Radiation retinopathy

Therapeutic radiation to the eye, or in close proximity to the eye, can result in damage to the retina. Manifestations of radiation retinopathy include: intraretinal hemorrhages, hard exudates, macular edema, cotton wool spots, microaneurysms, telangiectatic vessels, sheathed retinal vessels, retinal capillary non-perfusion, or neovascularization. Factors that influence the development of radiation retinopathy are discussed and a case report which includes radiation retinopathy in the differential diagnosis is presented.     

Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy

Retinopathy, characterized by an alteration of the retinal microvasculature, is a common complication of diabetes mellitus. These changes can cause increased permeability and alter endothelial cell proliferation, edema, and abnormal neovascularization and eventually result in blindness. The pathogenesis of diabetic retinopathy (DR) is complicated, involving many factors/mediators such as genetic susceptibility, microRNAs, and cytokines. One of the factors involved in DR pathogenesis is epigenetic changes that can have a key role in the regulation of gene expression; these include microRNAs, histone modifications, and methylation of DNA. The main epigenetic modifications are DNA methylation and posttranslational modifications of the histones. Generally, the studies on epigenetics can provide new opportunities to investigate the molecular basis of diseases with complicated pathogenesis, including DR, and provide essential insights into the potential design of strategies for its treatment. The aim of this study is an investigation of DR pathogenesis and epigenetic modifications that involve in DR development.     

Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation

Excessive retinal vascular permeability contributes to the pathogenesis of proliferative diabetic retinopathy and diabetic macular edema, leading causes of vision loss in working-age adults. Using mass spectroscopy-based proteomics, we detected 117 proteins in human vitreous and elevated levels of extracellular carbonic anhydrase-I (CA-I) in vitreous from individuals with diabetic retinopathy, suggesting that retinal hemorrhage and erythrocyte lysis contribute to the diabetic vitreous proteome. Intravitreous injection of CA-I in rats increased retinal vessel leakage and caused intraretinal edema. CA-I-induced alkalinization of vitreous increased kallikrein activity and its generation of factor XIIa, revealing a new pathway for contact system activation. CA-I-induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein and bradykinin receptor antagonism. Subdural infusion of CA-I in rats induced cerebral vascular permeability, suggesting that extracellular CA-I could have broad relevance to neurovascular edema. Inhibition of extracellular CA-I and kallikrein-mediated innate inflammation could provide new therapeutic opportunities for the treatment of hemorrhage-induced retinal and cerebral edema.     

Effects of endogenous cyclotronic ionic resonance (ICR) on macular diabetic edema: preliminary results

The intent in this research was to verify the effects of the application of low frequency magnetic fields to cases of macular diabetic edema. We treated six patients afflicted by non-proliferating diabetic retinopathy with macular oedema. Quantitative clinical appraisals of the retinal thickness were obtained for the Optical Coherence Tomography (OCT I). None of the cases affected by non-cystoid macular oedema (non-CMO), or with a relevant ischemic component, evidenced by retinal fluorangiography, had further worsening in their clinical course during the treatment. Only one of the patients, who underwent a long treatment period with ICR demonstrated a significant reduction of the macular edema, with no need of other invasive therapeutic procedures (intravitreous injection of triamcinolone and/or laser therapy).     

Betacellulin induces increased retinal vascular permeability in mice

Background

Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes.

Methods and Findings

In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans.

Conclusions

These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.     

miRNA-dependent cross-talk between VEGF and Ang-2 in hypoxia-induced microvascular dysfunction

Ocular neovascularization is a vision-threatening complication of ischemic retinopathy that develops in various ocular disorders, such as retinopathy of prematurity (ROP) and diabetic retinopathy. Both Ang-2 and VEGF are implicated in this pathogenesis. However, their inter-regulation still remains elusive. Competitive endogenous RNAs (ceRNAs) are messenger RNA (mRNA) molecules that affect each other expression through the competition for the shared miRNA. Herein, we assessed whether the expression of Ang-2 and VEGF is interdependent through the sequestration of common miRNAs. Bioinformatics prediction and 3′-UTR luciferase assay revealed that Ang-2 and VEGF is commonly targeted by miR-351. Silencing either Ang-2 or VEGF increases the availabilities of shared miR-351, therefore reduces the activity of Luc-Ang-2 3′-UTR. The interdependence of VEGF and Ang-2 is miRNA- and 3′-UTR dependent, as silencing Dicer abolishes the interdependence. We also found that miR-351 dependency of VEGF-Ang-2 crosstalk occurs in retinal endothelial cells and rat retinas. miR-351 over-expression significantly reduces the level of VEGF and Ang-2 expression in vivo and in vitro. Overall, miRNA-dependent crosstalk between Ang-2 and VEGF plays a role in hypoxia-induced microvascular response. miRNA-based therapy can affect the expression of Ang-2 and VEGF, which represents a therapeutic potential for the treatment of vascular disease.     

糖尿病性视网膜病变术后CRT、SFCT、mALB、MBG、HbA1c水平的变化及相关性

本研究通过观察糖尿病性视网膜病变术后患者黄斑中心凹视网膜厚度,脉络膜厚度,尿微量白蛋白、血糖、糖化血红蛋白的水平,试图了解其差异及相关性。我们选取2016年1月至2017年12月于我院就诊的糖尿病性视网膜病变患者200例,根据其有无视网膜病变、有无肾病、术后有无黄斑水肿分为合并组和未合并组,同时选取100例正常成年人作为对照。观察糖尿病患者和对照组、未合并和合并并发症糖尿病患者的黄斑中心凹视网膜厚度(central retinal thickness, CRT),凹下脉络膜厚度(subfoveal choroidal thickness,SFCT),尿微量白蛋白(microAlbunminuria, mALB)、平均血糖(mean blood glucose, MBG)和糖化血红蛋白(glycated haemoglobin, HbA1c)水平,进一步分析了糖尿病黄斑水肿患者的尿微量白蛋白水平与黄斑中心凹视网膜厚度、脉络膜厚度、血糖、糖化血红蛋白的相关性。研究结果表明,糖尿病组患者的CRT水平较对照组低,SFCT、mALB、MBG和HbA1c水平高于对照组;合并视网膜病变、合并肾病和合并黄斑水肿组患者的CRT水平较未合并组低,SFCT、mALB、MBG和HbA1c水平均高于未合并组;黄斑水肿患者的m ALB水平与CRT水平负相关,与SFCT、MBG和HbA1c水平正相关。本研究得出结论:糖尿病性视网膜病变术后患者黄斑中心凹视网膜厚度(CRT)较薄,脉络膜厚度(SFCT)变厚,且与尿微量白蛋白密切相关。     

A Higher Serum Calcium Level is an Independent Risk Factor for Vision-Threatening Diabetic Retinopathy in Patients with Type 2 Diabetes: Cross-Sectional and Longitudinal Analyses

ObjectiveAn elevated serum calcium level is associated with a higher risk of type 2 diabetes (T2D), but its role in microvascular complications remains unclear. This study was conducted to investigate the association between serum calcium levels and vision-threatening diabetic retinopathy (VTDR).MethodsThis study employed a cross-sectional and longitudinal design. The cross-sectional part included all patients treated for T2D at Shanghai General Hospital between 2007 and 2016, while the longitudinal part involved an overlapping cohort of diabetic patients without VTDR who were followed from their admission until December 2019. Multivariable logistic and Cox proportional hazard regression analyses were performed, respectively. VTDR was defined as severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, or clinically significant macular edema.ResultsA total of 3269 patients were included in the cross-sectional analysis, and 649 patients were included in the longitudinal analysis. In the cross-sectional analysis, higher corrected serum calcium (odds ratio: 1.31 per 0.1 mmol/L, 95% confidence interval: 1.16-1.49), younger age, longer diabetes duration, albuminuria, impaired renal function, and lower serum magnesium were independently associated with VTDR. In the longitudinal analysis, 95 subjects developed VTDR during follow-up (9.7 years, interquartile range: 7.4-10.9 years). Higher corrected serum calcium (hazard ratio: 1.38 per 0.1 mmol/L, 95% confidence interval: 1.10-1.72), younger age, longer diabetes duration, sub-VTDR, albuminuria, lower serum magnesium, and higher glycated hemoglobin were identified as independent risk factors for VTDR.ConclusionsA higher serum calcium level may be an independent risk factor for VTDR in patients with T2D.     

The effects of microRNAs in activating neovascularization pathways in diabetic retinopathy

Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus that causes diabetic macular edema and visual loss. DR is categorized, based on the presence of vascular lesions and neovascularization, into non-proliferative and proliferative DR. Vascular changes in DR correlate with the cellular damage and pathological changes in the capillaries of blood-retinal barrier. Several cytokines have been involved in inducing neovascularization. These cytokines activate different signaling pathways which are mainly responsible for the complications of DR. Recently; microRNAs (miRNAs) have been introduced as the key factors in the regulation of the cytokine expression which plays a critical role in neovascularization of retinal cells. Some studies have demonstrated that changing levels of miRNAs have essential role in the pathophysiology of vascular changes in patients with DR. The aim of this study is to identify the effects of miRNAs in the pathogenesis of DR via activating neovascularization pathways.     

RAGE and its ligands in retinal disease

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

SDOCT imaging to identify macular pathology in patients diagnosed with diabetic maculopathy by a digital photographic retinal screening programme

Introduction

Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients.

Methods

A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months.

Results

From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients’ SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist.

Discussion

This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population.     

Potent antiemetic effects of the new serotonin antagonists.

Diabetic retinopathy progresses through three distinct stages. A rational approach to management is based on an understanding of the pathophysiology of each stage. Based on the results of national multicentered clinical trials of laser photocoagulation and other treatments, advances in our understanding of the pathogenesis and treatment can now make a dramatic impact on blindness in the diabetic population: Panretinal laser photocoagulation treatment can reduce the risk of vision loss from high-risk proliferative diabetic retinopathy by at least 50%. Laser photocoagulation treatment of clinically significant diabetic macular edema can reduce the risk of vision loss by more than 50%. Vitrectomy can restore useful vision to some patients with severe diabetic retinopathy and vitreous hemorrhage with or without an accompanying traction retinal detachment. Diabetes 2000 is a new project sponsored by the American Academy of Ophthalmology, the goal of which is to eliminate preventable blindness from diabetes by the year 2000. As its name implies, Diabetes 2000 will be a long-term project aimed at a specific disease--diabetic retinopathy and its complications. It will provide the latest research findings to ophthalmologists and primary care physicians as the first priority, followed by the education of patients and the general public. Recent advances and treatment guidelines for the medical and surgical treatment of diabetic eye disease will be emphasized through the continuing education of ophthalmologists, other physicians, and allied health professionals. In later phases, educational programs for diabetic persons and the public will be developed.(ABSTRACT TRUNCATED AT 250 WORDS)     

RPE barrier breakdown in diabetic retinopathy: seeing is believing

Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in working-age Americans. DR is traditionally regarded as a disorder of blood–retina barriers, and the leakage of blood content is a major pathological characteristic of the disease. While the breakdown of the endothelial barrier in DR has been investigated extensively, the vascular leakage through the retinal pigment epithelium (RPE) barrier in the disease has not been widely acknowledged. As the blood content leaked through the RPE barrier causes excessive water influx to the retina, the breakdown of the RPE barrier is likely to play a causative role in the development of some forms of diabetic macular edema, a major cause of vision loss in DR. In this article, we will discuss the clinical evidences of the diabetes-induced RPE barrier breakdown, the alteration of the RPE in diabetes, the molecular and cellular mechanism of RPE barrier breakdown, and the research tools for the analysis of RPE barrier leakage. Finally, we will discuss the methodology and potential applications of our recently developed fluorescent microscopic imaging for the diabetes- or ischemia-induced RPE barrier breakdown in rodents.     

激光联合康柏西普治疗糖尿病视网膜病变伴黄斑水肿的临床效果及机制研究

目的:探讨激光联合康柏西普治疗糖尿病视网膜病变伴黄斑水肿的临床效果及可能机制。方法:选取2017年1月至2017年12月我院收治的糖尿病视网膜病变伴黄斑水肿患者92例作为研究对象,随机分为观察组46例(46眼)及对照组46例(46眼)。对照组患者实施激光治疗,观察组在注射康柏西普1周后再进行激光治疗。比较两组患者治疗后的临床疗效,治疗前后最佳矫正视力(BCVA)、黄斑中心厚度(CMT)、血管内皮生长因子(VEGF)、胰岛素样生长因子-1(IGF-1)及红细胞生成素(EPO)水平的变化。结果:治疗后,观察组的总有效率为91.30%,显著高于对照组(69.57%,P0.05);两组患者的BCVA均较治疗前明显提高(P0.05),CMT均低于治疗前(P0.05),但观察组BCVA较对照组更高(P0.05);CMT较对照组更低(P0.05)。治疗后,两组患者的VEGF、IGF-1、EPO均较治疗前明显降低,且观察组的VEGF、IGF-1、EPO均显著低于对照组(P0.05)。结论:激光联合康柏西普治疗糖尿病视网膜病变伴黄斑水肿的临床疗效显著优于单用激光治疗,并可有效改善VEGF、IGF-1、EPO水平,这可能对抑制血管新生产生积极作用。     

Peripheral Vasodilators in the Treatment of Macular Degenerative Changes in the Eye

Four peripheral vasodilators — tolazoline HCl (Priscoline), nicotinic acid, nicotinyl alcohol (Roniacol), and nylidrin HCl (Arlidin)—were studied in 203 patients over a 13-year period as treatment for macular degenerative changes in the eye.Visual acuity was improved or maintained in 87%. Excellent results were obtained in the treatment of macular edema following cataract surgery and in older patients with diabetic retinopathy. In 126 out of 145 patients with senile macular degeneration, improvement or stabilization was obtained.For all the types of macular degeneration, nylidrin HCl was the most effective of the drugs studied and had the fewest side effects.A recent report based upon animal experiments advises against the use of peripheral vasodilators in degenerative arterial diseases of the eye; however, the assumption made therein that blood volume is a measure of blood flow cannot be accepted. Peripheral vasodilator therapy, which long-term clinical study has shown to be valuable in the treatment of macular degeneration, should not therefore be denied to these patients.     

NAP modulates hyperglycemic–inflammatory event of diabetic retina by counteracting outer blood retinal barrier damage

Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Prolonged hyperglycemia stimulates inflammatory pathway characterized by the release of some cytokines leading to the impairment of blood retinal barrier (BRB). NAP exerts a protective effect in various eye diseases, including DR. So far, the role of NAP in the modulation of inflammatory event during early phase of this pathology has not been investigated yet. In the current study, we have studied the retinal protective effect of NAP, injected into the eye, in diabetic rats. NAP treatment exerts a dual effect downregulating interleukin (IL)-1β and its related receptors and upregulating IL-1Ra expression. We have also tested the role of this peptide in human retinal epithelial cells (ARPE19) cultured on a semipermeable support and exposed to hyperglycemic–inflammatory insult, representing a in vitro model of diabetic macular edema, a clinical manifestation of DR. The results have shown that NAP prevents outer BRB impairment by upregulating the tight junctions. In conclusion, deepened characterization of NAP action mechanism on hyperglycemic–inflammatory damage may be useful to develop a new strategy to prevent retinal damage during DR.     

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision‐threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry‐based label‐free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age‐related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.     

Anti-VEGF in treatment of diabetic macular edema

Diabetic macular edema is the leading cause of moderate visual deterioration in patients with diabetic retinopathy. Ranibizumab) blocks vascular endothelial growth factor (VEGF) induced hyperpermeability of blood vessels. In this prospective case series we investigated the efficacy and safety of anti-VEGF treatment in reduction of central retinal thickness (CRT) and improvement in visual acuity (VA) in patients with diabetic macular edema (DME). 9 patients were followed up for 6 months and treated monthly with intravitreal ranibizumab. VA and CRT were measured at each visit. Treatment was discontinued as the peak improvement of either parameter was reached and reinstituted in case of deterioration/recurrence of edema. Study endpoints included: VA using ETDRS chart, CRT and number of injections at 6 months. Mean VA from all 9 patients increased by 0.3 lines of logMAR (p < 0.05 compared to baseline), and CRT decreased from 515 +/- 123 microm to 310 +/- 110 microm. The improvement of VA after ranibizumab injection was in correlation with a decrease in CRT. Mean of 4 injections were needed to control the disease during the follow-up period. Ranibizumab treatment was effective in VA and reducing CRT. Several injections were needed to control the disease. Regular OCT examinations and retreatment are advised in order to maintain initially reached VA.     

Maternal immune system adaptation to pregnancy - a potential influence on the course of diabetic retinopathy

Background  

Progression of diabetic retinopathy occurs at least temporarily during pregnancy. Although the cause of this progression is not entirely understood, the immune phenomenon and chronic inflammation may play a significant role. During pregnancy in order to avoid fetus rejection, certain components of the immune system that are knowingly implicated in the pathogenesis of diabetic retinopathy are activated including generalized leukocyte activation and an increase in certain cytokine plasma levels. Activated leukocytes with up regulated adhesion molecules have an increased potential to bind to the endothelium cells of blood vessels. Leukocyte-endothelial interaction and the consequent leukostasis with capillary occlusion, ischemia and vascular leakage have a substantial role in the development of diabetic retinopathy. Furthermore, certain increased cytokines are known to cause blood-retinal-barrier breakdown whilst others promote angiogenic and fibrovascular proliferation and thereby can also be implicated in the pathogenesis of this diabetic complication.     

IL-1 Generated Subsequent to Radiation-Induced Tissue Injury Contributes to the Pathogenesis of Radiodermatitis

Radiation injury in the skin causes radiodermatitis, a condition in which the skin becomes inflamed and the epidermis can break down. This condition causes significant morbidity and if severe it can be an independent factor that contributes to radiation mortality. Radiodermatitis is seen in some settings of radiotherapy for cancer and is also of concern as a complication post-radiation exposure from accidents or weapons, such as a "dirty bomb". The pathogenesis of this condition is incompletely understood. Here we have developed a murine model of radiodermatitis wherein the skin is selectively injured by irradiation with high-energy electrons. Using this model we showed that the interleukin-1 (IL-1) pathway plays a significant role in the development of radiodermatitis. Mice that lack either IL-1 or the IL-1 receptor developed less inflammation and less severe pathological changes in their skin, especially at later time-points. These findings suggest that IL-1 pathway may be a potential therapeutic target for reducing the severity of radiodermatitis.