Five Year Nationwide Incidence of Rhegmatogenous Retinal Detachment Requiring Surgery in Korea

Purpose

To define the incidence and demographic characteristics of rhegmatogenous retinal detachment (RRD) requiring surgery in Korea.

Design

Nationwide population-based retrospective study.

Methods

Patients who underwent surgery for RRD from 2007 to 2011 were retrospectively identified using the diagnostic code for RRD and the surgical codes for retinal detachment surgeries in the national claim database. The average incidence rate of RRD during the 5-year period was estimated using the population data of the 2010 Census in Korea.

Results

A total of 24,928 surgically treated RRD cases were identified. The average incidence of surgery requiring RRD was 10.39 cases per 100,000 person-years [95% confidence interval (CI), 10.26–10.52). The incidence in men (11.32 cases per 100,000 person-years; 95% CI: 11.13–11.51) was significantly higher than that in women (9.47 cases per 100,000 person-years; 95% CI: 9.29–9.64) (p<0.001). The incidence of surgery requiring RRD showed a bimodal distribution across age groups, with one peak (28.55 cases per 100,000 person-years; 95% CI: 27.46–29.67) representing patients between 65 and 69 years of age and the second peak (approximately 8.5 per 100,000 person-years) representing patients between 20 and 29 years of age. The male-to-female ratio was approximately 1.0 for the peak-incidence age groups, whereas the ratio was higher for the other age groups.

Conclusions

The incidence of RRD in the Korean population was similar to that reported previously, with the peak incidence being lower than that in the Caucasian population. The age-specific RRD incidence pattern in Korea followed a bimodal distribution.     

正常猕猴与人视网膜血管的比较

目的比较正常猕猴与人视网膜血管的异同,为进一步利用猕猴建立动物模型来研究视网膜血管打下基础。方法取健康成年猕猴眼球6只和人角膜移植供体剩余眼杯8只的视网膜,用ADP酶法进行血管染色,对两者视网膜血管的走行、血管分级、毛细血管分层以及黄斑区血管拱环等进行比较,测量结果进行统计学检验。结果猕猴与人的视网膜铺片经ADP酶法染色后见视网膜血管自穿出视盘后的一级血管逐渐分支变细,直至五级血管即毛细血管;在视盘旁、赤道部、周边部两者血管面积百分比没有差异;视盘旁血管分为多层,赤道部有两层,且深浅层间相互交通,周边部仅见一层毛细血管且较稀疏;两者黄斑区毛细血管均较密集,有形态完整呈不规则状的血管拱环,血管面积百分比以及血管拱环的面积、周长和直径没有差异。结论猕猴与人在视网膜血管走行、分级、毛细血管分层以及黄斑区血管拱环等多方面有良好的相似性,可用作人类视网膜血管、尤其是黄斑区视网膜血管研究的良好动物模型。     

Retinal Pathology of Pediatric Cerebral Malaria in Malawi

Introduction

The causes of coma and death in cerebral malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy.

Methodology/Principal Findings

Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having cerebral malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with cerebral malaria and 29 with comas of other causes. Cerebral malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage.

Conclusions/Significance

We found significant differences in retinal histopathology between patients who died of cerebral malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in cerebral malaria.     

Retinal and choroidal neovascularization

The unique vascular supply of the retina, the ability to visualize the vasculature in vivo, and the ability to selectively express genes in the retina make the retina an ideal model system to study molecular mechanisms of angiogenesis. In addition, this area of investigation has great clinical significance, because retinal and choroidal neovascularization are the most common causes of severe visual loss in developed countries and new treatments are needed. As a result, interest in ocular neovascularization is rapidly growing and there has been considerable recent progress. Use of genetically engineered mice in recently developed murine models provides a means to investigate the role of individual gene products in neovascularization in two distinct vascular beds, the retinal vasculature and the choroidal vasculature. It appears that angiogenesis in different vascular beds has common themes, but also has tissue-specific aspects. This review summarizes recent progress in the field of ocular neovascularization and the prospects that it provides for the development of new treatments.     

Changes of Vision-Related Quality of Life in Retinal Detachment Patients after Cataract Surgery

Rhegmatenous retinal detachment (RRD) is one of the most serious complications after phacoemulsification combined with intraocular lens implantation surgery. It has been reported that vision-related quality of life (VRQoL), as well as visual acuity rapidly decreased when RRD developed. However, little is known of the VRQoL in those RRD patients after anatomical retinal re-attachment, especially whether or not the VRQoL is higher than that before cataract surgery. In this prospective case series study, we use the Chinese-version low vision quality of life questionnaire (CLVQOL) to assess the changes of VRQoL in age-related cataract patients who suffered from RRD after phacoemulsification with intraocular lens (phaco-IOL) implantation. All participants were asked to complete questionnaires in face- to-face interviews one day before and two weeks after cataract surgery, as well as one day before and three months after RRD surgery. A total of 10,127 consecutive age-related cataract patients were followed up to one year after phaco-IOL implantation; among these patients, 17 were diagnosed as RRD. The total CLVQOL scores and subscale scores except “Mobility” decreased significantly when RRD developed. After retinal surgery, only the score of “General vision and lighting” in the CLVQOL questionnaires improved when compared to the scores two weeks after cataract surgery, although the best corrected visual acuity of all patients significantly raised up. However, the mean CLVQOL scores and subscale scores were still considerably higher than the level prior to cataract surgery. Our study suggests that cataract patients at high risk of postoperative RRD should not deny the opportunity to undergo phaco-IOL implantation, even though potential VRQoL impairment induced by RRD exists.     

Increased Oxidative and Nitrative Stress Accelerates Aging of the Retinal Vasculature in the Diabetic Retina

Hyperglycemia-induced retinal oxidative and nitrative stress can accelerate vascular cell aging, which may lead to vascular dysfunction as seen in diabetes. There is no information on whether this may contribute to the progression of diabetic retinopathy (DR). In this study, we have assessed the occurrence of senescence-associated markers in retinas of streptozotocin-induced diabetic rats at 8 and 12 weeks of hyperglycemia as compared to normoglycemic aging (12 and 14 months) and adult (4.5 months) rat retinas. We have found that in the diabetic retinas there was an up-regulation of senescence-associated markers SA-β-Gal, p16^INK4a and miR34a, which correlated with decreased expression of SIRT1, a target of miR34a. Expression of senescence-associated factors primarily found in retinal microvasculature of diabetic rats exceeded levels measured in adult and aging rat retinas. In aging rats, retinal expression of senescence associated-factors was mainly localized at the level of the retinal pigmented epithelium and only minimally in the retinal microvasculature. The expression of oxidative/nitrative stress markers such as 4-hydroxynonenal and nitrotyrosine was more pronounced in the retinal vasculature of diabetic rats as compared to normoglycemic aging and adult rat retinas. Treatments of STZ-rats with the anti-nitrating drug FeTPPS (10mg/Kg/day) significantly reduced the appearance of senescence markers in the retinal microvasculature. Our results demonstrate that hyperglycemia accelerates retinal microvascular cell aging whereas physiological aging affects primarily cells of the retinal pigmented epithelium. In conclusion, hyperglycemia-induced retinal vessel dysfunction and DR progression involve vascular cell senescence due to increased oxidative/nitrative stress.     

Novel Fluorescein Angiography-Based Computer-Aided Algorithm for Assessment of Retinal Vessel Permeability

Purpose

To present a novel method for quantitative assessment of retinal vessel permeability using a fluorescein angiography-based computer algorithm.

Methods

Twenty-one subjects (13 with diabetic retinopathy, 8 healthy volunteers) underwent fluorescein angiography (FA). Image pre-processing included removal of non-retinal and noisy images and registration to achieve spatial and temporal pixel-based analysis. Permeability was assessed for each pixel by computing intensity kinetics normalized to arterial values. A linear curve was fitted and the slope value was assigned, color-coded and displayed. The initial FA studies and the computed permeability maps were interpreted in a masked and randomized manner by three experienced ophthalmologists for statistical validation of diagnosis accuracy and efficacy.

Results

Permeability maps were successfully generated for all subjects. For healthy volunteers permeability values showed a normal distribution with a comparable range between subjects. Based on the mean cumulative histogram for the healthy population a threshold (99.5%) for pathological permeability was determined. Clear differences were found between patients and healthy subjects in the number and spatial distribution of pixels with pathological vascular leakage. The computed maps improved the discrimination between patients and healthy subjects, achieved sensitivity and specificity of 0.974 and 0.833 respectively, and significantly improved the consensus among raters for the localization of pathological regions.

Conclusion

The new algorithm allows quantification of retinal vessel permeability and provides objective, more sensitive and accurate evaluation than the present subjective clinical diagnosis. Future studies with a larger patients’ cohort and different retinal pathologies are awaited to further validate this new approach and its role in diagnosis and treatment follow-up. Successful evaluation of vasculature permeability may be used for the early diagnosis of brain microvascular pathology and potentially predict associated neurological sequelae. Finally, the algorithm could be implemented for intraoperative evaluation of micovascular integrity in other organs or during animal experiments.     

苏州市玻璃体积血的临床病因分析

目的:探讨苏州市不同年龄组玻璃体积血的常见病因,为疾病预防提供依据。方法:对在2009年~2011年住我院的287例295眼玻璃体积血患者的临床资料进行回顾性分析。结果:在所有玻璃体积血患者中,糖尿病性视网膜病变(diabetic retinopathy,DRP)111例(38.7%),眼外伤60例(20.9%),视网膜静脉阻塞(retinal vein occlusion,RVO)59例(20.6%),孔源性视网膜脱离(rhegmatogenous retinal detachment,RRD)32例(11.1%)。年龄<45岁的青年组中,眼外伤导致的玻璃体积血最多,为36例(48.6%),其次为DRP 26例(35.1%),视网膜血管炎(retinal vasculitis,RV)10例(13.5%)。45~59岁中年组中,DRP导致玻璃体积血最多,为61例(50.8%),其次为RVO 20例(16.7%)、眼外伤17例(14.2%)、RRD 16例(13.3%)。≥60岁老年组中,RVO导致玻璃体积血最多,为38例(40.9%),其次为DRP 24例(25.8%),RRD 15例(16.1%)。结论:DRP、眼外伤、RVO、RRD是引起玻璃体积血最常见的病因。青年患者的主要病因是眼外伤、DRP和RV,而中老年患者的主要病因是DRP及RVO。     

Astrocyte-Derived Vascular Endothelial Growth Factor Stabilizes Vessels in the Developing Retinal Vasculature

Vascular endothelial growth factor (VEGF) plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans.     

Surgical Complications of Primary Rhegmatogenous Retinal Detachment: A Meta-Analysis

Background

To investigate the surgical complications of scleral buckling (SB) and pars plana vitrectomy (PPV) performed on primary rhegmatogenous retinal detachment (RRD) and to discover which surgical procedures bring fewer complications.

Methods

An electronic literature search using the PubMed database, ISI Web of Knowledge and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and observational studies comparing SB with PPV on primary RRD. Outcome measures included intra-operative complications and early and late post-operative complications.

Results

During the operation, significantly less subretinal hemorrhage occurred in the PPV group than in the SB group (OR = 4.71; 95%CI, 1.33–16.64; p = 0.02) and the hypotony incidence was significantly higher in the SB group (OR = 18.24; 95%CI, 2.37–140.44; p = 0.005); however, the occurrence of iatrogenic breaks was significantly lower in the SB group (OR = 0.05; 95%CI, 0.01–0.21; p<0.0001). In the early stage of post-operation, significantly higher incidence of choroidal detachment was identified in the SB group than in the PPV group (OR = 10.19; 95%CI, 2.36–44.09; p = 0.002); patients undergoing SB had significantly higher odds of residual subretinal fluid (OR = 14.71; 95%CI, 1.84–117.32; p = 0.01); the occurrence of high intraocular pressure was significantly lower in the SB group (OR = 0.46; 95%CI, 0.23–0.89; p = 0.02); and no significant difference was shown in the incidence of epithelia defect (p = 0.37) between the two groups. In the late stage of post-operation, the incidence of diplopia/extraocular muscle dysfunction was significantly higher in the SB group (OR = 4.04; 95%CI, 1.30–12.52; p = 0.02); and significantly less cataract was observed in the SB group (OR = 0.20; 95%CI, 0.14–0.30; p<0.00001); no significant difference was found in the incidences of cystoid macular edema (p = 0.65), macular pucker (p = 0.52), post-operative proliferative vitreoretinopathy (p = 0.73) and epiretinal membrane (p = 0.47) in other late post-operative complications.

Conclusions

This meta-analysis suggests that PPV could be considered as potential surgical management on primary RRD.     

Rhegmatogenous Retinal Detachment Surgery in Elderly People over 70 Years Old: Visual Acuity,Quality of Life,and Cost-Utility Values

Background and Purpose

To evaluate the influence of rhegmatogenous retinal detachment (RRD) surgery on elderly patients in terms of visual acuity, vision-related quality of life and its cost-effectiveness.

Methods

Elderly patients over 70 years old, who were diagnosed and underwent RRD surgery at Shanghai First People''s Hospital, Shanghai Jiao Tong University, China, from January 1, 2009, through January 1, 2013. The participants received scleral buckling surgery and vitreous surgery with or without scleral buckling under retrobulbar anesthesia. We followed the patients for 1 year and collected best-corrected visual acuity (BCVA), vision-related quality of life, and direct medical costs data. Utility values elicited by time-trade-off were analyzed to determine the quality of life. Quality-adjusted life years (QALYs) gained in life expectancy were calculated and discounted at 3% annually. Costs per QALY gained were reported using the bootstrap method. Further analyses were made for two age groups, age 70–79 and age over 80 years. Sensitivity analyses were performed to test stability of the results.

Results

98 patients were included in the study. The BCVA significantly improved by 0.53±0.44 (Logarithm of the Minimum Angle of Resolution (logMAR)) at the 1-year postoperative time point (p<0.001). Utility values increased from 0.77 to 0.84 (p<0.001), and an average of 0.4 QALYs were gained in the life expectancy. Costs per QALY gained from the RRD surgery were 33,186 Chinese Yuan (CNY) (5,276 US dollars (USD))/QALY; 24,535 CNY (3,901 USD)/QALY for the age group of 70–79 years and 71,240 CNY (11,326 USD)/QALY for the age group over 80 years.

Conclusions

RRD surgery improved the visual acuity and quality of life in the elderly patients over 70 years old. According to the World Health Organization’s recommendation, at a threshold of willingness to pay of 115,062 CNY (18,293 USD)/QALY, RRD surgery is cost effective in the elderly patients.     

Intravital Video Microscopy Measurements of Retinal Blood Flow in Mice

Alterations in retinal blood flow can contribute to, or be a consequence of, ocular disease and visual dysfunction. Therefore, quantitation of altered perfusion can aid research into the mechanisms of retinal pathologies. Intravital video microscopy of fluorescent tracers can be used to measure vascular diameters and bloodstream velocities of the retinal vasculature, specifically the arterioles branching from the central retinal artery and of the venules leading into the central retinal vein. Blood flow rates can be calculated from the diameters and velocities, with the summation of arteriolar flow, and separately venular flow, providing values of total retinal blood flow. This paper and associated video describe the methods for applying this technique to mice, which includes 1) the preparation of the eye for intravital microscopy of the anesthetized animal, 2) the intravenous infusion of fluorescent microspheres to measure bloodstream velocity, 3) the intravenous infusion of a high molecular weight fluorescent dextran, to aid the microscopic visualization of the retinal microvasculature, 4) the use of a digital microscope camera to obtain videos of the perfused retina, and 5) the use of image processing software to analyze the video. The same techniques can be used for measuring retinal blood flow rates in rats.     

Retinal Nerve Fiber and Optic Disc Morphology in Patients with Human Immunodeficiency Virus Using the Heidelberg Retina Tomography 3

Purpose

To use novel confocal scanning ophthalmoscopy technology to test hypothesis that HIV-seropositive patients without history of retinitis with a history of a low CD4 count are more likely to have damage to their retinal nerve fiber layer (RNFL) when compared to patients with high CD4 count. In addition, we compared optic disc morphologic changes with glaucoma.

Design

Cross-sectional study.

Participants and Controls

171 patients were divided into four groups. The control group consisted of 40 eyes of 20 HIV-seronegative patients. The second group consisted of 80 eyes of 41 HIV-positive patients whose CD4 cell count never dropped below 100 (1.0 x 10⁹/L). The third group consisted of 44 eyes of 26 HIV-positive patients with a history of low CD4 counts <100. Fourth group consisted of 79 eyes of 79 patients with confirmed glaucoma who served as positive controls.

Testing

Confocal scanning laser ophthalmoscopy was performed with the Heidelberg Retina Tomograph (HRT3) and data were analyzed with HRT3, software (Heyex version 1.5.10.0).

Main Outcome Measures

Disc area, cup area, cup volume, rim volume, mean cup depth, maximum cup depth, cup-to-disc ration, mean RNFL thickness, and RNFL cross-sectional area.

Results

Analysis of the global optic nerve and cup parameters showed no difference in disk area among the four groups. There was also no difference in cup, rim volume, mean cup depth, or maximum cup depth among the first three groups but they were all different from glaucoma group. The RNFL was thinner in glaucoma and both HIV-positive groups compared to HIV-seronegative subjects. The cross sectional RNFL area was thinner in both high and low CD4 HIV-positive groups compared to HIV-seronegative group in the nasal and temporal/inferior sectors, respectively. Glaucoma group showed thinning in all sectors.

Conclusions

HIV retinopathy results in retinal nerve fiber layer loss without structural optic nerve supportive tissue change. RNFL damage may occur early in HIV disease by mechanism different than in glaucoma.     

Comparative Evaluation of Methods for Estimating Retinal Ganglion Cell Loss in Retinal Sections and Wholemounts

To investigate the reliability of different methods of quantifying retinal ganglion cells (RGCs) in rat retinal sections and wholemounts from eyes with either intact optic nerves or those axotomised after optic nerve crush (ONC). Adult rats received a unilateral ONC and after 21 days the numbers of Brn3a⁺, βIII-tubulin⁺ and Islet-1⁺ RGCs were quantified in either retinal radial sections or wholemounts in which FluoroGold (FG) was injected 48 h before harvesting. Phenotypic antibody markers were used to distinguish RGCs from astrocytes, macrophages/microglia and amacrine cells. In wholemounted retinae, counts of FG⁺ and Brn3a⁺ RGCs were of similar magnitude in eyes with intact optic nerves and were similarly reduced after ONC. Larger differences in RGC number were detected between intact and ONC groups when images were taken closer to the optic nerve head. In radial sections, Brn3a did not stain astrocytes, macrophages/microglia or amacrine cells, whereas βIII-tubulin and Islet-1 did localize to amacrine cells as well as RGCs. The numbers of βIII-tubulin⁺ RGCs was greater than Brn3a⁺ RGCs, both in retinae from eyes with intact optic nerves and eyes 21 days after ONC. Islet-1 staining also overestimated the number of RGCs compared to Brn3a, but only after ONC. Estimates of RGC loss were similar in Brn3a-stained radial retinal sections compared to both Brn3a-stained wholemounts and retinal wholemounts in which RGCs were backfilled with FG, with sections having the added advantage of reducing experimental animal usage.     

Changes in Outer Retinal Microstructures during Six Month Period in Eyes with Acute Zonal Occult Outer Retinopathy-Complex

Purpose

To study the changes in the outer retinal microstructures during a six month period after the onset of acute zonal occult outer retinopathy (AZOOR)-complex by spectral-domain optical coherence tomography (SD-OCT).

Methods

Seventeen eyes of 17 patients with the AZOOR-complex were studied. The integrity of the external limiting membrane (ELM), ellipsoid zone (EZ; also called the inner/outer segment junction), and interdigitation zone (IDZ; also called the cone outer segment tips) were evaluated in the SD-OCT images obtained at the initial visit and at six months. The three highly reflective bands were divided into three types; continuous, discontinuous, and absent. The integrity of the outer nuclear layer (ONL) was also assessed.

Results

Among the three highly reflective bands, the IDZ was most altered at the initial visit and least recovered at six months. Fifteen of 17 eyes (88%) had a recovery of at least one of the three bands at six months in the retinal area where the ONL was intact, and these areas showed an improvement of visual field. Three eyes (18%) had retinal areas where the ONL was absent at the initial visit, and there was no recovery in both the retinal structures and visual fields in these areas.

Conclusions

Our results indicate that more than 85% eyes with AZOOR-complex show some recovery in the microstructures of the outer retina during a six month period if the ONL is intact. We conclude that SD-OCT is a useful method to monitor the changes of the outer retinal microstructure in eyes with the AZOOR-complex.     

Postoperative Vision-Related Quality of Life in Macula-Off Rhegmatogenous Retinal Detachment Patients and Its Relation to Visual Function

Objective

To determine the vision-related quality of life (VR-QOL) after surgery for macula-off rhegmatogenous retinal detachment (RRD) in relation to visual acuity, contrast acuity, and color vision.

Methods

In a prospective observational study, we included 55 patients with a macula-off RRD. Best corrected visual acuity (BCVA), color vision (saturated and desaturated color confusion indices (CCI)) and contrast acuity were measured at 12 months postoperatively in both the RRD eye and the fellow control eye, and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was filled out.

Results

Operated and fellow control eyes differed significantly in mean LogMAR BCVA (P<0.0001), median Log contrast acuity (P<0.0001), saturated CCI (P = 0.009), and desaturated CCI (P = 0.016). Significant correlations were observed between the NEI VFQ-25 overall composite score and postoperative LogMAR BCVA (R = −0.551, P<0.0001), contrast acuity (R = 0.472, P<0.0001), saturated CCI (R = −0.315, P = 0.023), and desaturated CCI (R = −0.283, P = 0.044).

Conclusions

A lower VR-QOL was highly correlated to a worse postoperative BCVA and contrast acuity and to a lesser extent to color vision disturbances.     

Adeno-Associated Virus Mediated Delivery of a Non-Membrane Targeted Human Soluble CD59 Attenuates Some Aspects of Diabetic Retinopathy in Mice

Diabetic retinopathy is the leading cause of visual dysfunction in working adults and is attributed to retinal vascular and neural cell damage. Recent studies have described elevated levels of membrane attack complex (MAC) and reduced levels of membrane associated complement regulators including CD55 and CD59 in the retina of diabetic retinopathy patients as well as in animal models of this disease. We have previously described the development of a soluble membrane-independent form of CD59 (sCD59) that when delivered via a gene therapy approach using an adeno-associated virus vector (AAV2/8-sCD59) to the eyes of mice, can block MAC deposition and choroidal neovascularization. Here, we examine AAV2/8-sCD59 mediated attenuation of MAC deposition and ensuing complement mediated damage to the retina of mice following streptozotocin (STZ) induced diabetes. We observed a 60% reduction in leakage of retinal blood vessels in diabetic eyes pre-injected with AAV2/8-sCD59 relative to negative control virus injected diabetic eyes. AAV2/8-sCD59 injected eyes also exhibited protection from non-perfusion of retinal blood vessels. In addition, a 200% reduction in retinal ganglion cell apoptosis and a 40% reduction in MAC deposition were documented in diabetic eyes pre-injected with AAV2/8-sCD59 relative to diabetic eyes pre-injected with the control virus. This is the first study characterizing a viral gene therapy intervention that targets MAC in a model of diabetic retinopathy. Use of AAV2/8-sCD59 warrants further exploration as a potential therapy for advanced stages of diabetic retinopathy.     

Suitability of UK Biobank Retinal Images for Automatic Analysis of Morphometric Properties of the Vasculature

PurposeTo assess the suitability of retinal images held in the UK Biobank - the largest retinal data repository in a prospective population-based cohort - for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease.MethodsNon-mydriatic fundus images from both eyes of 2,690 participants - people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345) - were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry.ResultsTotal operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001).ConclusionsA proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group.     

Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis

Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.