in the OCT image may be interpreted as different vascular patterns when the vascular networks are in fact very similar. To explain this circumstance, we simulate light scattering phenomena in the RPE and Choroid complexes using the finite difference time domain (FDTD) method. The simulation results are then used to describe and validate imaging features in a controlled multi-layered tissue phantom designed to replicate human RPE, choroid, and whole blood microstructure. Essentially, the results indicate that the strength of the OCT signal from choroidal vasculature is dependent on the health and function of the RPE, and may not necessarily directly reflect the health and function of the choroidal vasculature.

Vinpocetine protects inner retinal neurons with functional NMDA glutamate receptors against retinal ischemia.

PubMed

Nivison-Smith, Lisa; Khoo, Pauline; Acosta, Monica L; Kalloniatis, Michael

2018-02-01

Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate. Vinpocetine's actions to improve cation channel permeability and cell marker immunoreactivity following ischemia appeared to be limited to NMDA activation with no changes observed following kainate stimulation. Vinpocetine's actions were lost in the presence of an NMDA receptor inhibitor further suggesting they may be secondary to NMDA receptor activation. NMDA receptor function was also necessary for vinpocetine's actions on glucose availability during ischemia but not lactate dehydrogenase (LDH) activity in the ischemic retina suggesting not all of vinpocetine's actions are linked to NMDA receptor function. These results may explain vinpocetine's effectiveness as a neuroprotective agent as the NMDA receptor is implicated in the pathogenesis of ischemia in a range of tissues of the central nervous system. Copyright © 2017 Elsevier Ltd. All rights reserved.

Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats

NASA Astrophysics Data System (ADS)

Pardue, Machelle T.; Phillips, Michael J.; Yin, Hang; Fernandes, Alcides; Cheng, Yian; Chow, Alan Y.; Ball, Sherry L.

2005-03-01

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

Associations of human retinal very long-chain polyunsaturated fatty acids with dietary lipid biomarkers

PubMed Central

Gorusupudi, Aruna; Liu, Aihua; Hageman, Gregory S.; Bernstein, Paul S.

2016-01-01

The human retina is well-known to have unique lipid profiles enriched in long-chain polyunsaturated fatty acids (LC-PUFAs) and very long-chain polyunsaturated fatty acids (VLC-PUFAs) that appear to promote normal retinal structure and function, but the influence of diet on retinal lipid profiles in health and disease remains controversial. In this study, we examined two independent cohorts of donor eyes and related their retinal lipid profiles with systemic biomarkers of lipid intake. We found that serum and red blood cell lipids, and to a lesser extent orbital fat, are indeed excellent biomarkers of retinal lipid content and n-3/n-6 ratios in both the LC-PUFA and VLC-PUFA series. Eyes from age-related macular degeneration (AMD) donors have significantly decreased levels of VLC-PUFAs and low n-3/n-6 ratios. These results are consistent with the protective role of dietary n-3 LC-PUFAs against AMD and emphasize the importance of monitoring systemic biomarkers of lipid intake when undertaking clinical trials of lipid supplements for prevention and treatment of retinal disease. PMID:26764040

A system verification platform for high-density epiretinal prostheses.

PubMed

Chen, Kuanfu; Lo, Yi-Kai; Yang, Zhi; Weiland, James D; Humayun, Mark S; Liu, Wentai

2013-06-01

Retinal prostheses have restored light perception to people worldwide who have poor or no vision as a consequence of retinal degeneration. To advance the quality of visual stimulation for retinal implant recipients, a higher number of stimulation channels is expected in the next generation retinal prostheses, which poses a great challenge to system design and verification. This paper presents a system verification platform dedicated to the development of retinal prostheses. The system includes primary processing, dual-band power and data telemetry, a high-density stimulator array, and two methods for output verification. End-to-end system validation and individual functional block characterization can be achieved with this platform through visual inspection and software analysis. Custom-built software running on the computers also provides a good way for testing new features before they are realized by the ICs. Real-time visual feedbacks through the video displays make it easy to monitor and debug the system. The characterization of the wireless telemetry and the demonstration of the visual display are reported in this paper using a 256-channel retinal prosthetic IC as an example.

Stable and Efficient Gene Transfer into the Retina Using an HIV-Based Lentiviral Vector

NASA Astrophysics Data System (ADS)

Miyoshi, Hiroyuki; Takahashi, Masayo; Gage, Fred H.; Verma, Inder M.

1997-09-01

The development of methods for efficient gene transfer to terminally differentiated retinal cells is important to study the function of the retina as well as for gene therapy of retinal diseases. We have developed a lentiviral vector system based on the HIV that can transduce terminally differentiated neurons of the brain in vivo. In this study, we have evaluated the ability of HIV vectors to transfer genes into retinal cells. An HIV vector containing a gene encoding the green fluorescent protein (GFP) was injected into the subretinal space of rat eyes. The GFP gene under the control of the cytomegalovirus promoter was efficiently expressed in both photoreceptor cells and retinal pigment epithelium. However, the use of the rhodopsin promoter resulted in expression predominantly in photoreceptor cells. Most successfully transduced eyes showed that photoreceptor cells in >80% of the area of whole retina expressed the GFP. The GFP expression persisted for at least 12 weeks with no apparent decrease. The efficient gene transfer into photoreceptor cells by HIV vectors will be useful for gene therapy of retinal diseases such as retinitis pigmentosa.

Visual BOLD Response in Late Blind Subjects with Argus II Retinal Prosthesis

PubMed Central

Castaldi, E.; Cicchini, G. M.; Cinelli, L.; Rizzo, S.; Morrone, M. C.

2016-01-01

Retinal prosthesis technologies require that the visual system downstream of the retinal circuitry be capable of transmitting and elaborating visual signals. We studied the capability of plastic remodeling in late blind subjects implanted with the Argus II Retinal Prosthesis with psychophysics and functional MRI (fMRI). After surgery, six out of seven retinitis pigmentosa (RP) blind subjects were able to detect high-contrast stimuli using the prosthetic implant. However, direction discrimination to contrast modulated stimuli remained at chance level in all of them. No subject showed any improvement of contrast sensitivity in either eye when not using the Argus II. Before the implant, the Blood Oxygenation Level Dependent (BOLD) activity in V1 and the lateral geniculate nucleus (LGN) was very weak or absent. Surprisingly, after prolonged use of Argus II, BOLD responses to visual input were enhanced. This is, to our knowledge, the first study tracking the neural changes of visual areas in patients after retinal implant, revealing a capacity to respond to restored visual input even after years of deprivation. PMID:27780207

Retinal Determination genes function along with cell-cell signals to regulate Drosophila eye development: examples of multi-layered regulation by Master Regulators

PubMed Central

Baker, Nicholas E.; Firth, Lucy C.

2015-01-01

It is thought that Retinal Determination gene products define the response made to cell-cell signals within the eye developmental field by binding to enhancers of genes that are also regulated by cell-cell signaling pathways. In Drosophila, Retinal Determination genes including Eyeless, teashirt, eyes absent, dachsous and sine oculis, are required for normal eye development and can induce ectopic eyes when mis-expressed. Characterization of the enhancers responsible for eye expression of the hedgehog, shaven, and atonal genes, as well as the dynamics of Retinal Determination gene expression themselves, now suggest a multilayered network whereby transcriptional regulation by either Retinal Determination genes or cell-cell signaling pathways can sometimes be indirect and mediated by other transcription factor intermediates. In this updated view of the interaction between extracellular information and cell intrinsic programs during development, regulation of individual genes might sometimes be several steps removed from either the Retinal Determination genes or cell-cell signaling pathways that nevertheless govern their expression. PMID:21607995

Synthetic 9-cis-beta-carotene inhibits photoreceptor degeneration in cultures of eye cups from rpe65rd12 mouse model of retinoid cycle defect.

PubMed

Sher, Ifat; Tzameret, Adi; Peri-Chen, Sara; Edelshtain, Victoria; Ioffe, Michael; Sayer, Alon; Buzhansky, Ludmila; Gazit, Ehud; Rotenstreich, Ygal

2018-04-17

The retinoid cycle enzymes regenerate the visual chromophore 11-cis retinal to enable vision. Mutations in the genes encoding the proteins of the retinoid cycle are the leading cause for recessively inherited retinal dystrophies such as retinitis pigmentosa, Leber congenital amaurosis, congenital cone-rod dystrophy and fundus albipunctatus. Currently there is no treatment for these blinding diseases. In previous studies we demonstrated that oral treatment with the 9-cis-β-carotene rich Dunaliella Bardawil algae powder significantly improved visual and retinal functions in patients with retinitis pigmentosa and fundus albipunctatus. Here we developed a convenient and economical synthetic route for biologically active 9-cis-β-carotene from inexpensive building materials and demonstrated that the molecule is stable for at least one month. Synthetic 9-cis-β-carotene rescued cone photoreceptors from degeneration in eye cup cultures of mice with a retinoid cycle genetic defect. This study suggests that synthetic 9-cis-β-carotene may serve as an effective treatment for retinal dystrophies involving the retinoid cycle.

Retinal stimulation strategies to restore vision: Fundamentals and systems.

PubMed

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

2016-07-01

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

Functional imaging of hemodynamic stimulus response in the rat retina with ultrahigh-speed spectral / Fourier domain OCT

NASA Astrophysics Data System (ADS)

Choi, WooJhon; Baumann, Bernhard; Clermont, Allen C.; Feener, Edward P.; Boas, David A.; Fujimoto, James G.

2013-03-01

Measuring retinal hemodynamics in response to flicker stimulus is important for investigating pathophysiology in small animal models of diabetic retinopathy, because a reduction in the hyperemic response is thought to be one of the earliest changes in diabetic retinopathy. In this study, we investigated functional imaging of retinal hemodynamics in response to flicker stimulus in the rat retina using an ultrahigh speed spectral / Fourier domain OCT system at 840nm with an axial scan rate of 244kHz. At 244kHz the nominal axial velocity range that could be measured without phase wrapping was +/-37.7mm/s. Pulsatile total retinal arterial blood flow as a function of time was measured using an en face Doppler approach where a 200μm × 200μm area centered at the central retinal artery was repeatedly raster scanned at a volume acquisition rate of 55Hz. Three-dimensional capillary imaging was performed using speckle decorrelation which has minimal angle dependency compared to other angiography techniques based on OCT phase information. During OCT imaging, a flicker stimulus could be applied to the retina synchronously by inserting a dichroic mirror in the imaging interface. An acute transient increase in total retinal blood flow could be detected. At the capillary level, an increase in the degree of speckle decorrelation in capillary OCT angiography images could also be observed, which indicates an increase in the velocity of blood at the capillary level. This method promises to be useful for the investigation of small animal models of ocular diseases.

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases.

PubMed

Trezza, Alfonso; Bernini, Andrea; Langella, Andrea; Ascher, David B; Pires, Douglas E V; Sodi, Andrea; Passerini, Ilaria; Pelo, Elisabetta; Rizzo, Stanislao; Niccolai, Neri; Spiga, Ottavia

2017-10-01

The aim of this article is to report the investigation of the structural features of ABCA4, a protein associated with a genetic retinal disease. A new database collecting knowledge of ABCA4 structure may facilitate predictions about the possible functional consequences of gene mutations observed in clinical practice. In order to correlate structural and functional effects of the observed mutations, the structure of mouse P-glycoprotein was used as a template for homology modeling. The obtained structural information and genetic data are the basis of our relational database (ABCA4Database). Sequence variability among all ABCA4-deposited entries was calculated and reported as Shannon entropy score at the residue level. The three-dimensional model of ABCA4 structure was used to locate the spatial distribution of the observed variable regions. Our predictions from structural in silico tools were able to accurately link the functional effects of mutations to phenotype. The development of the ABCA4Database gathers all the available genetic and structural information, yielding a global view of the molecular basis of some retinal diseases. ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations. Additionally, our ABCA4 predicted structure is a good starting point for the creation of a new data analysis model, appropriate for precision medicine, in order to develop a deeper knowledge network of the disease and to improve the management of patients.

Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

PubMed

Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

2016-09-01

Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular Expression and Functional Activity of Efflux and Influx Transporters in Hypoxia Induced Retinal Pigment Epithelial Cells

PubMed Central

Vadlapatla, Ramya; Vadlapudi, Aswani Dutt; Ponnaluri, VK Chaithanya; Pal, Dhananjay; Mukherji, Mridul; Mitra, Ashim K.

2013-01-01

A decrease in tissue oxygen levels (aka hypoxia) mediates a number of vascular retinal diseases. Despite introduction of novel therapeutics, treatment of retinal disorders remains challenging, possibly due to complex nature of hypoxia signaling. To date, the differential effect of hypoxia on expression of efflux and influx transporters in retinal cells has not been studied. Therefore, the objective of this study was to delineate molecular and functional expression of membrane transporters in human retinal pigment epithelial (RPE) cells cultured under normoxic and hypoxic conditions. Quantitative real time polymerase chain reaction (qPCR), ELISA and immunoblot analysis were performed to examine the RNA and protein expression levels of transporters. Further, functional activity was evaluated by performing the uptake of various substrates in both normoxic and hypoxic conditions. qPCR analysis showed elevated expression of efflux transporters (P-glycoprotein, multidrug resistant protein 2, breast cancer resistant protein) and influx transporters (folate receptor-α, cationic and neutral amino acid transporter, sodium dependent multivitamin transporter) in a time dependent manner. Immunoblot analysis further confirmed elevated expression of breast cancer resistant protein and sodium dependent multivitamin transporter. A decrease in the uptake of efflux transporter substrates (digoxin, lopinavir and abacavir) and enhanced uptake of influx transporter substrates (arginine, folic acid and biotin) in hypoxia relative to normoxia further confirmed elevated expression of transporters, respectively. This study demonstrates for the first time that hypoxic conditions may alter expression of efflux and influx transporters in RPE cells. These findings suggest that hypoxia may further alter disposition of ophthalmic drugs. PMID:23827654

Porcine Skin Visible Lesion Thresholds for Near-Infrared Lasers Including Modeling at Two Pulse Durations and Spot Sizes

DTIC Science & Technology

2006-08-01

injuries, including corneal, lenticular , and retinal lesions as a function of pulse duration. American National Standards Institute (ANSI) laser...little for skin effects. Unlike most other laser wavelengths, 1315-nm irradiation has been shown to cause damage at corneal, lenticular , and retinal

Connecting Research on Retinitis Pigmentosa to the Practice of Orientation and Mobility.

ERIC Educational Resources Information Center

Geruschat, Duane R.; Turano, Kathleen A.

2002-01-01

Retinitis pigmentosa (RP) causes restriction of the visual field, progressive vision loss, and night blindness. This article presents an overview of the most common problems in orientation and mobility (O&M) for individuals with RP, appropriate interventions, vision science discoveries related to RP, and the impact of RP on functional visual…

Microglia in the Retina: Roles in Development, Maturity, and Disease.

PubMed

Silverman, Sean M; Wong, Wai T

2018-05-31

Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional roles in the retina at different life stages. During development, retinal microglia regulate neuronal survival by exerting trophic influences and influencing programmed cell death. During adulthood, ramified microglia in the plexiform layers interact closely with synapses to maintain synaptic structure and function that underlie the retina's electrophysiological response to light. Under pathological conditions, retinal microglia participate in potentiating neurodegeneration in diseases such as glaucoma, retinitis pigmentosa, and age-related neurodegeneration by producing proinflammatory neurotoxic cytokines and removing living neurons via phagocytosis. Modulation of pathogenic microglial activation states and effector mechanisms has been linked to neuroprotection in animal models of retinal diseases. These findings have led to the design of early proof-of-concept clinical trials with microglial modulation as a therapeutic strategy. Expected final online publication date for the Annual Review of Vision Science Volume 4 is September 15, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

FBG-based sensorized light pipe for robotic intraocular illumination facilitates bimanual retinal microsurgery.

PubMed

Horise, Yuki; He, Xingchi; Gehlbach, Peter; Taylor, Russell; Iordachita, Iulian

2015-01-01

In retinal surgery, microsurgical instruments such as micro forceps, scissors and picks are inserted through the eye wall via sclerotomies. A handheld intraocular light source is typically used to visualize the tools during the procedure. Retinal surgery requires precise and stable tool maneuvers as the surgical targets are micro scale, fragile and critical to function. Retinal surgeons typically control an active surgical tool with one hand and an illumination source with the other. In this paper, we present a "smart" light pipe that enables true bimanual surgery via utilization of an active, robot-assisted source of targeted illumination. The novel sensorized smart light pipe measures the contact force between the sclerotomy and its own shaft, thereby accommodating the motion of the patient's eye. Forces at the point of contact with the sclera are detected by fiber Bragg grating (FBG) sensors on the light pipe. Our calibration and validation results demonstrate reliable measurement of the contact force as well as location of the sclerotomy. Preliminary experiments have been conducted to functionally evaluate robotic intraocular illumination.

The potential roles of metallothionein as a therapeutic target for cerebral ischemia and retinal diseases.

PubMed

Ito, Yasushi; Tanaka, Hirotaka; Hara, Hideaki

2013-01-01

Methallothionein (MT) is a low molecular weight cysteine rich metalloprotein. In mammals, there are four isoforms (MT-1, -2, -3, and -4) and they have multiple roles, such as the detoxification of heavy metals, regulating essential metal homeostasis, and protecting against oxidative stress. Recently, accumulating studies have suggested that MTs (especially MT-1, -2, and -3) are an important neuroprotective substance for cerebral ischemia and retinal diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), that are characterized by a progressive retinal degeneration. Oxidative stress and/or zinc toxicity has been implicated as part of the common pathway in these diseases. Studying the expression patterns and functions of MTs may broaden our understanding of the endogenous molecular responses that these diseases trigger, and may help us to develop new therapeutic strategies to treat them. However, the precise roles of MTs within the brain and retina are not fully understood in terms of neuropathological conditions. In this review, we discuss the recent findings focusing on MTs' functions following cerebral ischemia, AMD, and RP.

Not just signal shutoff: the protective role of arrestin-1 in rod cells.

PubMed

Sommer, Martha E; Hofmann, Klaus Peter; Heck, Martin

2014-01-01

The retinal rod cell is an exquisitely sensitive single-photon detector that primarily functions in dim light (e.g., moonlight). However, rod cells must routinely survive light intensities more than a billion times greater (e.g., bright daylight). One serious challenge to rod cell survival in daylight is the massive amount of all-trans-retinal that is released by Meta II, the light-activated form of the photoreceptor rhodopsin. All-trans-retinal is toxic, and its condensation products have been implicated in disease. Our recent work has developed the concept that rod arrestin (arrestin-1), which terminates Meta II signaling, has an additional role in protecting rod cells from the consequences of bright light by limiting free all-trans-retinal. In this chapter we will elaborate upon the molecular mechanisms by which arrestin-1 serves as both a single-photon response quencher as well as an instrument of rod cell survival in bright light. This discussion will take place within the framework of three distinct functional modules of vision: signal transduction, the retinoid cycle, and protein translocation.

Intraocular gene transfer of ciliary neurotrophic factor rescues photoreceptor degeneration in RCS rats.

PubMed

Huang, Shun-Ping; Lin, Po-Kang; Liu, Jorn-Hon; Khor, Chin-Ni; Lee, Yih-Jing

2004-01-01

Ciliary neurotrophic factor (CNTF) is known as an important factor in the regulation of retinal cell growth. We used both recombinant CNTF and an adenovirus carrying the CNTF gene to regulate retinal photoreceptor expression in a retinal degenerative animal, Royal College of Surgeons (RCS) rats. Cells in the outer nuclear layer of the retinae from recombinant-CNTF-treated, adenoviral-CNTF-treated, saline-operated, and contralateral untreated preparations were examined for those exhibiting CNTF photoreceptor protective effects. Cell apoptosis in the outer nuclear layer of the retinae was also detected. It was found that CNTF had a potent effect on delaying the photoreceptor degeneration process in RCS rats. Furthermore, adenovirus CNTF gene transfer was proven to be better at rescuing photoreceptors than that when using recombinant CNTF, since adenoviral CNTF prolonged the photoreceptor protection effect. The function of the photoreceptors was also examined by taking electroretinograms of different animals. Adenoviral-CNTF-treated eyes showed better retinal function than did the contralateral control eyes. This study indicates that adenoviral CNTF effectively rescues degenerating photoreceptors in RCS rats. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration.

PubMed

Mehat, Manjit S; Sundaram, Venki; Ripamonti, Caterina; Robson, Anthony G; Smith, Alexander J; Borooah, Shyamanga; Robinson, Martha; Rosenthal, Adam N; Innes, William; Weleber, Richard G; Lee, Richard W J; Crossland, Michael; Rubin, Gary S; Dhillon, Baljean; Steel, David H W; Anglade, Eddy; Lanza, Robert P; Ali, Robin R; Michaelides, Michel; Bainbridge, James W B

2018-06-05

Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Retinal imaging as a source of biomarkers for diagnosis, characterization and prognosis of chronic illness or long-term conditions

PubMed Central

Trucco, E; Cameron, J R; Dhillon, B; Houston, J G; van Beek, E J R

2014-01-01

The black void behind the pupil was optically impenetrable before the invention of the ophthalmoscope by von Helmholtz over 150 years ago. Advances in retinal imaging and image processing, especially over the past decade, have opened a route to another unexplored landscape, the retinal neurovascular architecture and the retinal ganglion pathways linking to the central nervous system beyond. Exploiting these research opportunities requires multidisciplinary teams to explore the interface sitting at the border between ophthalmology, neurology and computing science. It is from the detail and depth of retinal phenotyping that novel metrics and candidate biomarkers are likely to emerge. Confirmation that in vivo retinal neurovascular measures are predictive of microvascular change in the brain and other organs is likely to be a major area of research activity over the next decade. Unlocking this hidden potential within the retina requires integration of structural and functional data sets, that is, multimodal mapping and longitudinal studies spanning the natural history of the disease process. And with further advances in imaging, it is likely that this area of retinal research will remain active and clinically relevant for many years to come. Accordingly, this review looks at state-of-the-art retinal imaging and its application to diagnosis, characterization and prognosis of chronic illness or long-term conditions. PMID:24936979

Decursin inhibits VEGF-mediated inner blood-retinal barrier breakdown by suppression of VEGFR-2 activation.

PubMed

Kim, Jin Hyoung; Kim, Jeong Hun; Lee, You Mie; Ahn, Eun-Mi; Kim, Kyu-Won; Yu, Young Suk

2009-09-01

The blood-retinal barrier (BRB) is essential for the normal structural and functional integrity of the retina, whose breakdown could cause the serious vision loss. Vascular endothelial growth factor (VEGF), as a permeable factor, induces alteration of tight junction proteins to result in BRB breakdown. Herein, we demonstrated that decursin inhibits VEGF-mediated inner BRB breakdown through suppression of VEGFR-2 signaling pathway. In retinal endothelial cells, decursin inhibited VEGF-mediated hyperpermeability. Decursin prevented VEGF-mediated loss of tight junction proteins including zonula occludens-1 (ZO-1), ZO-2, and occludin in retinal endothelial cells, which was also supported by restoration of tight junction proteins in intercellular junction. In addition, decursin significantly inhibited VEGF-mediated vascular leakage from retinal vessels, which was accompanied by prevention of loss of tight junction proteins in retinal vessels. Decursin significantly suppressed VEGF-induced VEGFR-2 phosphrylation that consequently led to inhibition of extracellular signal-regulated kinase (ERK) 1/2 activation. Moreover, decursin induced no cytotoxicity to retinal endothelial cells and no retinal toxicity under therapeutic concentrations. Therefore, our results suggest that decursin prevents VEGF-mediated BRB breakdown through blocking of loss of tight junction proteins, which might be regulated by suppression of VEGFR-2 activation. As a novel inhibitor to BRB breakdown, decursin could be applied to variable retinopathies with BRB breakdown.

Fluorescence lifetime imaging ophthalmoscopy.

PubMed

Dysli, Chantal; Wolf, Sebastian; Berezin, Mikhail Y; Sauer, Lydia; Hammer, Martin; Zinkernagel, Martin S

2017-09-01

Imaging techniques based on retinal autofluorescence have found broad applications in ophthalmology because they are extremely sensitive and noninvasive. Conventional fundus autofluorescence imaging measures fluorescence intensity of endogenous retinal fluorophores. It mainly derives its signal from lipofuscin at the level of the retinal pigment epithelium. Fundus autofluorescence, however, can not only be characterized by the spatial distribution of the fluorescence intensity or emission spectrum, but also by a characteristic fluorescence lifetime function. The fluorescence lifetime is the average amount of time a fluorophore remains in the excited state following excitation. Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging imaging modality for in vivo measurement of lifetimes of endogenous retinal fluorophores. Recent reports in this field have contributed to our understanding of the pathophysiology of various macular and retinal diseases. Within this review, the basic concept of fluorescence lifetime imaging is provided. It includes technical background information and correlation with in vitro measurements of individual retinal metabolites. In a second part, clinical applications of fluorescence lifetime imaging and fluorescence lifetime features of selected retinal diseases such as Stargardt disease, age-related macular degeneration, choroideremia, central serous chorioretinopathy, macular holes, diabetic retinopathy, and retinal artery occlusion are discussed. Potential areas of use for fluorescence lifetime imaging ophthalmoscopy will be outlined at the end of this review. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effect of subretinal injection on retinal structure and function in a rat oxygen-induced retinopathy model.

PubMed

Becker, Silke; Wang, Haibo; Stoddard, Gregory J; Hartnett, M Elizabeth

2017-01-01

Subretinal injections are used to deliver agents in experimental studies of retinal diseases, often through viral vectors. However, few studies have investigated the effects of subretinal injections alone on the structure and function of the healthy or diseased retina, particularly in models of oxygen-induced retinopathy (OIR). We report on the effects of subretinal injections in a rat OIR model, which is used to study mechanisms of retinopathy of prematurity. Within 6 h of birth, neonatal rat pups were exposed to repeated cycles of oxygen between 50% and 10% O 2 every 24 h for 14 days and subsequently moved to room air. On postnatal day 8 (P8), animals were treated in both eyes with advancement of the injection needle into the vitreous (pilot-treated) or with a subretinal PBS injection (sPBS-treated) or were left untreated (untreated). Additional control animals were exposed to microscope light after eyelid opening only (light-treated). Retinal fundus images were recorded on P26. Areas of the avascular retina and intravitreal neovascularization were determined in flat mounted retinas stained with isolectin B4 on P32. Retinal function of the respective eyes was assessed with the Ganzfeld electroretinogram (ERG) on P31 or P32 and with focal ERG in the central retina on P28 or P29. The thickness of the retinal layers was measured with spectral domain optical coherence tomography (OCT) on P30 and in opsin- and TO-PRO 3-stained retinal cryosections from pups euthanized on P32. Two sections were analyzed in each pup. For each section, three images of three different locations were analyzed accounting for 18 thickness measurements per pup. Compared to untreated animals, the avascular area of the retina was greater in the pilot-treated (p<0.05) and sPBS-treated eyes (p<0.01), and the sPBS-treated eyes had a greater avascular retinal area compared to the pilot-treated eyes (p<0.01). The intravitreal neovascular area was larger in the sPBS-treated eyes compared to the untreated eyes (p<0.01). The outer nuclear and outer segment layers were thinner in the pilot- (p<0.01) and sPBS-treated eyes (p<0.05) compared to the untreated eyes as measured with OCT and immunohistochemical staining of the retinal cryosections. Compared to the untreated eyes, the amplitudes of the scotopic a- and b-waves in the Ganzfeld ERG were reduced in the pilot-treated eyes (p<0.001 and p<0.01, respectively), but only the a-wave was reduced in the sPBS-treated eyes (p<0.001). The a-wave amplitude in the focal ERG was reduced in the pilot- and sPBS-treated eyes, and no difference was seen in the b-wave amplitude between any of the groups. There was no difference between the light-treated and untreated eyes in the areas of the avascular retina or intravitreal neovascularization or Ganzfeld or focal ERG. Pilot injections alone without injection into the subretinal space resulted in an increased avascular retinal area, reduced thickness of the photoreceptors, and reduced ERG function compared to the untreated animals. Although subretinal PBS injections further increased the areas of avascular retina and intravitreal neovascularization and resulted in similar retinal thinning compared to the pilot treatment, inner retinal function was improved, as evidenced by higher Ganzfeld b-wave amplitudes. Differences in the Ganzfeld and focal ERGs may indicate that the peripheral retina is more susceptible to remote beneficial effects from potential protective mechanisms induced by subretinal injection. This study stresses the importance of appropriate controls in experiments with subretinal delivery of agents.

A partial structural and functional rescue of a retinitis pigmentosa model with compacted DNA nanoparticles.

PubMed

Cai, Xue; Nash, Zack; Conley, Shannon M; Fliesler, Steven J; Cooper, Mark J; Naash, Muna I

2009-01-01

Previously we have shown that compacted DNA nanoparticles can drive high levels of transgene expression after subretinal injection in the mouse eye. Here we delivered compacted DNA nanoparticles containing a therapeutic gene to the retinas of a mouse model of retinitis pigmentosa. Nanoparticles containing the wild-type retinal degeneration slow (Rds) gene were injected into the subretinal space of rds(+/-) mice on postnatal day 5. Gene expression was sustained for up to four months at levels up to four times higher than in controls injected with saline or naked DNA. The nanoparticles were taken up into virtually all photoreceptors and mediated significant structural and biochemical rescue of the disease without histological or functional evidence of toxicity. Electroretinogram recordings showed that nanoparticle-mediated gene transfer restored cone function to a near-normal level in contrast to transfer of naked plasmid DNA. Rod function was also improved. These findings demonstrate that compacted DNA nanoparticles represent a viable option for development of gene-based interventions for ocular diseases and obviate major barriers commonly encountered with non-viral based therapies.

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

PubMed Central

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

2012-01-01

Objectives To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats. Methods Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls. Results Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p<0.01) and significant reduction one week (p<0.01) after light damage. In contrast, ketamine-xylazine pre-treated animals showed no significant alteration of total retinal or ONL thickness at either time point (p>0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03) were observed in non-treated vs. ketamine-xylazine treated animals. Conclusions Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage. PMID:22558200

Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa.

PubMed

Fernández-Sánchez, Laura; Lax, Pedro; Isiegas, Carolina; Ayuso, Eduard; Ruiz, José M; de la Villa, Pedro; Bosch, Fatima; de la Rosa, Enrique J; Cuenca, Nicolás

2012-12-01

Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi-) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa.

Cell-type specific roles for PTEN in establishing a functional retinal architecture.

PubMed

Cantrup, Robert; Dixit, Rajiv; Palmesino, Elena; Bonfield, Stephan; Shaker, Tarek; Tachibana, Nobuhiko; Zinyk, Dawn; Dalesman, Sarah; Yamakawa, Kazuhiro; Stell, William K; Wong, Rachel O; Reese, Benjamin E; Kania, Artur; Sauvé, Yves; Schuurmans, Carol

2012-01-01

The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture. In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam. We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina.

Primary Repair of Moderate Severity Rhegmatogenous Retinal Detachment: A Critical Decision-Making Algorithm.

PubMed

Velez-Montoya, Raul; Jacobo-Oceguera, Paola; Flores-Preciado, Javier; Dalma-Weiszhausz, Jose; Guerrero-Naranjo, Jose; Salcedo-Villanueva, Guillermo; Garcia-Aguirre, Gerardo; Fromow-Guerra, Jans; Morales-Canton, Virgilio

2016-01-01

We reviewed all the available data regarding the current management of non-complex rhegmatogenous retinal detachment and aimed to propose a new decision-making algorithm aimed to improve the single surgery success rate for mid-severity rhegmatogenous retinal detachment. An online review of the Pubmed database was performed. We searched for all available manuscripts about the anatomical and functional outcomes after the surgical management, by either scleral buckle or primary pars plana vitrectomy, of retinal detachment. The search was limited to articles published from January 1995 to December 2015. All articles obtained from the search were carefully screened and their references were manually reviewed for additional relevant data. Our search specifically focused on preoperative clinical data that were associated with the surgical outcomes. After categorizing the available data according to their level of evidence, with randomized-controlled clinical trials as the highest possible level of evidence, followed by retrospective studies, and retrospective case series as the lowest level of evidence, we proceeded to design a logical decision-making algorithm, enhanced by our experiences as retinal surgeons. A total of 7 randomized-controlled clinical trials, 19 retrospective studies, and 9 case series were considered. Additional articles were also included in order to support the observations further. Rhegmatogenous retinal detachment is a potentially blinding disorder. Its surgical management seems to depend more on a surgeon´s preference than solid scientific data or is based on a good clinical history and examination. The algorithms proposed herein strive to offer a more rational approach to improve both anatomical and functional outcomes after the first surgery.

[Atp6ap2/ (Pro) renin Receptor is Required for Laminar Formation during Retinal Development in Mice].

PubMed

Kanda, Atsuhiro

2015-11-01

(Pro) renin receptor [(P) RR], a key molecule for tissue renin-angiotensin system, was originally identified as Atp6ap2, an accessory subunit for vacuolar H(+)-ATPase that is a multi-subunit proton pump involved in fundamental cellular physiology. In this study, to elucidate the physiological functions of Atp6ap2/ (P) RR during retinal development in mammals, we used Cre-LoxP system to generate photoreceptor-specific conditional knock-out (CKO) mice, and revealed a critical role of Atp6ap2/(P) RR in photoreceptor development. Deletion of photoreceptor Atp6ap2/ (P) RR did not affect retinal cell differentiation, but led to laminar disorganization in the photoreceptor layer with dysfunction of photoreceptors. Cell adhesion and polarity molecules, all of which were co-localized with Atp6ap2 at the apical edge of the developing retina, were dispersed together with mislocalization of retinal progenitors apart from the apical surface in Atp6ap2 conditional knockout mice. Among these molecules, co-immunoprecipitation using retinal homogenates and Atp6ap2/(P) RR-transfected cells showed that Atp6ap2/(P) RR interacted with partitioning defective 3 homolog (Par3) protein, known to play a pivotal role in planar cell polarity in the Par-atypical protein kinase C system. Atp6ap2 interacted with Par3 protein that plays a pivotal role in planar cell polarity. Our data provide a novel function of Atp6ap2 required as a cell polarity determinant for retinal laminar formation.

Primary Repair of Moderate Severity Rhegmatogenous Retinal Detachment: A Critical Decision-Making Algorithm

PubMed Central

VELEZ-MONTOYA, Raul; JACOBO-OCEGUERA, Paola; FLORES-PRECIADO, Javier; DALMA-WEISZHAUSZ, Jose; GUERRERO-NARANJO, Jose; SALCEDO-VILLANUEVA, Guillermo; GARCIA-AGUIRRE, Gerardo; FROMOW-GUERRA, Jans; MORALES-CANTON, Virgilio

2016-01-01

We reviewed all the available data regarding the current management of non-complex rhegmatogenous retinal detachment and aimed to propose a new decision-making algorithm aimed to improve the single surgery success rate for mid-severity rhegmatogenous retinal detachment. An online review of the Pubmed database was performed. We searched for all available manuscripts about the anatomical and functional outcomes after the surgical management, by either scleral buckle or primary pars plana vitrectomy, of retinal detachment. The search was limited to articles published from January 1995 to December 2015. All articles obtained from the search were carefully screened and their references were manually reviewed for additional relevant data. Our search specifically focused on preoperative clinical data that were associated with the surgical outcomes. After categorizing the available data according to their level of evidence, with randomized-controlled clinical trials as the highest possible level of evidence, followed by retrospective studies, and retrospective case series as the lowest level of evidence, we proceeded to design a logical decision-making algorithm, enhanced by our experiences as retinal surgeons. A total of 7 randomized-controlled clinical trials, 19 retrospective studies, and 9 case series were considered. Additional articles were also included in order to support the observations further. Rhegmatogenous retinal detachment is a potentially blinding disorder. Its surgical management seems to depend more on a surgeon´s preference than solid scientific data or is based on a good clinical history and examination. The algorithms proposed herein strive to offer a more rational approach to improve both anatomical and functional outcomes after the first surgery. PMID:28289689

RPGR-Associated Retinal Degeneration in Human X-Linked RP and a Murine Model

PubMed Central

Huang, Wei Chieh; Wright, Alan F.; Roman, Alejandro J.; Cideciyan, Artur V.; Manson, Forbes D.; Gewaily, Dina Y.; Schwartz, Sharon B.; Sadigh, Sam; Limberis, Maria P.; Bell, Peter; Wilson, James M.; Swaroop, Anand; Jacobson, Samuel G.

2012-01-01

Purpose. We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model. Methods. XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5–72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset. Results. Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration. Conclusions. RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy. PMID:22807293

Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage.

PubMed

Braunger, Barbara M; Ohlmann, Andreas; Koch, Marcus; Tanimoto, Naoyuki; Volz, Cornelia; Yang, Ying; Bösl, Michael R; Cvekl, Ales; Jägle, Herbert; Seeliger, Mathias W; Tamm, Ernst R

2013-02-01

Norrin is a retinal signaling molecule which is expressed in Müller glia and binds to Frizzled-4 to activate canonical Wnt/β-catenin signaling. Norrin is part of an essential signaling system that controls the formation of retinal capillaries during development. To evaluate neuroprotective properties of Norrin independently from its function during retinal angiogenesis, we generated transgenic mice (Rpe65-Norrin) that constitutively express Norrin in the retinal pigmented epithelium. Substantial amounts of Norrin were secreted into the outer retina, which triggered retinal Wnt/β-catenin signaling in conjunction with an increase in the expression of endothelin-2 (EDN2), endothelin receptor B (EDNRB), and glial fibrillary acidic protein (GFAP). Photoreceptors of Norrin-overexpressing mice were significantly less vulnerable to light-induced damage compared to their wild-type littermates. Following light damage, we observed less apoptotic death of photoreceptors and a better retinal function than in controls. The protective effects were abolished if either Wnt/β-catenin or EDN2 signaling was blocked by intravitreal injection of Dickkopf-1 or BQ788, respectively. Light-damaged retinae from transgenic mice contained higher amounts of brain-derived neurotrophic factor (BDNF) and pAkt than those of wild-type littermates. We conclude that constitutive overexpression of Norrin protects photoreceptors from light damage, an effect that is mediated by Wnt/β-catenin and EDN2 signaling and involves neurotrophic activities of BDNF. The findings suggest that Norrin and its associated signaling pathways have strong potentials to attenuate photoreceptor death following injury. Copyright © 2012 Elsevier Inc. All rights reserved.

Probing the functional impact of sub-retinal prosthesis

PubMed Central

Roux, Sébastien; Matonti, Frédéric; Dupont, Florent; Hoffart, Louis; Takerkart, Sylvain; Picaud, Serge; Pham, Pascale; Chavane, Frédéric

2016-01-01

Retinal prostheses are promising tools for recovering visual functions in blind patients but, unfortunately, with still poor gains in visual acuity. Improving their resolution is thus a key challenge that warrants understanding its origin through appropriate animal models. Here, we provide a systematic comparison between visual and prosthetic activations of the rat primary visual cortex (V1). We established a precise V1 mapping as a functional benchmark to demonstrate that sub-retinal implants activate V1 at the appropriate position, scalable to a wide range of visual luminance, but with an aspect-ratio and an extent much larger than expected. Such distorted activation profile can be accounted for by the existence of two sources of diffusion, passive diffusion and activation of ganglion cells’ axons en passant. Reverse-engineered electrical pulses based on impedance spectroscopy is the only solution we tested that decreases the extent and aspect-ratio, providing a promising solution for clinical applications. DOI: http://dx.doi.org/10.7554/eLife.12687.001 PMID:27549126

Sodium Iodate Selectively Injuries the Posterior Pole of the Retina in a Dose-Dependent Manner: Morphological and Electrophysiological Study

PubMed Central

Machalińska, Anna; Lubiński, Wojciech; Kłos, Patrycja; Kawa, Miłosz; Baumert, Bartłomiej; Penkala, Krzysztof; Grzegrzółka, Ryszard; Karczewicz, Danuta; Wiszniewska, Barbara

2010-01-01

Sequential morphological and functional features of retinal damage in mice exposed to different doses (40 vs. 20 mg/kg) of sodium iodate (NaIO3) were analyzed. Retinal morphology, apoptosis (TUNEL assay), and function (electroretinography; ERG) were examined at several time points after NaIO3 administration. The higher dose of NaIO3 caused progressive degeneration of the whole retinal area and total suppression of scotopic and photopic ERG. In contrast, the lower dose induced much less severe degeneration in peripheral part of retina along with a moderate decline of b- and a-wave amplitudes in ERG, corroborating the presence of regions within retina that retain their function. The peak of photoreceptor apoptosis was found on the 3rd day, but the lower dose induced more intense reaction within the central retina than in its peripheral region. In conclusion, these results indicate that peripheral area of the retina reveals better resistance to NaIO3 injury than its central part. PMID:20725778

Conditional Ablation of Retinol Dehydrogenase 10 in the Retinal Pigmented Epithelium Causes Delayed Dark Adaption in Mice*

PubMed Central

Sahu, Bhubanananda; Sun, Wenyu; Perusek, Lindsay; Parmar, Vipulkumar; Le, Yun-Zheng; Griswold, Michael D.; Palczewski, Krzysztof; Maeda, Akiko

2015-01-01

Regeneration of the visual chromophore, 11-cis-retinal, is a crucial step in the visual cycle required to sustain vision. This cycle consists of sequential biochemical reactions that occur in photoreceptor cells and the retinal pigmented epithelium (RPE). Oxidation of 11-cis-retinol to 11-cis-retinal is accomplished by a family of enzymes termed 11-cis-retinol dehydrogenases, including RDH5 and RDH11. Double deletion of Rdh5 and Rdh11 does not limit the production of 11-cis-retinal in mice. Here we describe a third retinol dehydrogenase in the RPE, RDH10, which can produce 11-cis-retinal. Mice with a conditional knock-out of Rdh10 in RPE cells (Rdh10 cKO) displayed delayed 11-cis-retinal regeneration and dark adaption after bright light illumination. Retinal function measured by electroretinogram after light exposure was also delayed in Rdh10 cKO mice as compared with controls. Double deletion of Rdh5 and Rdh10 (cDKO) in mice caused elevated 11/13-cis-retinyl ester content also seen in Rdh5−/−Rdh11−/− mice as compared with Rdh5−/− mice. Normal retinal morphology was observed in 6-month-old Rdh10 cKO and cDKO mice, suggesting that loss of Rdh10 in the RPE does not negatively affect the health of the retina. Compensatory expression of other retinol dehydrogenases was observed in both Rdh5−/− and Rdh10 cKO mice. These results indicate that RDH10 acts in cooperation with other RDH isoforms to produce the 11-cis-retinal chromophore needed for vision. PMID:26391396

Application of stem cell-derived retinal pigmented epithelium in retinal degenerative diseases: present and future.

PubMed

Luo, Mingyue; Chen, Youxin

2018-01-01

As a constituent of blood-retinal barrier and retinal outer segment (ROS) scavenger, retinal pigmented epithelium (RPE) is fundamental to normal function of retina. Malfunctioning of RPE contributes to the onset and advance of retinal degenerative diseases. Up to date, RPE replacement therapy is the only possible method to completely reverse retinal degeneration. Transplantation of human RPE stem cell-derived RPE (hRPESC-RPE) has shown some good results in animal models. With promising results in terms of safety and visual improvement, human embryonic stem cell-derived RPE (hESC-RPE) can be expected in clinical settings in the near future. Despite twists and turns, induced pluripotent stem cell-derived RPE (iPSC-RPE) is now being intensely investigated to overcome genetic and epigenetic instability. By far, only one patient has received iPSC-RPE transplant, which is a hallmark of iPSC technology development. During follow-up, no major complications such as immunogenicity or tumorigenesis have been observed. Future trials should keep focusing on the safety of stem cell-derived RPE (SC-RPE) especially in long period, and better understanding of the nature of stem cell and the molecular events in the process to generate SC-RPE is necessary to the prosperity of SC-RPE clinical application.

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

PubMed Central

2016-01-01

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway. PMID:27818722

Astrocytes increase barrier properties and ZO-1 expression in retinal vascular endothelial cells.

PubMed

Gardner, T W; Lieth, E; Khin, S A; Barber, A J; Bonsall, D J; Lesher, T; Rice, K; Brennan, W A

1997-10-01

Diabetic retinopathy and other diseases associated with retinal edema are characterized by increased microvascular leakage. Astrocytes have been proposed to maintain endothelial function in the brain, suggesting that glial impairment may underlie the development of retinal edema. The purpose of this study was to test the effects of astrocytes on barrier properties in retinal microvascular endothelial cells. Bovine retinal microvascular endothelial cells were exposed to conditioned media from rat brain astrocytes. Transendothelial electrical resistance (TER) was determined on 24-mm Transwell (Cambridge, MA) polycarbonate filters with the End-Ohm device (World Precision Instruments, Sarasota, FL). ZO-1 protein content was quantified by microtiter enzyme-linked immunosorbent assay. Astrocyte-conditioned medium (ACM) significantly increased TER (P < 0.0001) and ZO-1 content (P < 0.01). Both serum-containing and serum-free N1B defined ACM increased ZO-1 expression, but heating abolished the effect. Serum-free ACM decreased cell proliferation by 16%. Astrocytes release soluble, heat-labile factors that increase barrier properties and tight junction protein content. These results suggest that astrocytes enhance blood-retinal barrier properties, at least in part by increasing tight junction protein expression. Our findings suggest that glial malfunction plays an important role in the pathogenesis of vasogenic retinal edema.

Changes in morphology of retinal ganglion cells with eccentricity in retinal degeneration.

PubMed

Anderson, E E; Greferath, U; Fletcher, E L

2016-05-01

Ganglion cells are the output neurons of the retina and are known to remodel during the subtle plasticity changes that occur following the death of photoreceptors in inherited retinal degeneration. We examine the influence of retinal eccentricity on anatomical remodelling and ganglion cell morphology well after photoreceptor loss. Rd1 mice that have a mutation in the β subunit of phosphodiesterase 6 were used as a model of retinal degeneration and gross remodelling events were examined by processing serial sections for immunocytochemistry. Retinal wholemounts from rd1-Thy1 and control Thy1 mice that contained a fluorescent protein labelling a subset of ganglion cells were processed for immunohistochemistry at 11 months of age. Ganglion cells were classified based on their soma size, dendritic field size and dendritic branching pattern and their dendritic fields were analysed for their length, area and quantity of branching points. Overall, more remodelling was found in the central compared with the peripheral retina. In addition, the size and complexity of A2, B1, C1 and D type ganglion cells located in the central region of the retina decreased. We propose that the changes in ganglion cell morphology are correlated with remodelling events in these regions and impact the function of retinal circuitry in the degenerated retina.

Filling in the retinal image

NASA Technical Reports Server (NTRS)

Larimer, James; Piantanida, Thomas

1990-01-01

The optics of the eye form an image on a surface at the back of the eyeball called the retina. The retina contains the photoreceptors that sample the image and convert it into a neural signal. The spacing of the photoreceptors in the retina is not uniform and varies with retinal locus. The central retinal field, called the macula, is densely packed with photoreceptors. The packing density falls off rapidly as a function of retinal eccentricity with respect to the macular region and there are regions in which there are no photoreceptors at all. The retinal regions without photoreceptors are called blind spots or scotomas. The neural transformations which convert retinal image signals into percepts fills in the gaps and regularizes the inhomogeneities of the retinal photoreceptor sampling mosaic. The filling-in mechamism plays an important role in understanding visual performance. The filling-in mechanism is not well understood. A systematic collaborative research program at the Ames Research Center and SRI in Menlo Park, California, was designed to explore this mechanism. It was shown that the perceived fields which are in fact different from the image on the retina due to filling-in, control some aspects of performance and not others. Researchers have linked these mechanisms to putative mechanisms of color coding and color constancy.

The spectrum of retinopathy in adults with Plasmodium falciparum malaria.

PubMed

Maude, Richard J; Beare, Nicholas A V; Abu Sayeed, Abdullah; Chang, Christina C; Charunwatthana, Prakaykaew; Faiz, M Abul; Hossain, Amir; Yunus, Emran Bin; Hoque, M Gofranul; Hasan, Mahtab Uddin; White, Nicholas J; Day, Nicholas P J; Dondorp, Arjen M

2009-07-01

A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%; P=0.038) or healthy controls (0/18, 0%; P<0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy.

Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina.

PubMed

Choi, Hannah; Zhang, Lei; Cembrowski, Mark S; Sabottke, Carl F; Markowitz, Alexander L; Butts, Daniel A; Kath, William L; Singer, Joshua H; Riecke, Hermann

2014-09-15

In many forms of retinal degeneration, photoreceptors die but inner retinal circuits remain intact. In the rd1 mouse, an established model for blinding retinal diseases, spontaneous activity in the coupled network of AII amacrine and ON cone bipolar cells leads to rhythmic bursting of ganglion cells. Since such activity could impair retinal and/or cortical responses to restored photoreceptor function, understanding its nature is important for developing treatments of retinal pathologies. Here we analyzed a compartmental model of the wild-type mouse AII amacrine cell to predict that the cell's intrinsic membrane properties, specifically, interacting fast Na and slow, M-type K conductances, would allow its membrane potential to oscillate when light-evoked excitatory synaptic inputs were withdrawn following photoreceptor degeneration. We tested and confirmed this hypothesis experimentally by recording from AIIs in a slice preparation of rd1 retina. Additionally, recordings from ganglion cells in a whole mount preparation of rd1 retina demonstrated that activity in AIIs was propagated unchanged to elicit bursts of action potentials in ganglion cells. We conclude that oscillations are not an emergent property of a degenerated retinal network. Rather, they arise largely from the intrinsic properties of a single retinal interneuron, the AII amacrine cell. Copyright © 2014 the American Physiological Society.

Diabetes accelerates retinal ganglion cell dysfunction in mice lacking sigma receptor 1

PubMed Central

Ha, Yonju; Saul, Alan; Tawfik, Amany; Zorrilla, Eric P.; Ganapathy, Vadivel

2012-01-01

Purpose Sigma receptor 1 (σR1) is a non-opioid transmembrane protein that may act as a molecular chaperone at the endoplasmic reticulum–mitochondrial membrane. Ligands for σR1, such as (+)-pentazocine [(+)-PTZ], confer marked retinal neuroprotection in vivo and in vitro. Recently we analyzed the retinal phenotype of mice lacking σR1 (σR1 KO) and observed normal retinal morphology and function in young mice (5–30 weeks) but diminished negative scotopic threshold responses (nSTRs), retinal ganglion cell (RGC) loss, and disruption of optic nerve axons consistent with inner retinal dysfunction by 1 year. These data led us to test the hypothesis that σR1 may be critical in forestalling chronic retinal stress; diabetes was used as the model of chronic stress. Methods To determine whether σR1 is required for (+)-PTZ neuroprotective effects, primary RGCs isolated from wild-type (WT) and σR1 KO mice were exposed to xanthine–xanthine oxidase (10 µM:2 mU/ml) to induce oxidative stress in the presence or absence of (+)-PTZ. Cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. To assess effects of chronic stress on RGC function, diabetes was induced in 3-week C57BL/6 (WT) and σR1 KO mice, using streptozotocin to yield four groups: WT nondiabetic (WT non-DB), WT diabetic (WT-DB), σR1 KO non-DB, and σR1 KO-DB. After 12 weeks of diabetes, when mice were 15-weeks old, intraocular pressure (IOP) was recorded, electrophysiologic testing was performed (including detection of nSTRs), and the number of RGCs was counted in retinal histological sections. Results In vitro studies showed that (+)-PTZ could not prevent oxidative stress-induced death of RGCs harvested from σR1 KO mice but afforded robust protection against death of RGCs harvested from WT mice. In the studies of chronic stress induced by diabetes, the IOP measured in the four mouse groups was within the normal range; however, there was a significant increase in the IOP of σR1 KO-DB mice (16±0.5 mmHg) compared to the other groups tested (σR1 KO non-DB, WT non-DB, WT-DB: ~12±0.6 mmHg). Regarding electrophysiologic testing, the nSTRs of σR1 KO non-DB mice were similar to WT non-DB mice at 15 weeks; however, they were significantly lower in σR1 KO-DB mice (5±1 µV) compared to the other groups, including, notably, σR1 KO-nonDB (12±2 µV). As expected, the number of RGCs in σR1 KO non-DB mice was similar to WT non-DB mice at 15 weeks, but under chronic stress of diabetes there were fewer RGCs in retinas of σR1 KO-DB mice. Conclusions This is the first report showing unequivocally that the neuroprotective effects of (+)-PTZ require σR1. σR1 KO mice show normal retinal structure and function at young ages; however, when subjected to the chronic stress of diabetes, there is an acceleration of retinal functional deficits in σR1 KO mice such that ganglion cell dysfunction is observed at a much earlier age than nondiabetic σR1 KO mice. The data support the hypothesis that σR1 plays a key role in modulating retinal stress and may be an important target for retinal disease. PMID:23233788

Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice.

PubMed

Ohlmann, Andreas; Scholz, Michael; Goldwich, Andreas; Chauhan, Bharesh K; Hudl, Kristiane; Ohlmann, Anne V; Zrenner, Eberhart; Berger, Wolfgang; Cvekl, Ales; Seeliger, Mathias W; Tamm, Ernst R

2005-02-16

Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

PubMed Central

Parmeggiani, Francesco; Barbaro, Vanessa; De Nadai, Katia; Lavezzo, Enrico; Toppo, Stefano; Chizzolini, Marzio; Palù, Giorgio; Parolin, Cristina; Di Iorio, Enzo

2016-01-01

The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of-function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures. PMID:27995965

Method to investigate temporal dynamics of ganglion and other retinal cells in the living human eye

NASA Astrophysics Data System (ADS)

Kurokawa, Kazuhiro; Liu, Zhuolin; Crowell, James; Zhang, Furu; Miller, Donald T.

2018-02-01

The inner retina is critical for visual processing, but much remains unknown about its neural circuitry and vulnerability to disease. A major bottleneck has been our inability to observe the structure and function of the cells composing these retinal layers in the living human eye. Here, we present a noninvasive method to observe both structural and functional information. Adaptive optics optical coherence tomography (AO-OCT) is used to resolve the inner retinal cells in all three dimensions and novel post processing algorithms are applied to extract structure and physiology down to the cellular level. AO-OCT captured the 3D mosaic of individual ganglion cell somas, retinal nerve fiber bundles of micron caliber, and microglial cells, all in exquisite detail. Time correlation analysis of the AO-OCT videos revealed notable temporal differences between the principal layers of the inner retina. The GC layer was more dynamic than the nerve fiber and inner plexiform layers. At the cellular level, we applied a customized correlation method to individual GCL somas, and found a mean time constant of activity of 0.57 s and spread of +/-0.1 s suggesting a range of physiological dynamics even in the same cell type. Extending our method to slower dynamics (from minutes to one year), time-lapse imaging and temporal speckle contrast revealed appendage and soma motion of resting microglial cells at the retinal surface.

Safety evaluation of poly(lactic-co-glycolic acid)/poly(lactic-acid) microspheres through intravitreal injection in rabbits.

PubMed

Rong, Xianfang; Yuan, Weien; Lu, Yi; Mo, Xiaofen

2014-01-01

Poly(lactic-co-glycolic acid) (PLGA) and/or poly(lactic-acid) (PLA) microspheres are important drug delivery systems. This study investigated eye biocompatibility and safety of PLGA/PLA microspheres through intravitreal injection in rabbits. Normal New Zealand rabbits were randomly selected and received intravitreal administration of different doses (low, medium, or high) of PLGA/PLA microspheres and erythropoietin-loaded PLGA/PLA microspheres. The animals were clinically examined and sacrificed at 1, 2, 4, 8, and 12 weeks postadministration, and retinal tissues were prepared for analysis. Retinal reactions to the microspheres were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end staining and glial fibrillary acidic protein immunohistochemistry. Retinal structure changes were assessed by hematoxylin and eosin staining and transmission electron microscopy. Finally, retinal function influences were explored by the electroretinography test. Terminal deoxynucleotidyl transferase-mediated dUTP nick end staining revealed no apoptotic cells in the injected retinas; immunohistochemistry did not detect any increased glial fibrillary acidic protein expression. Hematoxylin and eosin staining and transmission electron microscopy revealed no micro- or ultrastructure changes in the retinas at different time points postintravitreal injection. The electroretinography test showed no significant influence of scotopic or photopic amplitudes. The results demonstrated that PLGA/PLA microspheres did not cause retinal histological changes or functional damage and were biocompatible and safe enough for intravitreal injection in rabbits for controlled drug delivery.

RotundRacGAP Functions with Ras during Spermatogenesis and Retinal Differentiation in Drosophila melanogaster

PubMed Central

Bergeret, Evelyne; Pignot-Paintrand, Isabelle; Guichard, Annabel; Raymond, Karine; Fauvarque, Marie-Odile; Cazemajor, Michel; Griffin-Shea, Ruth

2001-01-01

Our analysis of rotund (rn) null mutations in Drosophila melanogaster revealed that deletion of the rn locus affects both spermatid and retinal differentiation. In the male reproductive system, the absence of RnRacGAP induced small testes, empty seminal vesicles, short testicular cysts, reduced amounts of interspermatid membrane, the absence of individualization complexes, and incomplete mitochondrial condensation. Flagellar growth continued within the short rn null cysts to produce large bulbous terminations of intertwined mature flagella. Organization of the retina was also severely perturbed as evidenced by grossly misshapen ommatidia containing reduced numbers of photoreceptor and pigment cells. These morphological phenotypes were rescued by genomic rnRacGAP transgenes, demonstrating that RnRacGAP function is critical to spermatid and retinal differentiation. The testicular phenotypes were suppressed by heterozygous hypomorphic mutations in the Dras1 and drk genes, indicating cross talk between RacGAP-regulated signaling and that of the Ras pathway. The observed genetic interactions are consistent with a model in which Rac signaling is activated by Ras and negatively regulated by RnRacGAP during spermatid differentiation. RnRacGAP and Ras cross talk also operated during retinal differentiation; however, while the heterozygous hypomorphic drk mutation continued to act as a suppressor of the rn null mutation, the heterozygous hypomorphic Dras1 mutation induced novel retinal phenotypes. PMID:11509670

A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration.

PubMed

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/

The protective effect of prophylactic ozone administration against retinal ischemia-reperfusion injury.

PubMed

Kal, Ali; Kal, Oznur; Akillioglu, Ishak; Celik, Esin; Yilmaz, Mustafa; Gonul, Saban; Solmaz, Merve; Onal, Ozkan

2017-03-01

Retinal ischemia-reperfusion (IR) injury is associated with many ocular diseases. Retinal IR injury leads to the death of retinal ganglion cells (RGCs), loss of retinal function and ultimately vision loss. The aim of this study was to show the protective effects of prophylactic ozone administration against retinal IR injury. A sham group (S) (n = 7) was administered physiological saline (PS) intraperitoneally (i.p.) for 7 d. An ischemia reperfusion (IR) group (n = 7) was subjected to retinal ischemia followed by reperfusion for 2 h. An ozone group (O) (n = 7) was administered 1 mg/kg of ozone i.p. for 7 d. In the ozone + IR (O + IR) group (n = 7), 1 mg/kg of ozone was administered i.p. for 7 d before the IR procedure and at 8 d, the IR injury was created (as in IR group). The rats were anesthetized after second hour of reperfusion and their intracardiac blood was drawn completely and they were sacrificed. Blood samples were sent to a laboratory for analysis of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total oxidant score (TOS) and total antioxidant capacity (TAC). The degree of retinal injury was evaluated according to changes in retinal cells and necrotic and apoptotic cells using the TUNEL method. Data were evaluated statistically with the Kruskal-Wallis test. The number of RGCs and the inner retinal thickness were significantly decreased after ischemia, and treatment with ozone significantly inhibited retinal ischemic injury. In the IR group, the degree of retinal injury was found to be the highest. In the O + IR group, retinal injury was found to be decreased in comparison to the IR group. In the ozone group without retinal IR injury, the retinal injury score was the lowest. The differences in the antioxidant parameters SOD, GSH-Px and TAC were increased in the ozone group and the lowest in the IR group. The oxidant parameters MDA and TOS were found to be the highest in the IR group and decreased in the ozone group. IR injury is also positively correlated with the degree of early apoptosis. This study demonstrated that ozone can attenuate subsequent ischemic damage in the rat retina through triggering the increase of the antioxidant capacity.

Evaluation of the Retinal Vasculature in Hypertension and Chronic Kidney Disease in an Elderly Population of Irish Nuns.

PubMed

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

2015-01-01

Chronic kidney disease (CKD) and hypertension are global public health problems associated with considerable morbidity, premature mortality and attendant healthcare costs. Previous studies have highlighted that non-invasive examination of the retinal microcirculation can detect microvascular pathology that is associated with systemic disorders of the circulatory system such as hypertension. We examined the associations between retinal vessel caliber (RVC) and fractal dimension (DF), with both hypertension and CKD in elderly Irish nuns. Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study (INES) were assessed from digital photographs with a standardized protocol using computer-assisted software. Multivariate regression analyses were used to assess associations with hypertension and CKD, with adjustment for age, body mass index (BMI), refraction, fellow eye RVC, smoking, alcohol consumption, ischemic heart disease (IHD), cerebrovascular accident (CVA), diabetes and medication use. In total, 1122 (91%) participants (mean age: 76.3 [range: 56-100] years) had gradable retinal images of sufficient quality for blood vessel assessment. Hypertension was significantly associated with a narrower central retinal arteriolar equivalent (CRAE) in a fully adjusted analysis (P = 0.002; effect size = -2.16 μm; 95% confidence intervals [CI]: -3.51, -0.81 μm). No significant associations between other retinal vascular parameters and hypertension or between any retinal vascular parameters and CKD were found. Individuals with hypertension have significantly narrower retinal arterioles which may afford an earlier opportunity for tailored prevention and treatment options to optimize the structure and function of the microvasculature, providing additional clinical utility. No significant associations between retinal vascular parameters and CKD were detected.

The Self-Concept of Spanish Young Adults with Retinitis Pigmentosa

ERIC Educational Resources Information Center

Lopez-Justicia, Maria Dolores; Cordoba, Inmaculada Nieto

2006-01-01

Retinitis pigmentosa (RP) is a degenerative disease of the retina that causes the severe impairment of visual functioning similar to low vision, leading, in many cases, to blindness. Because the construct of self-concept plays a key role in personality, this study was designed to measure self-concept in a group of young adults with RP. The…

Prospectives for Gene Therapy of Retinal Degenerations

PubMed Central

Thumann, Gabriele

2012-01-01

Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell growth factors (VEGF), have been used to prevent the neovascularization that accompanies AMD and DR resulting in the amelioration of vision in a significant number of patients. In animal models it has been shown that transfection of RPE cells with the gene for PEDF and other growth factors can prevent or slow degeneration. A limited number of studies in humans have also shown that transfection of RPE cells in vivo with the gene for PEDF is effective in preventing degeneration and restore vision. Most of these studies have used virally mediated gene delivery with all its accompanying side effects and have not been widely used. New techniques using non-viral protocols that allow efficient delivery and permanent integration of the transgene into the host cell genome offer novel opportunities for effective treatment of retinal degenerations. PMID:23372421

Subthreshold and micropulse diode laser photocoagulation.

PubMed

Dorin, Giorgio

2003-09-01

Retinal laser photocoagulation is a proven, effective treatment for various retinal disorders. Common clinical protocols use intra-operatively visible endpoints that cause iatrogenic chorioretinal damage. For this reason, laser therapy is normally limited to levels of disease severity for which the benefit-to-risk ratio justifies its application. The use of 810 nm diode lasers in the MicroPulse mode offers the surgeon the possibility to minimize iatrogenic retinal damage. A less destructive laser therapy with a more favorable benefit-to-risk ratio could justify treatment earlier in the course of the disease, allowing for stabilization or improvement of less compromised visual functions.

In vivo cellular-resolution retinal imaging in infants and children using an ultracompact handheld probe

NASA Astrophysics Data System (ADS)

Larocca, Francesco; Nankivil, Derek; Dubose, Theodore; Toth, Cynthia A.; Farsiu, Sina; Izatt, Joseph A.

2016-09-01

Enabled by adaptive optics, retinal photoreceptor cell imaging is changing our understanding of retinal structure and function, as well as the pathogenesis of numerous ocular diseases. To date, use of this technology has been limited to cooperative adult subjects due to the size, weight and inconvenience of the equipment, thus excluding study of retinal maturation during human development. Here, we report the design and operation of a handheld probe that can perform both scanning laser ophthalmoscopy and optical coherence tomography of the parafoveal photoreceptor structure in infants and children without the need for adaptive optics. The probe, featuring a compact optical design weighing only 94 g, was able to quantify packing densities of parafoveal cone photoreceptors and visualize cross-sectional photoreceptor substructure in children with ages ranging from 14 months to 12 years. The probe will benefit paediatric research by improving the understanding of retinal development, maldevelopment and early onset of disease during human growth.

Ultrahigh resolution retinal imaging by visible light OCT with longitudinal achromatization

PubMed Central

Chong, Shau Poh; Zhang, Tingwei; Kho, Aaron; Bernucci, Marcel T.; Dubra, Alfredo; Srinivasan, Vivek J.

2018-01-01

Chromatic aberrations are an important design consideration in high resolution, high bandwidth, refractive imaging systems that use visible light. Here, we present a fiber-based spectral/Fourier domain, visible light OCT ophthalmoscope corrected for the average longitudinal chromatic aberration (LCA) of the human eye. Analysis of complex speckles from in vivo retinal images showed that achromatization resulted in a speckle autocorrelation function that was ~20% narrower in the axial direction, but unchanged in the transverse direction. In images from the improved, achromatized system, the separation between Bruch’s membrane (BM), the retinal pigment epithelium (RPE), and the outer segment tips clearly emerged across the entire 6.5 mm field-of-view, enabling segmentation and morphometry of BM and the RPE in a human subject. Finally, cross-sectional images depicted distinct inner retinal layers with high resolution. Thus, with chromatic aberration compensation, visible light OCT can achieve volume resolutions and retinal image quality that matches or exceeds ultrahigh resolution near-infrared OCT systems with no monochromatic aberration compensation. PMID:29675296

Accelerated and Improved Differentiation of Retinal Organoids from Pluripotent Stem Cells in Rotating-Wall Vessel Bioreactors.

PubMed

DiStefano, Tyler; Chen, Holly Yu; Panebianco, Christopher; Kaya, Koray Dogan; Brooks, Matthew J; Gieser, Linn; Morgan, Nicole Y; Pohida, Tom; Swaroop, Anand

2018-01-09

Pluripotent stem cells can be differentiated into 3D retinal organoids, with major cell types self-patterning into a polarized, laminated architecture. In static cultures, organoid development may be hindered by limitations in diffusion of oxygen and nutrients. Herein, we report a bioprocess using rotating-wall vessel (RWV) bioreactors to culture retinal organoids derived from mouse pluripotent stem cells. Organoids in RWV demonstrate enhanced proliferation, with well-defined morphology and improved differentiation of neurons including ganglion cells and S-cone photoreceptors. Furthermore, RWV organoids at day 25 (D25) reveal similar maturation and transcriptome profile as those at D32 in static culture, closely recapitulating spatiotemporal development of postnatal day 6 mouse retina in vivo. Interestingly, however, retinal organoids do not differentiate further under any in vitro condition tested here, suggesting additional requirements for functional maturation. Our studies demonstrate that bioreactors can accelerate and improve organoid growth and differentiation for modeling retinal disease and evaluation of therapies. Published by Elsevier Inc.

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

PubMed Central

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease. PMID:26881135

Photoreceptor Outer Segment-like Structures in Long-Term 3D Retinas from Human Pluripotent Stem Cells.

PubMed

Wahlin, Karl J; Maruotti, Julien A; Sripathi, Srinivasa R; Ball, John; Angueyra, Juan M; Kim, Catherine; Grebe, Rhonda; Li, Wei; Jones, Bryan W; Zack, Donald J

2017-04-10

The retinal degenerative diseases, which together constitute a leading cause of hereditary blindness worldwide, are largely untreatable. Development of reliable methods to culture complex retinal tissues from human pluripotent stem cells (hPSCs) could offer a means to study human retinal development, provide a platform to investigate the mechanisms of retinal degeneration and screen for neuroprotective compounds, and provide the basis for cell-based therapeutic strategies. In this study, we describe an in vitro method by which hPSCs can be differentiated into 3D retinas with at least some important features reminiscent of a mature retina, including exuberant outgrowth of outer segment-like structures and synaptic ribbons, photoreceptor neurotransmitter expression, and membrane conductances and synaptic vesicle release properties consistent with possible photoreceptor synaptic function. The advanced outer segment-like structures reported here support the notion that 3D retina cups could serve as a model for studying mature photoreceptor development and allow for more robust modeling of retinal degenerative disease in vitro.

a Review of Retinal Prosthesis Approaches

NASA Astrophysics Data System (ADS)

Kien, Tran Trung; Maul, Tomas; Bargiela, Andrzej

Age-related macular degeneration and retinitis pigmentosa are two of the most common diseases that cause degeneration in the outer retina, which can lead to several visual impairments up to blindness. Vision restoration is an important goal for which several different research approaches are currently being pursued. We are concerned with restoration via retinal prosthetic devices. Prostheses can be implemented intraocularly and extraocularly, which leads to different categories of devices. Cortical Prostheses and Optic Nerve Prostheses are examples of extraocular solutions while Epiretinal Prostheses and Subretinal Prostheses are examples of intraocular solutions. Some of the prostheses that are successfully implanted and tested in animals as well as humans can restore basic visual functions but still have limitations. This paper will give an overview of the current state of art of Retinal Prostheses and compare the advantages and limitations of each type. The purpose of this review is thus to summarize the current technologies and approaches used in developing Retinal Prostheses and therefore to lay a foundation for future designs and research directions.

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

PubMed Central

Acland, Gregory M.

2014-01-01

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision. PMID:22065099

Retinal Remodeling in Human Retinitis Pigmentosa

PubMed Central

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

2016-01-01

Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758

Autologous neurosensory retinal free patch transplantation for persistent full-thickness macular hole.

PubMed

De Giacinto, Chiara; D'Aloisio, Rossella; Cirigliano, Gabriella; Pastore, Marco Rocco; Tognetto, Daniele

2018-03-27

To evaluate anatomical and functional outcomes after autologous neurosensory retinal free patch (ANRFP) transplantation for persistent idiopathic full-thickness macular hole (iFTMH). A 65-year-old woman with persistent macular hole in her right eye after previous 27-gauge pars plana vitrectomy with internal limiting membrane peeling and long-acting gas tamponade underwent ANRFP transplantation. Before surgery, best corrected visual acuity in her right eye was 20/800. Optical coherence tomography (OCT) showed a 715-micron-diameter FTMH. To treat the persistent FTMH, a small autologous neurosensory retinal patch was transplanted and placed inside the macular hole under perfluorocarbon liquids (PFCL). PFCL-air exchange was performed, and long-acting gas tamponade was carried out. Clinical features of the macular area, visual acuity (VA), fundus autofluorescence, microperimetry and OCT were recorded during the 10-month follow-up. The macular hole appeared successfully closed with retinal patch stable and well plugged into the hole during the whole follow-up. VA improved to 20/100 and microperimetry revealed an increase in mean retinal sensitivity from 14.7 dB at 1 month to 15.6 dB at 10 months postoperatively. OCT showed a well-distinguishable retinal patch into the hole 1 month after surgery and a completely integrated retinal patch between the retinal layers 10 months postoperatively. No intra- and postoperative complications were noticed. ANRFP transplantation may represent an innovative technique for persistent iFTMH treatment.

Concurrent OCT imaging of stimulus evoked retinal neural activation and hemodynamic responses

NASA Astrophysics Data System (ADS)

Son, Taeyoon; Wang, Benquan; Lu, Yiming; Chen, Yanjun; Cao, Dingcai; Yao, Xincheng

2017-02-01

It is well established that major retinal diseases involve distortions of the retinal neural physiology and blood vascular structures. However, the details of distortions in retinal neurovascular coupling associated with major eye diseases are not well understood. In this study, a multi-modal optical coherence tomography (OCT) imaging system was developed to enable concurrent imaging of retinal neural activity and vascular hemodynamics. Flicker light stimulation was applied to mouse retinas to evoke retinal neural responses and hemodynamic changes. The OCT images were acquired continuously during the pre-stimulation, light-stimulation, and post-stimulation phases. Stimulus-evoked intrinsic optical signals (IOSs) and hemodynamic changes were observed over time in blood-free and blood regions, respectively. Rapid IOSs change occurred almost immediately after stimulation. Both positive and negative signals were observed in adjacent retinal areas. The hemodynamic changes showed time delays after stimulation. The signal magnitudes induced by light stimulation were observed in blood regions and did not show significant changes in blood-free regions. These differences may arise from different mechanisms in blood vessels and neural tissues in response to light stimulation. These characteristics agreed well with our previous observations in mouse retinas. Further development of the multimodal OCT may provide a new imaging method for studying how retinal structures and metabolic and neural functions are affected by age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and other diseases, which promises novel noninvasive biomarkers for early disease detection and reliable treatment evaluations of eye diseases.

Structural analysis of retinal photoreceptor ellipsoid zone and postreceptor retinal layer associated with visual acuity in patients with retinitis pigmentosa by ganglion cell analysis combined with OCT imaging

PubMed Central

Liu, Guodong; Li, Hui; Liu, Xiaoqiang; Xu, Ding; Wang, Fang

2016-01-01

Abstract The aim of this study was to examine changes in photoreceptor ellipsoid zone (EZ) and postreceptor retinal layer in retinitis pigmentosa (RP) patients by ganglion cell analysis (GCA) combined with optical coherence tomography (OCT) imaging to evaluate the structure–function relationships between retinal layer changes and best corrected visual acuity (BCVA). Sixty-eight eyes of 35 patients with RP and 65 eyes of 35 normal controls were analyzed in the study. The average length of EZ was 911.1 ± 208.8 μm in RP patients, which was shortened with the progression of the disease on the OCT images. The average ganglion cell–inner plexiform layer thickness (GCIPLT) was 54.7 ± 18.9 μm in RP patients, while in normal controls it was 85.6 ± 6.8 μm. The GCIPLT in all quarters became significantly thinner along with outer retinal thinning. There was a significantly positive correlation between BCVA and EZ (r = −0.7622, P < 0.001) and GCIPLT (r = −0.452, P < 0.001). Therefore, we assess the retinal layer changes from a new perspective in RP patients, which suggests that EZ and GCIPLT obtained by GCA combined with OCT imaging are the direct and valid indicators to diagnosis and predict the pathological process of RP. PMID:28033301

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

PubMed

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.

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies.

PubMed

Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D

2012-02-01

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

Toward high-resolution optoelectronic retinal prosthesis

NASA Astrophysics Data System (ADS)

Palanker, Daniel; Huie, Philip; Vankov, Alexander; Asher, Alon; Baccus, Steven

2005-04-01

It has been already demonstrated that electrical stimulation of retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. Current retinal implants provide very low resolution (just a few electrodes), while several thousand pixels are required for functional restoration of sight. We present a design of the optoelectronic retinal prosthetic system that can activate a retinal stimulating array with pixel density up to 2,500 pix/mm2 (geometrically corresponding to a visual acuity of 20/80), and allows for natural eye scanning rather than scanning with a head-mounted camera. The system operates similarly to "virtual reality" imaging devices used in military and medical applications. An image from a video camera is projected by a goggle-mounted infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. Such a system provides a broad field of vision by allowing for natural eye scanning. The goggles are transparent to visible light, thus allowing for simultaneous utilization of remaining natural vision along with prosthetic stimulation. Optical control of the implant allows for simple adjustment of image processing algorithms and for learning. A major prerequisite for high resolution stimulation is the proximity of neural cells to the stimulation sites. This can be achieved with sub-retinal implants constructed in a manner that directs migration of retinal cells to target areas. Two basic implant geometries are described: perforated membranes and protruding electrode arrays. Possibility of the tactile neural stimulation is also examined.

Iron homeostasis and toxicity in retinal degeneration

PubMed Central

He, Xining; Hahn, Paul; Iacovelli, Jared; Wong, Robert; King, Chih; Bhisitkul, Robert; Massaro-Giordano, Mina; Dunaief, Joshua L.

2007-01-01

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels build up with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich’s Ataxia, and panthothenate kinase associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age- matched controls. Over the past ten years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter 1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential. PMID:17921041

TrkB signalling pathway mediates the protective effects of exercise in the diabetic rat retina.

PubMed

Allen, Rachael S; Hanif, Adam M; Gogniat, Marissa A; Prall, Brian C; Haider, Raza; Aung, Moe H; Prunty, Megan C; Mees, Lukas M; Coulter, Monica M; Motz, Cara T; Boatright, Jeffrey H; Pardue, Machelle T

2018-05-01

Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats.

PubMed

Deng, Wen-Tao; Dinculescu, Astra; Li, Qiuhong; Boye, Sanford L; Li, Jie; Gorbatyuk, Marina S; Pang, Jijing; Chiodo, Vince A; Matthes, Michael T; Yasumura, Douglas; Liu, Li; Alkuraya, Fowzan S; Zhang, Kang; Vollrath, Douglas; LaVail, Matthew M; Hauswirth, William W

2012-04-06

The absence of Mertk in RCS rats results in defective RPE phagocytosis, accumulation of outer segment (OS) debris in the subretinal space, and subsequent death of photoreceptors. Previous research utilizing Mertk gene replacement therapy in RCS rats provided proof of concept for treatment of this form of recessive retinitis pigmentosa (RP); however, the beneficial effects on retinal function were transient. In the present study, we evaluated whether delivery of a MERTK transgene using a tyrosine-mutant AAV8 capsid could lead to more robust and longer-term therapeutic outcomes than previously reported. An AAV8 Y733F vector expressing a human MERTK cDNA driven by a RPE-selective promoter was administrated subretinally at postnatal day 2. Functional and morphological analyses were performed at 4 months and 8 months post-treatment. Retinal vasculature and Müller cell activation were analyzed by quantifying acellular capillaries and glial fibrillary acidic protein immunostaining, respectively. Electroretinographic responses from treated eyes were more than one-third of wild-type levels and OS were well preserved in the injection area even at 8 months. Rescue of RPE phagocytosis, prevention of retinal vasculature degeneration, and inhibition of Müller cell activation were demonstrated in the treated eyes for at least 8 months. This research describes a longer and much more robust functional and morphological rescue than previous studies. We also demonstrate for the first time that an AAV8 mutant capsid serotype vector has a substantial therapeutic potential for RPE-specific gene delivery. These results suggest that tyrosine-mutant AAV8 vectors hold promise for the treatment of individuals with MERTK-associated RP.

Tyrosine-Mutant AAV8 Delivery of Human MERTK Provides Long-Term Retinal Preservation in RCS Rats

PubMed Central

Deng, Wen-Tao; Dinculescu, Astra; Li, Qiuhong; Boye, Sanford L.; Li, Jie; Gorbatyuk, Marina S.; Pang, Jijing; Chiodo, Vince A.; Matthes, Michael T.; Yasumura, Douglas; Liu, Li; Alkuraya, Fowzan S.; Zhang, Kang; Vollrath, Douglas; LaVail, Matthew M.; Hauswirth, William W.

2012-01-01

Purpose. The absence of Mertk in RCS rats results in defective RPE phagocytosis, accumulation of outer segment (OS) debris in the subretinal space, and subsequent death of photoreceptors. Previous research utilizing Mertk gene replacement therapy in RCS rats provided proof of concept for treatment of this form of recessive retinitis pigmentosa (RP); however, the beneficial effects on retinal function were transient. In the present study, we evaluated whether delivery of a MERTK transgene using a tyrosine-mutant AAV8 capsid could lead to more robust and longer-term therapeutic outcomes than previously reported. Methods. An AAV8 Y733F vector expressing a human MERTK cDNA driven by a RPE-selective promoter was administrated subretinally at postnatal day 2. Functional and morphological analyses were performed at 4 months and 8 months post-treatment. Retinal vasculature and Müller cell activation were analyzed by quantifying acellular capillaries and glial fibrillary acidic protein immunostaining, respectively. Results. Electroretinographic responses from treated eyes were more than one-third of wild-type levels and OS were well preserved in the injection area even at 8 months. Rescue of RPE phagocytosis, prevention of retinal vasculature degeneration, and inhibition of Müller cell activation were demonstrated in the treated eyes for at least 8 months. Conclusions. This research describes a longer and much more robust functional and morphological rescue than previous studies. We also demonstrate for the first time that an AAV8 mutant capsid serotype vector has a substantial therapeutic potential for RPE-specific gene delivery. These results suggest that tyrosine-mutant AAV8 vectors hold promise for the treatment of individuals with MERTK-associated RP. PMID:22408006

Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis.

PubMed

Deeg, Cornelia A; Amann, Barbara; Lutz, Konstantin; Hirmer, Sieglinde; Lutterberg, Karina; Kremmer, Elisabeth; Hauck, Stefanie M

2016-04-23

Müller glial cells are important regulators of physiological function of retina. In a model disease of retinal inflammation and spontaneous recurrent uveitis in horses (ERU), we could show that retinal Müller glial cells significantly change potassium and water channel protein expression during autoimmune pathogenesis. The most significantly changed channel protein in neuroinflammatory ERU was aquaporin 11 (AQP11). Aquaporins (AQP, 13 members) are important regulators of water and small solute transport through membranes. AQP11 is an unorthodox member of this family and was assigned to a third group of AQPs because of its difference in amino acid sequence (conserved sequence is only 11 %) and especially its largely unknown function. In order to gain insight into the distribution, localization, and function of AQP11 in the retina, we first developed a novel monoclonal antibody for AQP11 enabling quantification, localization, and functional studies. In the horse retina, AQP11 was exclusively expressed at Müller glial cell membranes. In uveitic condition, AQP11 disappeared from gliotic Müller cells concomitant with glutamine synthase. Since function of AQP11 is still under debate, we assessed the impact of AQP11 channel on cell volume regulation of primary Müller glial cells under different osmotic conditions. We conclude a concomitant role for AQP11 with AQP4 in water efflux from these glial cells, which is disturbed in ERU. This could probably contribute to swelling and subsequent severe complication of retinal edema through impaired intracellular fluid regulation. Therefore, AQP11 is important for physiological Müller glia function and the expression pattern and function of this water channel seems to have distinct functions in central nervous system. The significant reduction in neuroinflammation points to a crucial role in pathogenesis of autoimmune uveitis.

Retinal Image Quality During Accommodation

PubMed Central

López-Gil, N.; Martin, J.; Liu, T.; Bradley, A.; Díaz-Muñoz, D.; Thibos, L.

2013-01-01

Purpose We asked if retinal image quality is maximum during accommodation, or sub-optimal due to accommodative error, when subjects perform an acuity task. Methods Subjects viewed a monochromatic (552nm), high-contrast letter target placed at various viewing distances. Wavefront aberrations of the accommodating eye were measured near the endpoint of an acuity staircase paradigm. Refractive state, defined as the optimum target vergence for maximising retinal image quality, was computed by through-focus wavefront analysis to find the power of the virtual correcting lens that maximizes visual Strehl ratio. Results Despite changes in ocular aberrations and pupil size during binocular viewing, retinal image quality and visual acuity typically remain high for all target vergences. When accommodative errors lead to sub-optimal retinal image quality, acuity and measured image quality both decline. However, the effect of accommodation errors of on visual acuity are mitigated by pupillary constriction associated with accommodation and binocular convergence and also to binocular summation of dissimilar retinal image blur. Under monocular viewing conditions some subjects displayed significant accommodative lag that reduced visual performance, an effect that was exacerbated by pharmacological dilation of the pupil. Conclusions Spurious measurement of accommodative error can be avoided when the image quality metric used to determine refractive state is compatible with the focusing criteria used by the visual system to control accommodation. Real focusing errors of the accommodating eye do not necessarily produce a reliably measurable loss of image quality or clinically significant loss of visual performance, probably because of increased depth-of-focus due to pupil constriction. When retinal image quality is close to maximum achievable (given the eye’s higher-order aberrations), acuity is also near maximum. A combination of accommodative lag, reduced image quality, and reduced visual function may be a useful sign for diagnosing functionally-significant accommodative errors indicating the need for therapeutic intervention. PMID:23786386

Retinal image quality during accommodation.

PubMed

López-Gil, Norberto; Martin, Jesson; Liu, Tao; Bradley, Arthur; Díaz-Muñoz, David; Thibos, Larry N

2013-07-01

We asked if retinal image quality is maximum during accommodation, or sub-optimal due to accommodative error, when subjects perform an acuity task. Subjects viewed a monochromatic (552 nm), high-contrast letter target placed at various viewing distances. Wavefront aberrations of the accommodating eye were measured near the endpoint of an acuity staircase paradigm. Refractive state, defined as the optimum target vergence for maximising retinal image quality, was computed by through-focus wavefront analysis to find the power of the virtual correcting lens that maximizes visual Strehl ratio. Despite changes in ocular aberrations and pupil size during binocular viewing, retinal image quality and visual acuity typically remain high for all target vergences. When accommodative errors lead to sub-optimal retinal image quality, acuity and measured image quality both decline. However, the effect of accommodation errors of on visual acuity are mitigated by pupillary constriction associated with accommodation and binocular convergence and also to binocular summation of dissimilar retinal image blur. Under monocular viewing conditions some subjects displayed significant accommodative lag that reduced visual performance, an effect that was exacerbated by pharmacological dilation of the pupil. Spurious measurement of accommodative error can be avoided when the image quality metric used to determine refractive state is compatible with the focusing criteria used by the visual system to control accommodation. Real focusing errors of the accommodating eye do not necessarily produce a reliably measurable loss of image quality or clinically significant loss of visual performance, probably because of increased depth-of-focus due to pupil constriction. When retinal image quality is close to maximum achievable (given the eye's higher-order aberrations), acuity is also near maximum. A combination of accommodative lag, reduced image quality, and reduced visual function may be a useful sign for diagnosing functionally-significant accommodative errors indicating the need for therapeutic intervention. © 2013 The Authors Ophthalmic & Physiological Optics © 2013 The College of Optometrists.

Relation Between Macular Retinal Ganglion Cell/Inner Plexiform Layer Thickness and Multifocal Electroretinogram Measures in Experimental Glaucoma

PubMed Central

Luo, Xunda; Patel, Nimesh B.; Rajagopalan, Lakshmi P.; Harwerth, Ronald S.; Frishman, Laura J.

2014-01-01

Purpose. We investigated relations between macular retinal ganglion cell plus inner plexiform layer (RGC+IPL) thickness and macular retinal function revealed by multifocal electroretinonography (mfERG) in a nonhuman primate model of experimental glaucoma. Methods. Retinal ganglion cell (RGC) structure and function were followed with spectral-domain optical coherence tomography (SD-OCT) and ERGs in five macaques with unilateral experimental glaucoma. Linear regression was used to study correlations in control (Con) and experimental (Exp) eyes between peripapillary retinal nerve fiber layer (RNFL) thickness, macular RGC+IPL thickness, multifocal photopic negative response (mfPhNR) and high-frequency multifocal oscillatory potentials (mfOP) in slow-sequence mfERG, and low-frequency component (mfLFC) in global-flash mfERG. We used ANOVA and paired t-tests to compare glaucoma-related mfERG changes between superior and inferior hemifields, foveal hexagon, inner three rings, and four quadrants of macula. Results. Average macular RGC+IPL and temporal RNFL thickness were strongly correlated (r2 = 0.90, P < 0.001). In hexagon-by-hexagon analysis, all three mfERG measures were correlated (P < 0.001) with RGC+IPL thickness for Con (r2, 0.33–0.51) and Exp eyes (r2, 0.17–0.35). The RGC structural and functional metrics decreased as eccentricity increased. The reduction in amplitude of mfERG measures in Exp eyes relative to Con eyes was proportionally greater, in general, than the relative thinning of RGC+IPL at the same location for eyes in which structural loss was not evident, or mild to moderate. Although not statistically significant, percent amplitude reduction of mfERG measures was greatest in the inferior temporal quadrant. Conclusions. Macular RGC+IPL thickness and mfERG measures of RGC function can be complementary tools in assessing glaucomatous neuropathy. PMID:24970256

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia.

PubMed

Yan, Lulu; Lee, Sangmi; Lazzaro, Douglas R; Aranda, Jacob; Grant, Maria B; Chaqour, Brahim

2015-09-18

The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia*

PubMed Central

Yan, Lulu; Lee, Sangmi; Lazzaro, Douglas R.; Aranda, Jacob; Grant, Maria B.; Chaqour, Brahim

2015-01-01

The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR-155 binds to the 3′-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair. PMID:26242736

Investigation of tissue cysts in the retina in a mouse model of ocular toxoplasmosis: distribution and interaction with glial cells.

PubMed

Song, Hyun Beom; Jung, Bong-Kwang; Kim, Jin Hyoung; Lee, Young-Ha; Choi, Min-Ho; Kim, Jeong Hun

2018-06-02

The conversion of tachyzoites into bradyzoites is a way for Toxoplasma gondii to establish a chronic and asymptomatic infection and achieve lifelong persistence in the host. The bradyzoites form tissue cysts in the retina, but not much is known about the horizontal distribution of the cysts or their interactions with glial cells in the retina. A chronic ocular toxoplasmosis model was induced by per oral administration of T. gondii Me49 strain cysts to BALB/c mice. Two months after the infection, retinas were flat-mounted and immunostained to detect cysts, ganglion cells, Müller cells, astrocytes, and microglial cells, followed by observation under fluorescence and confocal microscope. The horizontal distribution showed a rather clustered pattern, but the clusters were not restricted to certain location of the retina. Axial distribution was confined to the inner retina, mostly in ganglion cell layer or the inner plexiform layer. Both ganglion cells, a type of retinal neurons, and Müller cells, predominant retinal glial cells, could harbor cysts. The cysts were spatially separated from astrocytes, the most abundant glial cells in the ganglion cell layer, while close spatial distribution of microglial cells was observed in two thirds of retinal cysts. In this study, we demonstrated that the retinal cysts were not evenly distributed horizontally and were confined to the inner retina axially. Both neurons and one type of glial cells could harbor cysts, and topographic analysis of other glial cells suggests role of microglial cells in chronic ocular toxoplasmosis.

Structural and Functional Changes Associated with Normal and Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa

PubMed Central

Greenstein, Vivienne C.; Duncker, Tobias; Holopigian, Karen; Carr, Ronald E.; Greenberg, Jonathan; Tsang, Stephen H.; Hood, Donald C.

2013-01-01

Purpose To analyze the structure and visual function of regions bordering the hyperautofluorescent ring/arcs in retinitis pigmentosa (RP). Methods Twenty -one RP patients (21 eyes) with rings/arcs and 21 normals (21 eyes) were studied. Visual sensitivity in the central 10° was measured with microperimetry. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT). The distance from the fovea to disruption/loss of the inner outer segment (IS/OS) junction and thicknesses of the total receptor plus retinal pigment epithelial (RPE) complex (R+), and outer segment plus RPE complex (OS+) layers were measured. Results were compared to measurements of the distance from the fovea to the inner and outer borders of the ring/arc seen on fundus autofluorescence (FAF). Results Disruption/loss of the IS/OS junction occurred closer to the inner border of the ring/arc and it was closer to the fovea in 8 eyes. For 19 eyes, OS+ and R+ thicknesses were significantly decreased at locations closer to the fovea than the appearance of the inner border of hyperautofluorescence. Mean visual sensitivity was decreased inside, across and outside the ring/arc by 3.5 ± 3.8, 8.9 ± 4.8 and 17.0±2.4 dB respectively. Conclusions Structural and functional changes can occur inside the hyperfluorescent ring/arc in RP. PMID:21909055

Resveratrol Based Oral Nutritional Supplement Produces Long-Term Beneficial Effects on Structure and Visual Function in Human Patients

PubMed Central

Richer, Stuart; Patel, Shana; Sockanathan, Shivani; Ulanski, Lawrence J.; Miller, Luke; Podella, Carla

2014-01-01

Background: Longevinex® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D3 and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. Methods: We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). Results: We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient’s pathophysiology. No side effects were observed. Conclusions: These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities. PMID:25329968

Resveratrol based oral nutritional supplement produces long-term beneficial effects on structure and visual function in human patients.

PubMed

Richer, Stuart; Patel, Shana; Sockanathan, Shivani; Ulanski, Lawrence J; Miller, Luke; Podella, Carla

2014-10-17

Longevinex® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D3 and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy. We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus). We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient's pathophysiology. No side effects were observed. These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.

Protective effect of basic fibroblast growth factor on retinal injury induced by argon laser photocoagulation

NASA Astrophysics Data System (ADS)

Chen, P.; Zhang, C. P.; San, Q.; Wang, C. Z.; Yang, Z. F.; Kang, H. X.; Qian, H. W.

2010-12-01

Laser photocoagulation treatment is often complicated by a side effect of visual impairment, which is caused by the unavoidable laser-induced retinal destruction. At present no specific is found to cure this retinopathy. The aim of this study was to observe the neuroprotective effect of bFGF on laser-induced retinal injury. Chinchilla rabbits were divided into three groups and argon laser lesions were created in the retinas. Then bFGF or dexamethasone, a widely used ophthalmic preparation, or saline was given severally by retrobulbar injection. The retinal lesions were evaluated histologically and morphometrically, and visual function was examined by ERG. The results showed that bFGF administration better preserved morphology of retinal photoreceptors and significantly diminished the area of the lesions. Furthermore, bFGF promoted the restoration of the ERG b-wave amplitude. In rabbits treated with dexamethasone, however, the lesions showed almost no ameliorative changes. This is the first study to investigate the potential role of bFGF as a remedial agent in laser photocoagulation treatment. These findings suggest that bFGF has significant neuroprotective properties in the retina and this type of neuroprotection may be of clinical significance in reducing iatrogenic laser-induced retinal injuries in humans.

Retinal image restoration by means of blind deconvolution

NASA Astrophysics Data System (ADS)

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.

Connective Tissue Growth Factor Is Involved in Structural Retinal Vascular Changes in Long-Term Experimental Diabetes

PubMed Central

Van Geest, Rob J.; Leeuwis, Jan Willem; Dendooven, Amélie; Pfister, Frederick; Bosch, Klazien; Hoeben, Kees A.; Vogels, Ilse M.C.; Van der Giezen, Dionne M.; Dietrich, Nadine; Hammes, Hans-Peter; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J.F.

2014-01-01

Early retinal vascular changes in the development of diabetic retinopathy (DR) include capillary basal lamina (BL) thickening, pericyte loss and the development of acellular capillaries. Expression of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family member CCN2 or connective tissue growth factor (CTGF), a potent inducer of the expression of BL components, is upregulated early in diabetes. Diabetic mice lacking one functional CTGF allele (CTGF+/−) do not show this BL thickening. As early events in DR may be interrelated, we hypothesized that CTGF plays a role in the pathological changes of retinal capillaries other than BL thickening. We studied the effects of long-term (6-8 months) streptozotocin-induced diabetes on retinal capillary BL thickness, numbers of pericytes and the development of acellular capillaries in wild type and CTGF+/− mice. Our results show that an absence of BL thickening of retinal capillaries in long-term diabetic CTGF+/− mice is associated with reduced pericyte dropout and reduced formation of acellular capillaries. We conclude that CTGF is involved in structural retinal vascular changes in diabetic rodents. Inhibition of CTGF in the eye may therefore be protective against the development of DR. PMID:24217924

Dopamine D1 Receptors Regulate the Light Dependent Development of Retinal Synaptic Responses

PubMed Central

He, Quanhua; Xu, Hong-ping; Wang, Ping; Tian, Ning

2013-01-01

Retinal synaptic connections and function are developmentally regulated. Retinal synaptic activity plays critical roles in the development of retinal synaptic circuitry. Dopamine receptors have been thought to play important roles in the activity-dependent synaptic plasticity in central nervous system. The primary goal of this study is to determine whether dopamine D1 receptor regulates the activity-dependent development of retinal light responsiveness. Accordingly, we recorded electroretinogram from wild type mice and mice with genetic deletion of D1 dopamine receptor (D1−/− mice) raised under cyclic light conditions and constant darkness. Our results demonstrated that D1−/− mice have reduced amplitudes of all three major components of electroretinogram in adulthood. When the relative strength of the responses is considered, the D1−/− mice have selective reduction of the amplitudes of a-wave and oscillatory potentials evoked by low-intermediate intensities of lights. During postnatal development, D1−/− mice have increased amplitude of b-wave at the time of eye-opening but reduced developmental increase of the amplitude of b-wave after eye opening. Light deprivation from birth significantly reduced the amplitudes of b-wave and oscillatory potentials, increased the outer retinal light response gain and altered the light response kinetics of both a- and b-waves of wild type mice. In D1−/− mice, the effect of dark rearing on the amplitude of oscillatory potentials was diminished and dark rearing induced effects on the response gain of outer retina and the kinetics of a-wave were reversed. These results demonstrated roles of dopamine D1 receptor in the activity-dependent functional development of mouse retina. PMID:24260267

Directionality of Individual Cone Photoreceptors in the Parafoveal Region

PubMed Central

Morris, Hugh J.; Blanco, Leonardo; Codona, Johanan L.; Li, Simone; Choi, Stacey S.; Doble, Nathan

2015-01-01

The pointing direction of cone photoreceptors can be inferred from the Stiles-Crawford Effect of the First Kind (SCE-I) measurement. Healthy retinas have tightly packed cones with a SCE-I function peak either centered in the pupil or with a slight nasal bias. Various retinal pathologies can change the profile of the SCE-I function implying that the arrangement or the light capturing properties of the cone photoreceptors are affected. Measuring the SCE-I may reveal early signs of photoreceptor change before actual cell apoptosis occurs. In vivo retinal imaging with adaptive optics (AO) was used to measure the pointing direction of individual cones at eight retinal locations in four control human subjects. Retinal images were acquired by translating an aperture in the light delivery arm through 19 different locations across a subject’s entrance pupil. Angular tuning properties of individual cones were calculated by fitting a Gaussian to the reflected intensity profile of each cone projected onto the pupil. Results were compared to those from an accepted psychophysical SCE-I measurement technique. The maximal difference in cone directionality of an ensemble of cones, ρ̄, between the major and minor axes of the Gaussian fit was 0.05 versus 0.29 mm−2 in one subject. All four subjects were found to have a mean nasal bias of 0.81 mm with a standard deviation of ±0.30 mm in the peak position at all retinal locations with mean ρ̄ value decreasing by 23% with increasing retinal eccentricity. Results show that cones in the parafoveal region converge towards the center of the pupillary aperture, confirming the anterior pointing alignment hypothesis. PMID:26494187

Islet-1 Controls the Differentiation of Retinal Bipolar and Cholinergic Amacrine Cells

PubMed Central

Elshatory, Yasser; Everhart, Drew; Deng, Min; Xie, Xiaoling; Barlow, Robert B.; Gan, Lin

2010-01-01

Whereas the mammalian retina possesses a repertoire of factors known to establish general retinal cell types, these factors alone cannot explain the vast diversity of neuronal subtypes. In other CNS regions, the differentiation of diverse neuronal pools is governed by coordinately acting LIM-homeodomain proteins including the Islet-class factor Islet-1 (Isl1). We report that deletion of Isl1 profoundly disrupts retinal function as assessed by electroretinograms and vision as assessed by optomotor behavior. These deficits are coupled with marked reductions in mature ON- and OFF-bipolar (>76%), cholinergic amacrine (93%), and ganglion (71%) cells. Mosaic deletion of Isl1 permitted a chimeric analysis of “wild-type” cells in a predominantly Isl1-null environment, demonstrating a cell-autonomous role for Isl1 in rod bipolar and cholinergic amacrine development. Furthermore, the effects on bipolar cell development appear to be dissociable from the preceding retinal ganglion cell loss, because Pou4f2-null mice are devoid of similar defects in bipolar cell marker expression. Expression of the ON- and OFF-bipolar cell differentiation factors Bhlhb4 and Vsx1, respectively, requires the presence of Isl1, whereas the early bipolar cell marker Prox1 initially did not. Thus, Isl1 is required for engaging bipolar differentiation pathways but not for general bipolar cell specification. Spatiotemporal expression analysis of additional LIM-homeobox genes identifies a LIM-homeobox gene network during bipolar cell development that includes Lhx3 and Lhx4. We conclude that Isl1 has an indispensable role in retinal neuron differentiation within restricted cell populations and this function may reflect a broader role for other LIM-homeobox genes in retinal development, and perhaps in establishing neuronal subtypes. PMID:18003851

A Potential Role for Angiopoietin 2 in the Regulation of the Blood–Retinal Barrier in Diabetic Retinopathy

PubMed Central

Rangasamy, Sampathkumar; Srinivasan, Ramprasad; Maestas, Joann; Das, Arup

2011-01-01

Purpose. Although VEGF has been identified as an important mediator of the blood–retinal barrier alteration in diabetic retinopathy, the hypothesis for this study was that that other molecules, including the angiopoietins (Ang-1 and -2), may play a role. The expression of angiopoietins was analyzed in an animal model of diabetic retinopathy, and the role of Ang-2 in the regulation of diabetes-induced alterations of vascular permeability was characterized. Methods. Diabetes was induced in rats, and human retinal endothelial cells (HRECs) were grown in media with 5.5 or 30.5 mM glucose. Levels of Ang-1 and -2 mRNA and protein were analyzed. Fluorescence-based assays were used to assess the effect of Ang-2 on vascular permeability in vivo and in vitro. The effect of Ang-2 on VE-cadherin function was assessed by measuring the extent of tyrosine phosphorylation. Results. Ang-2 mRNA and protein increased in the retinal tissues after 8 weeks of diabetes and in high-glucose–treated cells. Intravitreal injection of Ang-2 in rats produced a significant increase in retinal vascular permeability. Ang-2 increased HREC monolayer permeability that was associated with a decrease in VE-cadherin and a change in monolayer morphology. High glucose and Ang-2 produced a significant increase in VE-cadherin phosphorylation. Conclusions. Ang-2 is upregulated in the retina in an animal model of diabetes, and hyperglycemia induces the expression of Ang-2 in isolated retinal endothelial cells. Increased Ang-2 alters VE-cadherin function, leading to increased vascular permeability. Thus, Ang-2 may play an important role in increased vasopermeability in diabetic retinopathy. PMID:21310918

A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy.

PubMed

Rangasamy, Sampathkumar; Srinivasan, Ramprasad; Maestas, Joann; McGuire, Paul G; Das, Arup

2011-06-01

Although VEGF has been identified as an important mediator of the blood-retinal barrier alteration in diabetic retinopathy, the hypothesis for this study was that that other molecules, including the angiopoietins (Ang-1 and -2), may play a role. The expression of angiopoietins was analyzed in an animal model of diabetic retinopathy, and the role of Ang-2 in the regulation of diabetes-induced alterations of vascular permeability was characterized. Diabetes was induced in rats, and human retinal endothelial cells (HRECs) were grown in media with 5.5 or 30.5 mM glucose. Levels of Ang-1 and -2 mRNA and protein were analyzed. Fluorescence-based assays were used to assess the effect of Ang-2 on vascular permeability in vivo and in vitro. The effect of Ang-2 on VE-cadherin function was assessed by measuring the extent of tyrosine phosphorylation. Ang-2 mRNA and protein increased in the retinal tissues after 8 weeks of diabetes and in high-glucose-treated cells. Intravitreal injection of Ang-2 in rats produced a significant increase in retinal vascular permeability. Ang-2 increased HREC monolayer permeability that was associated with a decrease in VE-cadherin and a change in monolayer morphology. High glucose and Ang-2 produced a significant increase in VE-cadherin phosphorylation. CONCLUSIONS; Ang-2 is upregulated in the retina in an animal model of diabetes, and hyperglycemia induces the expression of Ang-2 in isolated retinal endothelial cells. Increased Ang-2 alters VE-cadherin function, leading to increased vascular permeability. Thus, Ang-2 may play an important role in increased vasopermeability in diabetic retinopathy.

Protective Effects of Morus alba Leaves Extract on Ocular Functions of Pups from Diabetic and Hypercholesterolemic Mother Rats

PubMed Central

El-Sayyad, H.I.H.; El-Sherbiny, M.A.; Sobh, M.A.; Abou-El-Naga, A.M.; Ibrahim, M.A.N.; Mousa, S.A.

2011-01-01

Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract. PMID:21697998

Protective effects of Morus alba leaves extract on ocular functions of pups from diabetic and hypercholesterolemic mother rats.

PubMed

El-Sayyad, H I H; El-Sherbiny, M A; Sobh, M A; Abou-El-Naga, A M; Ibrahim, M A N; Mousa, S A

2011-01-01

Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract.

The fundus photo has met its match: optical coherence tomography and adaptive optics ophthalmoscopy are here to stay

PubMed Central

Morgan, Jessica I. W.

2016-01-01

Purpose Over the past 25 years, optical coherence tomography (OCT) and adaptive optics (AO) ophthalmoscopy have revolutionised our ability to non-invasively observe the living retina. The purpose of this review is to highlight the techniques and human clinical applications of recent advances in OCT and adaptive optics scanning laser/light ophthalmoscopy (AOSLO) ophthalmic imaging. Recent findings Optical coherence tomography retinal and optic nerve head (ONH) imaging technology allows high resolution in the axial direction resulting in cross-sectional visualisation of retinal and ONH lamination. Complementary AO ophthalmoscopy gives high resolution in the transverse direction resulting in en face visualisation of retinal cell mosaics. Innovative detection schemes applied to OCT and AOSLO technologies (such as spectral domain OCT, OCT angiography, confocal and non-confocal AOSLO, fluorescence, and AO-OCT) have enabled high contrast between retinal and ONH structures in three dimensions and have allowed in vivo retinal imaging to approach that of histological quality. In addition, both OCT and AOSLO have shown the capability to detect retinal reflectance changes in response to visual stimuli, paving the way for future studies to investigate objective biomarkers of visual function at the cellular level. Increasingly, these imaging techniques are being applied to clinical studies of the normal and diseased visual system. Summary Optical coherence tomography and AOSLO technologies are capable of elucidating the structure and function of the retina and ONH noninvasively with unprecedented resolution and contrast. The techniques have proven their worth in both basic science and clinical applications and each will continue to be utilised in future studies for many years to come. PMID:27112222

The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness.

PubMed

Mallery, Robert M; Poolman, Pieter; Thurtell, Matthew J; Wang, Jui-Kai; Garvin, Mona K; Ledolter, Johannes; Kardon, Randy H

2016-07-01

The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure-function relationship between fixation and areas of preserved GCC in patients with ON.

The Pattern of Visual Fixation Eccentricity and Instability in Optic Neuropathy and Its Spatial Relationship to Retinal Ganglion Cell Layer Thickness

PubMed Central

M. Mallery, Robert; Poolman, Pieter; J. Thurtell, Matthew; Wang, Jui-Kai; K. Garvin, Mona; Ledolter, Johannes; Kardon, Randy H.

2016-01-01

Purpose The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. Methods Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. Results Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. Conclusions Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure–function relationship between fixation and areas of preserved GCC in patients with ON. PMID:27409502

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

PubMed Central

Xie, Z; Chen, F; Wu, X; Zhuang, C; Zhu, J; Wang, J; Ji, H; Wang, Y; Hua, X

2012-01-01

Purpose To elucidate the safety and efficacy of exogenous erythropoietin (EPO) for the protection of photoreceptor cells in a rat model of retinal detachment (RD). Methods Recombinant rat EPO (400 ng) was injected into the vitreous cavity of normal rats to observe the eye manifestations. Retinal function was assessed by flash electroretinograms. Histopathological examination of retinal tissue was performed at 14 days and 2 months after injection, respectively. To investigate the inhibitory effect of EPO on photoreceptor cell apoptosis in RD rats, 100, 200, or 400 ng EPO was injected into the vitreous cavity immediately after RD model establishment. Apoptosis of photoreceptor cells was determined at 3 days after injection. Caspase-3 activation was measured by western blot analysis and immunofluorescence, respectively, and the level of Bcl-XL expression was analyzed by western blot. Results Intravitreal injection of EPO 400 ng into normal rats had no significant impact on retinal function, morphology, or structure. Apoptosis of retinal photoreceptor cells apparently increased after RD and was significantly reduced following EPO treatment. The thickness of the outer nuclear layer in the RD+400 ng group was significantly thicker than that in other experimental RD groups both at 14 days and at 2 months after RD (P<0.05). Western blot and immunofluorescence analyses showed decreased caspase-3 activation and increased Bcl-XL expression following EPO treatment. Conclusion Intravitreal injection of EPO 400 ng is safe, and EPO may suppress caspase-3 activation and enhance Bcl-XL expression, resulting in inhibition of apoptosis and protection of photoreceptor cells. PMID:22020175

Histopathological and immunohistochemical findings associated with a null mutation in the Norrie disease gene.

PubMed

Schroeder, B; Hesse, L; Brück, W; Gal, A

1997-06-01

To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene. Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods. A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB(1) antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a 'functional null-allele' due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids. Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

PubMed Central

Beltran, William A.; Cideciyan, Artur V.; Iwabe, Simone; Swider, Malgorzata; Kosyk, Mychajlo S.; McDaid, Kendra; Martynyuk, Inna; Ying, Gui-Shuang; Shaffer, James; Deng, Wen-Tao; Boye, Sanford L.; Lewin, Alfred S.; Hauswirth, William W.; Jacobson, Samuel G.; Aguirre, Gustavo D.

2015-01-01

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP. PMID:26460017

Vision function testing for a suprachoroidal retinal prosthesis: effects of image filtering

NASA Astrophysics Data System (ADS)

Barnes, Nick; Scott, Adele F.; Lieby, Paulette; Petoe, Matthew A.; McCarthy, Chris; Stacey, Ashley; Ayton, Lauren N.; Sinclair, Nicholas C.; Shivdasani, Mohit N.; Lovell, Nigel H.; McDermott, Hugh J.; Walker, Janine G.; BVA Consortium,the

2016-06-01

Objective. One strategy to improve the effectiveness of prosthetic vision devices is to process incoming images to ensure that key information can be perceived by the user. This paper presents the first comprehensive results of vision function testing for a suprachoroidal retinal prosthetic device utilizing of 20 stimulating electrodes. Further, we investigate whether using image filtering can improve results on a light localization task for implanted participants compared to minimal vision processing. No controlled implanted participant studies have yet investigated whether vision processing methods that are not task-specific can lead to improved results. Approach. Three participants with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal retinal prosthesis. All three completed multiple trials of a light localization test, and one participant completed multiple trials of acuity tests. The visual representations used were: Lanczos2 (a high quality Nyquist bandlimited downsampling filter); minimal vision processing (MVP); wide view regional averaging filtering (WV); scrambled; and, system off. Main results. Using Lanczos2, all three participants successfully completed a light localization task and obtained a significantly higher percentage of correct responses than using MVP (p≤slant 0.025) or with system off (p\\lt 0.0001). Further, in a preliminary result using Lanczos2, one participant successfully completed grating acuity and Landolt C tasks, and showed significantly better performance (p=0.004) compared to WV, scrambled and system off on the grating acuity task. Significance. Participants successfully completed vision tasks using a 20 electrode suprachoroidal retinal prosthesis. Vision processing with a Nyquist bandlimited image filter has shown an advantage for a light localization task. This result suggests that this and targeted, more advanced vision processing schemes may become important components of retinal prostheses to enhance performance. ClinicalTrials.gov Identifier: NCT01603576.

Neuroprotective effect of subretinal implants in the RCS rat.

PubMed

Pardue, Machelle T; Phillips, Michael J; Yin, Hang; Sippy, Brian D; Webb-Wood, Sarah; Chow, Alan Y; Ball, Sherry L

2005-02-01

Retinal prosthetics have been designed to interface with the neural retina by electrically stimulating the remaining retinal circuits after photoreceptor degeneration. However, the electrical stimulation provided by the subretinal implant may also stimulate neurotrophic factors that provide neuroprotection to the retina. This study was undertaken to determine whether electrical stimulation from a subretinal photodiode-based implant has a neuroprotective effect on photoreceptors in the RCS rat, a model of photoreceptor degeneration. Eyes of RCS rats were implanted with an active or inactive device or underwent sham surgery before photoreceptor degeneration. Outer retinal function was assessed with electroretinogram (ERG) recordings weekly until 8 weeks after surgery, at which time retinal tissue was collected and processed for morphologic assessment, including photoreceptor cell counts and retinal layer thickness. At 4 to 6 weeks after surgery, the ERG responses in the active-implant eyes were 30% to 70% greater in b-wave amplitude than the responses from eyes implanted with inactive devices, those undergoing sham surgery, or the nonsurgical control eyes. At 8 weeks after surgery the ERG responses from active-implant eyes were not significantly different from the control groups. However, the number of photoreceptors in eyes implanted with the active or inactive device was significantly greater in the regions over and around the implant versus sham-surgical and nonsurgical control eyes. These results suggest that subretinal electrical stimulation provides temporary preservation of retinal function in the RCS rat. In addition, implantation of an active or inactive device into the subretinal space causes morphologic preservation of photoreceptors in the RCS rat until 8 weeks after surgery. Further studies are needed to determine whether the correlation of neuropreservation with subretinal implantation is due to electrical stimulation and/or a mechanical presence of the implant in the subretinal space.

The fundus photo has met its match: optical coherence tomography and adaptive optics ophthalmoscopy are here to stay.

PubMed

Morgan, Jessica I W

2016-05-01

Over the past 25 years, optical coherence tomography (OCT) and adaptive optics (AO) ophthalmoscopy have revolutionised our ability to non-invasively observe the living retina. The purpose of this review is to highlight the techniques and human clinical applications of recent advances in OCT and adaptive optics scanning laser/light ophthalmoscopy (AOSLO) ophthalmic imaging. Optical coherence tomography retinal and optic nerve head (ONH) imaging technology allows high resolution in the axial direction resulting in cross-sectional visualisation of retinal and ONH lamination. Complementary AO ophthalmoscopy gives high resolution in the transverse direction resulting in en face visualisation of retinal cell mosaics. Innovative detection schemes applied to OCT and AOSLO technologies (such as spectral domain OCT, OCT angiography, confocal and non-confocal AOSLO, fluorescence, and AO-OCT) have enabled high contrast between retinal and ONH structures in three dimensions and have allowed in vivo retinal imaging to approach that of histological quality. In addition, both OCT and AOSLO have shown the capability to detect retinal reflectance changes in response to visual stimuli, paving the way for future studies to investigate objective biomarkers of visual function at the cellular level. Increasingly, these imaging techniques are being applied to clinical studies of the normal and diseased visual system. Optical coherence tomography and AOSLO technologies are capable of elucidating the structure and function of the retina and ONH noninvasively with unprecedented resolution and contrast. The techniques have proven their worth in both basic science and clinical applications and each will continue to be utilised in future studies for many years to come. © 2016 The Authors Ophthalmic & Physiological Optics © 2016 The College of Optometrists.

Functional Optical Coherence Tomography Enables In Vivo Physiological Assessment of Retinal Rod and Cone Photoreceptors

PubMed Central

Zhang, Qiuxiang; Lu, Rongwen; Wang, Benquan; Messinger, Jeffrey D.; Curcio, Christine A.; Yao, Xincheng

2015-01-01

Transient intrinsic optical signal (IOS) changes have been observed in retinal photoreceptors, suggesting a unique biomarker for eye disease detection. However, clinical deployment of IOS imaging is challenging due to unclear IOS sources and limited signal-to-noise ratios (SNRs). Here, by developing high spatiotemporal resolution optical coherence tomography (OCT) and applying an adaptive algorithm for IOS processing, we were able to record robust IOSs from single-pass measurements. Transient IOSs, which might reflect an early stage of light phototransduction, are consistently observed in the photoreceptor outer segment almost immediately (<4 ms) after retinal stimulation. Comparative studies of dark- and light-adapted retinas have demonstrated the feasibility of functional OCT mapping of rod and cone photoreceptors, promising a new method for early disease detection and improved treatment of diseases such as age-related macular degeneration (AMD) and other eye diseases that can cause photoreceptor damage. PMID:25901915

Coherent control of an opsin in living brain tissue

NASA Astrophysics Data System (ADS)

Paul, Kush; Sengupta, Parijat; Ark, Eugene D.; Tu, Haohua; Zhao, Youbo; Boppart, Stephen A.

2017-11-01

Retinal-based opsins are light-sensitive proteins. The photoisomerization reaction of these proteins has been studied outside cellular environments using ultrashort tailored light pulses. However, how living cell functions can be modulated via opsins by modifying fundamental nonlinear optical properties of light interacting with the retinal chromophore has remained largely unexplored. We report the use of chirped ultrashort near-infrared pulses to modulate light-evoked ionic current from Channelrhodopsin-2 (ChR2) in brain tissue, and consequently the firing pattern of neurons, by manipulating the phase of the spectral components of the light. These results confirm that quantum coherence of the retinal-based protein system, even in a living neuron, can influence its current output, and open up the possibilities of using designer-tailored pulses for controlling molecular dynamics of opsins in living tissue to selectively enhance or suppress neuronal function for adaptive feedback-loop applications in the future.

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

PubMed

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

2013-01-11

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

Functional Optical Coherence Tomography Enables In Vivo Physiological Assessment of Retinal Rod and Cone Photoreceptors

NASA Astrophysics Data System (ADS)

Zhang, Qiuxiang; Lu, Rongwen; Wang, Benquan; Messinger, Jeffrey D.; Curcio, Christine A.; Yao, Xincheng

2015-04-01

Transient intrinsic optical signal (IOS) changes have been observed in retinal photoreceptors, suggesting a unique biomarker for eye disease detection. However, clinical deployment of IOS imaging is challenging due to unclear IOS sources and limited signal-to-noise ratios (SNRs). Here, by developing high spatiotemporal resolution optical coherence tomography (OCT) and applying an adaptive algorithm for IOS processing, we were able to record robust IOSs from single-pass measurements. Transient IOSs, which might reflect an early stage of light phototransduction, are consistently observed in the photoreceptor outer segment almost immediately (<4 ms) after retinal stimulation. Comparative studies of dark- and light-adapted retinas have demonstrated the feasibility of functional OCT mapping of rod and cone photoreceptors, promising a new method for early disease detection and improved treatment of diseases such as age-related macular degeneration (AMD) and other eye diseases that can cause photoreceptor damage.

Retinal Information Processing for Minimum Laser Lesion Detection and Cumulative Damage

DTIC Science & Technology

1992-09-17

TAL3Unaqr~orJ:ccd [] J ,;--Wicic tion --------------... MYRON....... . ................... ... ....... ...........................MYRON L. WOLBARSHT B D ist...possible beneficial visual function of the small retinal image movements. B . Visual System Models Prior models of visual system information processing have...against standard secondary sources whose calibrations can be traced to the National Bureau of Standards. B . Electrophysiological Techniques Extracellular

Restoration of the Retinal Structure and Function after Injury

DTIC Science & Technology

2013-10-01

cells in the retina, pan-retinal photocoagulation for proliferative diabetic retinopathy involves the purposeful destruction of a significant fraction of...also causes scotomata and scarring (Morgan and Schatz, 1989; Schatz et al., 1991; Early Treatment Diabetic Retinopathy Study Research Group, 1995... Retinopathy Study Research Group 1995 Focal photocoagulation treatment of diabetic macular edema–relationship of treatment effect to fluorescein

Reduction in Retinal Nerve Fiber Layer Thickness in Young Adults with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Emberti Gialloreti, Leonardo; Pardini, Matteo; Benassi, Francesca; Marciano, Sara; Amore, Mario; Mutolo, Maria Giulia; Porfirio, Maria Cristina; Curatolo, Paolo

2014-01-01

Recent years have seen an increase in the use of retinal nerve fiber layer (RNFL) evaluation as an easy-to-use, reproducible, proxy-measure of brain structural abnormalities. Here, we evaluated RNFL thickness in a group of subjects with high functioning autism (HFA) or with Asperger Syndrome (AS) to its potential as a tool to study autism…

Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations

NASA Astrophysics Data System (ADS)

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.

In vivo biocompatibility of a new cyanine dye for ILM peeling.

PubMed

Thaler, S; Haritoglou, C; Schuettauf, F; Choragiewicz, T; May, C A; Gekeler, F; Fischer, M D; Langhals, H; Schatz, A

2015-03-01

To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4-sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. DSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG). No significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection. DSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application.

The rhodopsins: structure and function. Introduction

NASA Technical Reports Server (NTRS)

Lanyi, J. K.

1992-01-01

Nature makes use of the propensity of retinal for light-dependent double-bond isomerization in a number of systems and in a variety of ways. The common theme for light receptors based on this kind of chemistry is that (1) the retinal is bound in most cases to a small membrane protein via a protonated lysine-retinal Schiff base, (2) the absorption maximum in the visible is tuned to a suitable wavelength largely by electrostatic interaction with polar protein residues, and (3) the light-induced bond rotations and strains in the retinal set off reaction chains during which at least part of the excess free energy acquired is transferred to the protein and causes pK shifts of acidic residues and/or backbone conformational changes. The physiological consequence of the process initiated by absorption of light is either the activation of an information transfer chain (sensory and visual rhodopsins) or energy transduction which drives the electrogenic movement of ions across the membrane (ion-motive rhodopsins). Rhodopsins with these functions occur in bacteria and in higher organisms; from an evolutionary standpoint they are not related to one another. Nevertheless, all of these proteins are remarkably similar and form a distinct family.

Multispectral fundus imaging for early detection of diabetic retinopathy

NASA Astrophysics Data System (ADS)

Beach, James M.; Tiedeman, James S.; Hopkins, Mark F.; Sabharwal, Yashvinder S.

1999-04-01

Functional imaging of the retina and associated structures may provide information for early assessment of risks of developing retinopathy in diabetic patients. Here we show results of retinal oximetry performed using multi-spectral reflectance imaging techniques to assess hemoglobin (Hb) oxygen saturation (OS) in blood vessels of the inner retina and oxygen utilization at the optic nerve in diabetic patients without retinopathy and early disease during experimental hyperglycemia. Retinal images were obtained through a fundus camera and simultaneously recorded at up to four wavelengths using image-splitting modules coupled to a digital camera. Changes in OS in large retinal vessels, in average OS in disk tissue, and in the reduced state of cytochrome oxidase (CO) at the disk were determined from changes in reflectance associated with the oxidation/reduction states of Hb and CO. Step to high sugar lowered venous oxygen saturation to a degree dependent on disease duration. Moderate increase in sugar produced higher levels of reduced CO in both the disk and surrounding tissue without a detectable change in average tissue OS. Results suggest that regulation of retinal blood supply and oxygen consumption are altered by hyperglycemia and that such functional changes are present before clinical signs of retinopathy.

Radial optic neurotomy for ischaemic central vein occlusion

PubMed Central

Martínez-Jardón, C S; Meza-de Regil, A; Dalma-Weiszhausz, J; Leizaola-Fernández, C; Morales-Cantón, V; Guerrero-Naranjo, J L; Quiroz-Mercado, H

2005-01-01

Background/aims: Ischaemic central retinal vein occlusion (CRVO) accounts for 20–50% of all CRVO. No treatment has been proved to be effective. The efficacy of radial optic neurotomy (RON) was evaluated in eyes with ischaemic CRVO. Methods: 10 patients with ischaemic CRVO underwent RON. After pars plana vitrectomy, a microvitreoretinal blade was used to incise the scleral ring, cribriform plate, and adjacent sclera at the nasal edge of the optic disc. Best corrected visual acuity (BCVA), intraocular pressure (IOP), fluorescein angiography (FA), multifocal electroretinography (mfERG), and optical coherence tomography (OCT) were measured preoperatively and at 1, 3, and 6 months postoperatively. Results: No visual improvement was noted in the eyes that underwent RON. FA and mfERG showed no increase in retinal perfusion or retinal function postoperatively. Mean macular central thickness changed from 841 (SD 170) μm preoperatively to 162 (SD 34) μm at the sixth postoperative month. One patient had retinal central artery perforation intraoperatively. One patient developed neovascular glaucoma. Conclusion: RON in ischaemic CRVO did not improve visual function (by mfERG) or visual acuity although macular thickness did improve. This technique may be associated with potential risks. Randomised studies are needed to corroborate these results. PMID:15834084

Features and functions of nonlinear spatial integration by retinal ganglion cells.

PubMed

Gollisch, Tim

2013-11-01

Ganglion cells in the vertebrate retina integrate visual information over their receptive fields. They do so by pooling presynaptic excitatory inputs from typically many bipolar cells, which themselves collect inputs from several photoreceptors. In addition, inhibitory interactions mediated by horizontal cells and amacrine cells modulate the structure of the receptive field. In many models, this spatial integration is assumed to occur in a linear fashion. Yet, it has long been known that spatial integration by retinal ganglion cells also incurs nonlinear phenomena. Moreover, several recent examples have shown that nonlinear spatial integration is tightly connected to specific visual functions performed by different types of retinal ganglion cells. This work discusses these advances in understanding the role of nonlinear spatial integration and reviews recent efforts to quantitatively study the nature and mechanisms underlying spatial nonlinearities. These new insights point towards a critical role of nonlinearities within ganglion cell receptive fields for capturing responses of the cells to natural and behaviorally relevant visual stimuli. In the long run, nonlinear phenomena of spatial integration may also prove important for implementing the actual neural code of retinal neurons when designing visual prostheses for the eye. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Fundus Autofluorescence Imaging].

PubMed

Schmitz-Valckenberg, S

2015-09-01

Fundus autofluorescence (FAF) imaging allows for non-invasive mapping of changes at the level of the retinal pigment epithelium/photoreceptor complex and of alterations of macular pigment distribution. This imaging method is based on the visualisation of intrinsic fluorophores and may be easily and rapidly used in routine patient care. Main applications include degenerative disorders of the outer retina such as age-related macular degeneration, hereditary and acquired retinal diseases. FAF imaging is particularly helpful for differential diagnosis, detection and extent of involved retinal areas, structural-functional correlations and monitoring of changes over time. Recent developments include - in addition to the original application of short wavelength light for excitation ("blue" FAF imaging) - the use of other wavelength ranges ("green" or "near-infrared" FAF imaging), widefield imaging for visualisation of peripheral retinal areas and quantitative FAF imaging. Georg Thieme Verlag KG Stuttgart · New York.

[Aphakic retinal detachment as a function of the technic and course of cataract extraction].

PubMed

Engels, T; Wollensak, J

1977-01-01

Myopic patients, in particular, should be carefully observed by contactglass examination prior to and after cataract surgery, in order to be able to perform prophylactic photocoagulation. In cases of vitreous loss, the risk of having an aphakic retinal detachment will be 20 times as high; that is to say, in one of every five cases cataract extraction with vitreous loss can be expected to produce a retinal detachment. It can be said, therefore, that the best cataract procedure- as far as aphakic retinal detachment is concerned-will be that in which we can expect the lowest rate of vitreous loss. Whether an extensive anterior vitrectomy will reduce the number of aphakic detachments, we cannot yet say defintely, because in these cases we have only routinely performed vitrectomy during the past 2 years.

Restorative retinal laser therapy: Present state and future directions.

PubMed

Chhablani, Jay; Roh, Young Jung; Jobling, Andrew I; Fletcher, Erica L; Lek, Jia Jia; Bansal, Pooja; Guymer, Robyn; Luttrull, Jeffrey K

Because of complications and side effects, conventional laser therapy has taken a back seat to drugs in the treatment of macular diseases. Despite this, research on new laser modalities remains active. In particular, various approaches are being pursued to preserve and improve retinal structure and function. These include micropulsing, various exposure titration algorithms, and real-time temperature feedback control of short-pulse continuous wave lasers, and ultra-short-pulse nanosecond lasers. Some of these approaches are at the preclinical stage of development, whereas others are available for clinical use. Cell biology is providing important insights into the mechanisms of action of retinal laser treatment. We outline the technological bases of current laser platforms, their basic science, therapeutic concepts, clinical experience, and future directions for retinal laser treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants

PubMed Central

Jacobson, Samuel G.; Cideciyan, Artur V.; Peshenko, Igor V.; Sumaroka, Alexander; Olshevskaya, Elena V.; Cao, Lihui; Schwartz, Sharon B.; Roman, Alejandro J.; Olivares, Melani B.; Sadigh, Sam; Yau, King-Wai; Heon, Elise; Stone, Edwin M.; Dizhoor, Alexander M.

2013-01-01

The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months—37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1. PMID:23035049

Clinical characteristics of children with severe visual impairment but favorable retinal structural outcomes from the Early Treatment for Retinopathy of Prematurity (ETROP) study.

PubMed

Siatkowski, R Michael; Good, William V; Summers, C Gail; Quinn, Graham E; Tung, Betty

2013-04-01

To describe visual function and associated characteristics at the 6-year examination in children enrolled in the Early Treatment for Retinopathy of Prematurity Study who had unfavorable visual outcomes despite favorable structural outcomes in one or both eyes. The clinical examination records of children completing the 6-year follow-up examination were retrospectively reviewed. Eligible subjects were those with visual acuity of ≤20/200 in each eye (where recordable) and a normal fundus or straightening of the temporal retinal vessels with or without macular ectopia in at least one eye. Data regarding visual function, retinal structure, presence of nystagmus, optic atrophy, optic disk cupping, seizures/shunts, and Functional Independence Measure for Children (ie, WeeFIM: pediatric functional independence measure) developmental test scores were reviewed. Of 342 participants who completed the 6-year examination, 39 (11%) met inclusion criteria. Of these, 29 (74%) had normal retinal structure, 18 (46%) had optic atrophy, and 3 (8%) had increased cupping of the optic disk in at least one eye. Latent and/or manifest nystagmus occurred in 30 children (77%). The presence of nystagmus was not related to the presence of optic atrophy. Of the 39 children, 28 (72%) had a below-normal WeeFIM score. In 25 participants (7%) completing the 6-year examination, cortical visual impairment was considered the primary cause of visual loss. The remainder likely had components of both anterior and posterior visual pathway disease. Clinical synthesis of ocular anatomy and visual and neurologic function is required to determine the etiology of poor vision in these children. Copyright © 2013 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.

[Multifocal visual electrophysiology in visual function evaluation].

PubMed

Peng, Shu-Ya; Chen, Jie-Min; Liu, Rui-Jue; Zhou, Shu; Liu, Dong-Mei; Xia, Wen-Tao

2013-08-01

Multifocal visual electrophysiology, consisting of multifocal electroretinography (mfERG) and multifocal visual evoked potential (mfVEP), can objectively evaluate retina function and retina-cortical conduction pathway status by stimulating many local retinal regions and obtaining each local response simultaneously. Having many advantages such as short testing time and high sensitivity, it has been widely used in clinical ophthalmology, especially in the diagnosis of retinal disease and glaucoma. It is a new objective technique in clinical forensic medicine involving visual function evaluation of ocular trauma in particular. This article summarizes the way of stimulation, the position of electrodes, the way of analysis, the visual function evaluation of mfERG and mfVEP, and discussed the value of multifocal visual electrophysiology in forensic medicine.

Lithium chloride protects retinal neurocytes from nutrient deprivation by promoting DNA non-homologous end-joining

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhuang Jing; Li Fan; Liu Xuan

2009-03-13

Lithium chloride is a therapeutic agent for treatment of bipolar affective disorders. Increasing numbers of studies have indicated that lithium has neuroprotective effects. However, the molecular mechanisms underlying the actions of lithium have not been fully elucidated. This study aimed to investigate whether lithium chloride produces neuroprotective function by improving DNA repair pathway in retinal neurocyte. In vitro, the primary cultured retinal neurocytes (85.7% are MAP-2 positive cells) were treated with lithium chloride, then cultured with serum-free media to simulate the nutrient deprived state resulting from ischemic insult. The neurite outgrowth of the cultured cells increased significantly in a dose-dependentmore » manner when exposed to different levels of lithium chloride. Genomic DNA electrophoresis demonstrated greater DNA integrity of retinal neurocytes when treated with lithium chloride as compared to the control. Moreover, mRNA and protein levels of Ligase IV (involved in DNA non-homologous end-joining (NHEJ) pathway) in retinal neurocytes increased with lithium chloride. The end joining activity assay was performed to determine the role of lithium on NHEJ in the presence of extract from retinal neurocytes. The rejoining levels in retinal neurocytes treated with lithium were significantly increased as compared to the control. Furthermore, XRCC4, the Ligase IV partner, and the transcriptional factor, CREB and CTCF, were up-regulated in retinal cells after treating with 1.0 mM lithium chloride. Therefore, our data suggest that lithium chloride protects the retinal neural cells from nutrient deprivation in vitro, which may be similar to the mechanism of cell death in glaucoma. The improvement in DNA repair pathway involving in Ligase IV might have an important role in lithium neuroprotection. This study provides new insights into the neural protective mechanisms of lithium chloride.« less

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

PubMed

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.

Methane attenuates retinal ischemia/reperfusion injury via anti-oxidative and anti-apoptotic pathways.

PubMed

Liu, Lin; Sun, Qinglei; Wang, Ruobing; Chen, Zeli; Wu, Jiangchun; Xia, Fangzhou; Fan, Xian-Qun

2016-09-01

Retinal ischemia/reperfusion injury (IRI) may cause incurable visual impairment due to neural regeneration limits. Methane was shown to exert a protective effect against IRI in many organs. This study aims to explore the possible protective effects of methane-rich saline against retinal IRI in rat. Retinal IRI was performed on the right eyes of male Sprague-Dawley rats, which were immediately injected intraperitoneally with methane-saturated saline (25ml/kg). At one week after surgery, the number of retinal ganglion cells (RGCs), total retinal thickness, visual function were measured by hematoxylin and eosin staining, FluoroGold anterograde labeling and flash visual evoked potentials. The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 4-Hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-9, B cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in retinas were assessed by immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. As expected, methane treatment significantly improved the retinal IRI-induced RGC loss, total retinal layer thinning and visual dysfunction. Moreover, methane treatment significantly reduced the levels of oxidative stress biomarkers (8-OHdG, 4-HNE, MDA) and increased the antioxidant enzyme activities (SOD, CAT, GPx) in the retinas with IRI. Meanwhile, methane treatment significantly increased the anti-apoptotic gene (Bcl-2) expression and decreased the pro-apoptotic gene (Bax) expression, accompanied by the suppression of caspase-3 and caspase-9 activity. Thus, these data demonstrated that methane can exert a neuroprotective role against retinal IRI through anti-oxidative and anti-apoptotic pathways. Copyright © 2016. Published by Elsevier B.V.

The effects of retinal abnormalities on the multifocal visual evoked potential.

PubMed

Chen, John Y; Hood, Donald C; Odel, Jeffrey G; Behrens, Myles M

2006-10-01

To examine the effects on the amplitude and latency of the multifocal visual evoked potential (mfVEP) in retinal diseases associated with depressed multifocal electroretinograms (mfERG). Static automated perimetry (SAP), mfERGs, and mfVEPs were obtained from 15 individuals seen by neuro-ophthalmologists and diagnosed with retinal disease based on funduscopic examination, visual field, and mfERG. Optic neuropathy was ruled out in all cases. Diagnoses included autoimmune retinopathy (n = 3), branch retinal arterial occlusion (n = 3), branch retinal vein occlusion (n = 1), vitamin A deficiency (n = 1), digoxin/age-related macular degeneration (n = 1), multiple evanescent white dot syndrome (n = 1), and nonspecific retinal disease (n = 5). Patients were selected from a larger group based on abnormal mfERG amplitudes covering a diameter of 20 degrees or greater. Fourteen (93%) of 15 patients showed significant mfVEP delays, as determined by either mean latency or the probability of a cluster of delayed local responses. Thirteen of 15 patients had normal mfVEP amplitudes in regions corresponding to markedly reduced or nonrecordable mfERG responses. These findings can be mimicked in normal individuals by viewing the display through a neutral-density filter. Retinal diseases can result in mfVEPs of relatively normal amplitudes, often with delays, in regions showing decreased mfERG responses and visual field sensitivity loss. Consequently, a retinal problem can be missed, or dismissed as functional, if a diagnosis is based on an mfVEP of normal or near-normal amplitude. Further, in patients with marked mfVEP delays, a retinal problem could be confused with optic neuritis, especially in a patient with a normal appearing fundus.

Microsystems Technology for Retinal Implants

NASA Astrophysics Data System (ADS)

Weiland, James

2005-03-01

The retinal prosthesis is targeted to treat age-related macular degeneration, retinitis pigmentosa, and other outer retinal degenerations. Simulations of artificial vision have predicted that 600-1000 individual pixels will be needed if a retinal prosthesis is to restore function such as reading large print and face recognition. An implantable device with this many electrode contacts will require microsystems technology as part of its design. An implantable retinal prosthesis will consist of several subsystems including an electrode array and hermetic packaging. Microsystems and microtechnology approaches are being investigated as possible solutions for these design problems. Flexible polydimethylsiloxane (PDMS) substrate electrode arrays and silicon micromachined electrode arrays are under development. Inactive PDMS electrodes have been implanted in 3 dogs to assess mechanical biocompatibility. 3 dogs were followed for 6 months. The implanted was securely fastened to the retina with a single retinal tack. No post-operative complications were evident. The array remained within 100 microns of the retinal surface. Histological evaluation showed a well preserved retina underneath the electrode array. A silicon device with electrodes suspended on micromachined springs has been implanted in 4 dogs (2 acute implants, 2 chronic implants). The device, though large, could be inserted into the eye and positioned on the retina. Histological analysis of the retina from the spring electrode implants showed that spring mounted posts penetrated the retina, thus the device will be redesigned to reduce the strength of the springs. These initial implants will provide information for the designers to make the next generation silicon device. We conclude that microsystems technology has the potential to make possible a retinal prosthesis with 1000 individual contacts in close proximity to the retina.

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

PubMed

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

2016-05-02

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

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

PubMed Central

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

2016-01-01

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. PMID:27144578

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa.

PubMed

Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S; Iwabe, Simone; Khanna, Hemant; Sumaroka, Alexander; Chiodo, Vince A; Fajardo, Diego S; Román, Alejandro J; Deng, Wen-Tao; Swider, Malgorzata; Alemán, Tomas S; Boye, Sanford L; Genini, Sem; Swaroop, Anand; Hauswirth, William W; Jacobson, Samuel G; Aguirre, Gustavo D

2012-02-07

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.

The spectrum of retinopathy in adults with Plasmodium falciparum malaria

PubMed Central

Maude, Richard J.; Beare, Nicholas A.V.; Sayeed, Abdullah Abu; Chang, Christina C.; Charunwatthana, Prakaykaew; Faiz, M. Abul; Hossain, Amir; Yunus, Emran Bin; Hoque, M. Gofranul; Hasan, Mahtab Uddin; White, Nicholas J.; Day, Nicholas P.J.; Dondorp, Arjen M.

2009-01-01

Summary A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P = 0.039), bacterial sepsis (0/5, 0%; P = 0.038) or healthy controls (0/18, 0%; P < 0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P = 0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy. PMID:19344925

Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.

PubMed

LeGates, Tara A; Altimus, Cara M; Wang, Hui; Lee, Hey-Kyoung; Yang, Sunggu; Zhao, Haiqing; Kirkwood, Alfredo; Weber, E Todd; Hattar, Samer

2012-11-22

The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep-wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.

Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury

PubMed Central

van der Merwe, Yolandi

2015-01-01

Abstract Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring. Extracellular matrix (ECM) technology can reduce inflammation, while increasing functional tissue remodeling, over scarring, in various tissues and organs, including the peripheral nervous system. However, applying ECM technology to CNS injuries has been limited and virtually unstudied in the visual system. Here we discuss advances in deriving fetal CNS-specific ECMs, like fetal porcine brain, retina, and optic nerve, and fetal non-CNS-specific ECMs, like fetal urinary bladder, and the potential for using tissue-specific ECMs to treat retinal or optic nerve injuries in two platforms. The first platform is an ECM hydrogel that can be administered as a retrobulbar, periocular, or even intraocular injection. The second platform is an ECM hydrogel and polymer “biohybrid” sheet that can be readily shaped and wrapped around a nerve. Both platforms can be tuned mechanically and biochemically to deliver factors like neurotrophins, immunotherapeutics, or stem cells. Since clinical CNS therapies often use general anti-inflammatory agents, which can reduce tissue-destructive inflammation but also suppress tissue-reparative immune system functions, tissue-specific, ECM-based devices may fill an important need by providing naturally derived, biocompatible, and highly translatable platforms that can modulate the innate immune response to promote a positive functional outcome. PMID:26478910

Retinal vascular injuries and intravitreal human embryonic stem cell-derived haemangioblasts.

PubMed

Wang, Jin-Da; An, Ying; Zhang, Jing-Shang; Wan, Xiu-Hua; Zhang, Wei; Lanza, Robert; Lu, Shi-Jiang; Jonas, Jost B; Xu, Liang

2017-09-01

To investigate whether intravitreally applied haemangioblasts (HB) derived from human embryonic stem cells (hESCs) are helpful for the repair of vascular damage caused in animals by an oxygen-induced retinopathy (OIR), by an induced diabetic retinopathy (DR) or by an induced retinal ischaemia with subsequent reperfusion. Human embryonic stem cell-derived HBs were transplanted intravitreally into C57BL/6J mice (OIR model), into male Wistar rats with an induced DR and into male Wistar rats undergoing induced retinal ischaemia with subsequent reperfusion. Control groups of animals received an intravitreal injection of endothelial cells (ECs) or phosphate-buffered saline (PBS). We examined the vasculature integrity in the mice with OIR, the blood-retina barrier in the rats with induced DR, and retinal thickness and retinal ganglion cell density in retina flat mounts of the rats with the retinal ischaemic-reperfusion retinopathy. In the OIR model, the study group versus control groups showed a significantly (p < 0.001) smaller retinal avascular area [5.1 ± 2.7%;n = 18 animals versus 12.2 ± 2.8% (PBS group; n = 10 animals) and versus 11.8 ± 3.7% (EC group; n = 8 animals)] and less retinal neovascularization [6.3 ± 2.5%;n = 18 versus 15.2 ± 6.3% (n = 10; PBS group) and versus 15.8 ± 3.3% (n = 8; EC group)]. On retinal flat mounts, hESC-HBs were integrated into damaged retinal vessels and stained positive for PECAM (CD31) as EC marker. In the DR model, the study group versus the EC control group showed a significantly (p = 0.001) better blood-retina barrier function as measured at 2 days after the intravitreal injections [study group: 20.2 ± 12.8 μl/(g × hr); n = 6; versus EC control group: 52.9 ± 9.9 μl/(g × hr; n = 6)]. In the retinal ischaemia-reperfusion model, the groups did not differ significantly in retinal thickness and retinal ganglion cell density at 2, 5 and 7 days after baseline. By integrating into damaged retinal vessels and differentiating into ECs, intravitreally administered hESC-HBs may have partially repaired a retinal vascular injury caused by OIR model and DR. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

The use of microperimetry in assessing visual function in age-related macular degeneration.

PubMed

Cassels, Nicola K; Wild, John M; Margrain, Tom H; Chong, Victor; Acton, Jennifer H

Microperimetry is a novel technique for assessing visual function that appears particularly suitable for age-related macular degeneration (AMD). Compared with standard automated perimetry, microperimetry offers several unique features. It simultaneously images the fundus, incorporates an eye-tracking system to correct the stimulus location for fixation loss, and identifies any preferred retinal loci. We identified 52 articles that met the inclusion criteria for a systematic review of microperimetry in the assessment of visual function in AMD. We discuss microperimetry and AMD in relation to disease severity, structural imaging outcomes, other measures of visual function, and evaluation of the efficacy of surgical and/or medical therapies in clinical trials. The evidence for the use of microperimetry in the functional assessment of AMD is encouraging. Disruptions of the ellipsoid zone band and retinal pigment epithelium are clearly associated with reduced differential light sensitivity despite the maintenance of good visual acuity. Reduced differential light sensitivity is also associated with outer segment thinning and retinal pigment epithelium thickening in early AMD and with both a thickening and a thinning of the whole retina in choroidal neovascularization. Microperimetry, however, lacks the robust diffuse and focal loss age-corrected probability analyses associated with standard automated perimetry, and the technique is currently limited by this omission. Copyright © 2017 Elsevier Inc. All rights reserved.

The Python pit organ: imaging and immunocytochemical analysis of an extremely sensitive natural infrared detector.

PubMed

Grace, M S; Church, D R; Kelly, C T; Lynn, W F; Cooper, T M

1999-01-01

The Python infrared-sensitive pit organ is a natural infrared imager that combines high sensitivity, ambient temperature function, microscopic dimensions, and self-repair. We are investigating the spectral sensitivity and signal transduction process in snake infrared-sensitive neurons, neither of which is understood. For example, it is unknown whether infrared receptor neurons function on a thermal or a photic mechanism. We imaged pit organs in living Python molurus and Python regius using infrared-sensitive digital video cameras. Pit organs were significantly more absorptive and/or emissive than surrounding tissues in both 3-5 microns and 8-12 microns wavelength ranges. Pit organs exhibited greater absorption/emissivity in the 8-12 microns range than in the 3-5 microns range. To directly test the relationship between photoreceptors and pit organ infrared-sensitive neurons, we performed immunocytochemistry using antisera directed against retinal photoreceptor opsins. Retinal photoreceptors were labeled with antisera specific for retinal opsins, but these antisera failed to label terminals of infrared-sensitive neurons in the pit organ. Infrared-receptive neurons were also distinguished from retinal photoreceptors on the basis of their calcium-binding protein content. These results indicate that the pit organ absorbs infrared radiation in two major atmospheric transmission windows, one of which (8-12 microns) matches emission of targeted prey, and that infrared receptors are biochemically distinct from retinal photoreceptors. These results also provide the first identification of prospective biochemical components of infrared signal transduction in pit organ receptor neurons.

Development of an Advanced Aidman Vision Screener (AVS) for selective assessment of outer and inner laser induced retinal injury

NASA Astrophysics Data System (ADS)

Boye, Michael W.; Zwick, Harry; Stuck, Bruce E.; Edsall, Peter R.; Akers, Andre

2007-02-01

The need for tools that can assist in evaluating visual function is an essential and a growing requirement as lasers on the modern battlefield mature and proliferate. The requirement for rapid and sensitive vision assessment under field conditions produced the USAMRD Aidman Vision Screener (AVS), designed to be used as a field diagnostic tool for assessing laser induced retinal damage. In this paper, we describe additions to the AVS designed to provide a more sensitive assessment of laser induced retinal dysfunction. The AVS incorporates spectral LogMar Acuity targets without and with neural opponent chromatic backgrounds. Thus, it provides the capability of detecting selective photoreceptor damage and its functional consequences at the level of both the outer and inner retina. Modifications to the original achromatic AVS have been implemented to detect selective cone system dysfunction by providing LogMar acuity Landolt rings associated with the peak spectral absorption regions of the S (short), M (middle), and L (long) wavelength cone photoreceptor systems. Evaluation of inner retinal dysfunction associated with selective outer cone damage employs LogMar spectral acuity charts with backgrounds that are neurally opponent. Thus, the AVS provides the capability to assess the effect of selective cone dysfunction on the normal neural balance at the level of the inner retinal interactions. Test and opponent background spectra have been optimized by using color space metrics. A minimal number of three AVS evaluations will be utilized to provide an estimate of false alarm level.

Nerve fiber layer (NFL) degeneration associated with acute q-switched laser exposure in the nonhuman primate

NASA Astrophysics Data System (ADS)

Zwick, Harry; Zuclich, Joseph A.; Stuck, Bruce E.; Gagliano, Donald A.; Lund, David J.; Glickman, Randolph D.

1995-01-01

We have evaluated acute laser retinal exposure in non-human primates using a Rodenstock scanning laser ophthalmoscope (SLO) equipped with spectral imaging laser sources at 488, 514, 633, and 780 nm. Confocal spectral imaging at each laser wavelength allowed evaluation of the image plane from deep within the retinal vascular layer to the more superficial nerve fiber layer in the presence and absence of the short wavelength absorption of the macular pigment. SLO angiography included both fluorescein and indocyanine green procedures to assess the extent of damage to the sensory retina, the retinal pigment epithelium (RPE), and the choroidal vasculature. All laser exposures in this experiment were from a Q-switched Neodymium laser source at an exposure level sufficient to produce vitreous hemorrhage. Confocal imaging of the nerve fiber layer revealed discrete optic nerve sector defects between the lesion site and the macula (retrograde degeneration) as well as between the lesion site and the optic disk (Wallerian degeneration). In multiple hemorrhagic exposures, lesions placed progressively distant from the macula or overlapping the macula formed bridging scars visible at deep retinal levels. Angiography revealed blood flow disturbance at the retina as well as at the choroidal vascular level. These data suggest that acute parafoveal laser retinal injury can involve both direct full thickness damage to the sensory and non-sensory retina and remote nerve fiber degeneration. Such injury has serious functional implications for both central and peripheral visual function.

Retinal micropseudocysts in diabetic retinopathy: prospective functional and anatomic evaluation.

PubMed

Forte, Raimondo; Cennamo, Gilda; Finelli, Maria Luisa; Bonavolontà, Paola; Greco, Giovanni Maria; de Crecchio, Giuseppe

2012-01-01

To evaluate the prevalence, progression and functional predictive value of retinal micropseudocysts (MPCs) in diabetic patients. Prospective controlled observational study. From among all the type 2 diabetic patients evaluated during a period of 5 months between September 2009 and January 2010, we enrolled all patients with retinal MPCs at spectral-domain scanning laser ophthalmoscope/optical coherence tomography (SD-SLO/OCT) not previously treated for diabetic retinopathy. Forty diabetic patients without MPCs served as the control group. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular sensitivity and stability of fixation at SD-SLO/OCT microperimetry were measured monthly for 12 months. 22/156 patients with type 2 diabetes (14.1%, 32 eyes) met the inclusion criteria. The 95% confidence interval for the prevalence estimate of MPCs was 12.3-16.6%. Mean BCVA, CRT and central retinal sensitivity at baseline were 77.53 ± 2.2 Early Treatment Diabetic Retinopathy Study letters, 242.31 ± 31.0 µm and 15.95 ± 0.61 dB, respectively. Fixation was stable in all cases. Compared to the control group, eyes with MPCs had similar BCVA but greater CRT (p = 0.01) and reduced macular sensitivity (p = 0.001) at baseline and at each follow-up visit. Over time, CRT remained stable in eyes with MPCs, whereas macular sensitivity progressively decreased. MPCs in diabetic retinopathy are associated, temporally or causally, with a progressive reduction of macular sensitivity despite a stable BCVA, CRT and fixation. Copyright © 2011 S. Karger AG, Basel.

[Internal limiting membrane peeling as prophylaxis of epimacular membrane formation in eyes undergoing vitrectomy for rhegmatogenous retinal detachement].

PubMed

Hejsek, L; Dusová, J; Stepanov, A; Rozsíval, P

2014-06-01

Rhegmatogenous retinal detachment is a serious condition that can significantly impair visual function, even after a successful surgery. One of the complications that can significantly impair visual acuity in the postoperative period is a development of the epimacular membrane (ERM). The aim of this work is to monitor the effect of peeling of the internal limiting membrane (ILM) in the macula at the anatomical and functional results in the postoperative period, especially with regard to the development of ERM. Prospective study of 21 eyes, which underwent peeling of ILM during pars plana vitrectomy for rhegmatogenous retinal detachment (on detached macula). The ILM peeling was done without using decalin during this procedure. We tested best corrected visual acuity (BCVA) and followed fundus biomicroscopic findings. Proliferative vitreoretinopathy (PVR) was evaluated according to the recommendations of the Retina Society Terminology Committee. To exclude the development of ERM in the macula optical coherence tomography (OCT) was performed at the end of the 18-month follow-up period. In total, the results of 21 eyes of 21 patients who underwent PPV for rhegmatogenous retinal detachment were evaluated. In all of them was during PPV performed ILM peeling on detached macula, these are followed prospectively. ILM peeling without using decalin was sufficient in all eyes. All eyes with ILM peeling did not develop ERM at the end of the follow-up period. ILM peeling during PPV for rhegmatogenous retinal detachment reduces the risk of developing secondary ERM.

IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells.

PubMed

Mellough, Carla B; Collin, Joseph; Khazim, Mahmoud; White, Kathryn; Sernagor, Evelyne; Steel, David H W; Lako, Majlinda

2015-08-01

We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling. © 2015 AlphaMed Press.

Ocular Changes in TgF344-AD Rat Model of Alzheimer's Disease

PubMed Central

Tsai, Yuchun; Lu, Bin; Ljubimov, Alexander V.; Girman, Sergey; Ross-Cisneros, Fred N.; Sadun, Alfredo A.; Svendsen, Clive N.; Cohen, Robert M.; Wang, Shaomei

2014-01-01

Purpose. Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed. Methods. Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques. Results. As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature. Conclusions. Further studies are needed to elucidate the significance and mechanisms of this pathological change and luminance threshold recording from the superior colliculus. PMID:24398104

Hyperspectral Computed Tomographic Imaging Spectroscopy of Vascular Oxygen Gradients in the Rabbit Retina In Vivo

PubMed Central

Kashani, Amir H.; Kirkman, Erlinda; Martin, Gabriel; Humayun, Mark S.

2011-01-01

Diagnosis of retinal vascular diseases depends on ophthalmoscopic findings that most often occur after severe visual loss (as in vein occlusions) or chronic changes that are irreversible (as in diabetic retinopathy). Despite recent advances, diagnostic imaging currently reveals very little about the vascular function and local oxygen delivery. One potentially useful measure of vascular function is measurement of hemoglobin oxygen content. In this paper, we demonstrate a novel method of accurately, rapidly and easily measuring oxygen saturation within retinal vessels using in vivo imaging spectroscopy. This method uses a commercially available fundus camera coupled to two-dimensional diffracting optics that scatter the incident light onto a focal plane array in a calibrated pattern. Computed tomographic algorithms are used to reconstruct the diffracted spectral patterns into wavelength components of the original image. In this paper the spectral components of oxy- and deoxyhemoglobin are analyzed from the vessels within the image. Up to 76 spectral measurements can be made in only a few milliseconds and used to quantify the oxygen saturation within the retinal vessels over a 10–15 degree field. The method described here can acquire 10-fold more spectral data in much less time than conventional oximetry systems (while utilizing the commonly accepted fundus camera platform). Application of this method to animal models of retinal vascular disease and clinical subjects will provide useful and novel information about retinal vascular disease and physiology. PMID:21931729

[Retinal vasculopathy with cerebral leukoencephalopathy carrying TREX1 mutation diagnosed by the intracranial calcification: a case report].

PubMed

Komaki, Ryouhei; Ueda, Takehiro; Tsuji, Yukio; Miyawaki, Toko; Kusuhara, Sentaro; Hara, Shigeo; Toda, Tatsushi

2018-02-28

A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c.703_704insG (p.Val235GlyfsX6), thereby we diagnosed her as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RVCL is an autosomal dominant condition caused by C-terminal frame-shift mutation in TREX1. TREX1 protein is a major 3' to 5' DNA exonuclease, which are important in DNA repair. While TREX1 mutations identified in Aicardi-Goutieres syndrome patients lead to a reduction of enzyme activity, it is suggested that mutations in RVCL alter an intracellular location of TREX1 protein. There are no treatments based evidences in RVCL. We administered cilostazol to protect endothelial function, and her brain lesions and renal function have not become worse for 10 months after. It is necessary to consider RVCL associated with TREX1 mutation if a patient has retinal lesions, white matter lesions accompanied with calcifications, and multiple organ dysfunction.

Water maze performance of aged Sprague-Dawley rats in relation to retinal morphologic measures.

PubMed

Spencer, R L; O'Steen, W K; McEwen, B S

1995-06-01

The spatial learning ability of aged male and female Sprague-Dawley rats was assessed using the Morris water maze. To determine the influence of age-related visual deficits on performance levels, retinal morphologic measures were correlated with water maze performance for each rat. Rats were first trained on the water maze task at 21 months of age and were retrained 3 or 4 times at 6-week intervals. After the last training session the rats were killed and their eyes were removed for histopathologic and morphometric evaluation of the retinas. There was a large degree of retinal degeneration in all of the aged Sprague-Dawley rats with an average decrease in the thickness of the retinal outer nuclear layer (photoreceptor nuclei containing layer) of 85% in old males and 95% in old females. Some rats, however, had less degeneration of the retinas than others, and the degree of retinal degeneration was strongly related to performance levels on the water maze task. Among the aged rats in this study with the least retinal degeneration, there was little evidence for a subset of rats that were unable, with extensive training, to learn a platform position. Of the 41 rats with the least retinal degeneration (out of a total of 81), only one was a clear non-learner on the water maze task, whereas, of the 27 rats with the most retinal degeneration, 20 were non-learners. These results illustrate the potentially serious confounding effects of deteriorating visual ability on attempts to assess cognitive functioning of aged albino rats on tasks requiring utilization of visual cues.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation

PubMed Central

López-Rubio, Salvador; Chacon-Camacho, Oscar F.; Matsui, Rodrigo; Guadarrama-Vallejo, Dalia; Astiazarán, Mirena C.

2018-01-01

Purpose To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype–phenotype correlations. PMID:29422768