Ocular neovascularization: Implication of endogenous angiogenic inhibitors and potential therapy

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and as a consequence, there is no satisfactory therapy for ocular NV. In the last 10 years, a number of studies provided increasing evidence demonstrating that the imbalance between angiogenic stimulating factors and angiogenic inhibitors is a major contributor to the angiogenesis induced by various insults, such as hypoxia or ischemia, inflammation and tumor. The angiogenic inhibitors alone or in combination with other existing therapies are, therefore, believed to be promising in the treatment of ocular NV in the near future. This article reviews recent progress in studies on the mechanisms and treatment of ocular NV, focusing on the implication and therapeutic potential of endogenous angiogenic inhibitors in ocular NV.     

Experimental models of autoimmune inflammatory ocular diseases

Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin). Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.     

血管内皮生长因子 A的选择性剪接与眼内新生血管的生成

眼内新生血管的生成是多种眼病致盲的重要原因.血管内皮生长因子A(VEGF-A)家族是促进眼内新生血管生成的关键因素,其通过调控病理性血管的发生和增加血管的通透性而起作用.VEGF-A依选择性剪接方式的不同,可形成2个蛋白家族,分别是具有促血管生成作用的VEGFxxx家族和具有抗血管生成作用的VEGFxxxb家族.VEGFxxxb家族蛋白在正常眼组织中均有表达,而在糖尿病性视网膜病变患者的眼组织中表达水平降低.VEGF165b是VEGFxxxb家族中最早分离出来且研究最为广泛的分子结构,其可以明显抑制视网膜前新生血管的生成,而对视网膜生理性血管的发生无抑制作用.随着对VEGFxxxb家族研究的逐步深入,选择性剪接调节VEGFxxx与VEGFxxxb两者之间的平衡,可作为糖尿病性视网膜病变、年龄相关性黄斑变性等眼内新生血管性疾病的治疗新策略.     

血管内皮生长因子 A的选择性剪接与眼内新生血管的生成

眼内新生血管的生成是多种眼病致盲的重要原因.血管内皮生长因子A(VEGF-A)家族是促进眼内新生血管生成的关键因素,其通过调控病理性血管的发生和增加血管的通透性而起作用.VEGF-A依选择性剪接方式的不同,可形成2个蛋白家族,分别是具有促血管生成作用的VEGFxxx家族和具有抗血管生成作用的VEGFxxxb家族.VEGFxxxb家族蛋白在正常眼组织中均有表达,而在糖尿病性视网膜病变患者的眼组织中表达水平降低.VEGF165b是VEGFxxxb家族中最早分离出来且研究最为广泛的分子结构,其可以明显抑制视网膜前新生血管的生成,而对视网膜生理性血管的发生无抑制作用.随着对VEGFxxxb家族研究的逐步深入,选择性剪接调节VEGFxxx与VEGFxxxb两者之间的平衡,可作为糖尿病性视网膜病变、年龄相关性黄斑变性等眼内新生血管性疾病的治疗新策略.

Abstract：

Ocular neovascularization is the primary cause of blindness in a wide range of ocular diseases. The vascular endothelial growth factor A (VEGF-A) is the key factor involved in ocular angiogenesis, which can cause eye diseases through the development of pathological angiogenesis and increase of vascular permeability. There are two families of VEGF-A isoforms formed by alternative splicing,the angiogenic VEGF-A family ( VEGFxxx ), known to contribute to ocular neovascularization, and the antiangiogenic VEGF-A family ( VEGFxxx b), which is found in normal ocular tissues but downregulated in human diabetic retinopathy. The first member of the VEGFxxxb family to be isolated was VEGF165b. It can significantly reduce preretinal neovascularization without inhibition of physiological intraretinal angiogenesis.As the studies on the VEGFxxxb family proceed more deeply, controlling the balance of VEGFxxx to VEGFxxxb isoforms may be therapeutically valuable in the treatment of angiogenic eye diseases such as diabetic retinopathy and age-related macular degeneration.     

血管内皮生长因子 A的选择性剪接与眼内新生血管的生成

眼内新生血管的生成是多种眼病致盲的重要原因.血管内皮生长因子A(VEGF-A)家族是促进眼内新生血管生成的关键因素,其通过调控病理性血管的发生和增加血管的通透性而起作用.VEGF-A依选择性剪接方式的不同,可形成2个蛋白家族,分别是具有促血管生成作用的VEGFxxx家族和具有抗血管生成作用的VEGFxxxb家族.VEGFxxxb家族蛋白在正常眼组织中均有表达,而在糖尿病性视网膜病变患者的眼组织中表达水平降低.VEGF165b是VEGFxxxb家族中最早分离出来且研究最为广泛的分子结构,其可以明显抑制视网膜前新生血管的生成,而对视网膜生理性血管的发生无抑制作用.随着对VEGFxxxb家族研究的逐步深入,选择性剪接调节VEGFxxx与VEGFxxxb两者之间的平衡,可作为糖尿病性视网膜病变、年龄相关性黄斑变性等眼内新生血管性疾病的治疗新策略.     

Ocular problems of young adults in rural Nigeria

Objectives: To determine the common eye diseases as well as the prevalence and causes of blindness and visual impairment in young adult residents of rural areas of Anambra State, Nigeria. Materials and methods: Three rural villages in Anambra State, Nigeria were selected by simple random sampling. A structured questionnaire on demographic characteristics, symptoms and attitude to eye diseases was administered to residents aged 18–49 years. Ocular examination included visual acuity estimation, colour vision test, tonometry, refraction and ophthalmoscopy. Skin-snip was examined for microfilaria. Results: The common ocular problems in the 510 young adults examined were presbyopia (33.3%), refractive errors (41.1%), allergic conjunctivitis (8.2%), pterygium (8.2%), pingueculum (5.9%) and colour vision defect (2.4%). Bilateral blindness occurredin 1.2%, uniocular blindness in 0.8% and 1.7% had visual impairment in their better eyes. Glaucoma and sequelae of congenital cataract caused bilateral blindness while visual impairment was due to refractive errors, cataract, corneal opacities and uveitis. Trauma predisposed to uniocular blindness and visual impairment. Conclusions: Eyeglasses alone would alleviate visual impairment and ensure good near vision in more than 47% of the subjects. The prevalence of blindness could be reduced through early detection of glaucoma, congenital cataract and ocular trauma. This revised version was published online in July 2006 with corrections to the Cover Date.     

Ocular manifestations of incontinentia pigmenti

PURPOSE: The study aimed to evaluate the ocular manifestations in patients with incontinentia pigmenti (IP). METHODS: Thirty patients from different parts of Sweden participated. Orthoptic and ocular examinations were performed as well as evaluation of refraction and visual acuity. RESULTS: Ocular manifestations, probably associated with IP, were found in 77% (23/30) of the patients. Thirteen had serious or vision-threatening eye manifestations in one eye, of whom 7 were totally blind in that eye from retinal detachments. Ten patients had minor retinal and/or corneal changes. CONCLUSION: Ocular lesions in patients with IP may be serious and lead to blindness because of retinal disease. Ophthalmological follow-up is essential in the neonatal period and such a programme is recommended.     

长链非编码RNA与眼部增生性疾病

眼部增生性疾病,如增生性玻璃体视网膜病变(PVR)、糖尿病视网膜病变(DR)、脉络膜新生血管、角膜新生血管等常导致眼结构和功能的损伤,晚期治疗效果差.长链非编码RNA(lncRNA)是一类长度大于200个核苷酸的RNA转录本,虽不能直接编码蛋白质但可通过各种途径调节蛋白编码基因的表达,从而广泛参与调控个体的生长发育以及细胞凋亡、增生、分化等生命活动.越来越多的证据表明lncRNA参与多种眼部疾病的发生和发展,并有望成为其诊断和治疗的新靶点.本文就lncRNA的概念、分类、作用机制及其与PVR、DR、脉络膜新生血管、角膜新生血管的研究进展进行综述.     

Glaucoma after open globe injury

Ocular trauma remains a core root of avoidable blindness worldwide. Corneal scarring, lens injury, glaucoma, vitreous hemorrhage, retinal or choroidal detachment and endophthalmitis are sequel to ocular trauma that can lead to blindness. Very few studies have been published to tackle the risk of developing post-traumatic glaucoma after open globe injuries (OGI), however, there are many articles discussing closed eye injury. This review article aims to cover the incidence, risk factors, causes and treatment of glaucoma after open globe injury.     

Peters Anomaly in Twins: A Case Report of a Rare Incident with Novel Comorbidities

IntroductionPeters anomaly is a rare developmental malformation involving the anterior segment of the eye, which culminates in amblyopia or congenital blindness. Multiple ocular and/or systemic malformations have been observed with this anomaly, and novel comorbidities continue to be reported.ConclusionThe novel concordance of Peters anomaly in these monozygotic twins sharing a mutation in PROC gene provides further evidence that this anomaly has a genetic basis. Hypoplasia of the optic nerves and optic chiasm, along with severe protein C deficiency and bilateral absence of the pupils, are associated comorbidities that have not previously been reported with this anomaly.Key Words: Peters anomaly, Genetic basis, Comorbidities, Ocular abnormalities, Systemic malformation, Monozygotic twins     

Ocular fluorometry: standardization and instrumentation development

A Concerted Action on Ocular Fluorometry, stressing standardization and instrumentation development has been funded by the European Community. Agreement was reached on harmonization of protocols.The results obtained show that the protocols proposed for Clinical Ocular Fluorometry were generally appropriate and may be followed closely, with reproducible and meaningful results. In each group, areas for improvement could, however, be detected, particularly regarding facility of use of the newly developed softwares.The success of the ECNOF was very rewarding and every effort is being made to consolidate this success in the publication and dissemination of the agreed guidelines and results.The field of Ocular Fluorometry appears to have even more potential than was apparent at the beginning of this Concerted Action. The needs for instrumentation development have been clarified and four main directions where progress has been achieved are identifiable: spectral fluorescence analysis of naturally occurring ocular fluorophores, light scattering analysis of ocular structures and fluids, improved axial resolution for better quantification of ocular permeabilities and, finally, development of simple routine clinical instrumentation.Corneal and lens natural fluorescence appear extremely promising as indicators of disease status, particularly in diabetes. Blood-retinal barrier permeability has the potential to become a screening test isolating the eyes at risk for developing diabetic blindness and, therefore needing closer follow-up and earlier treatment. Light scattering methodologies particularly in association with ocular fluorometry, may allow improved monitorization of chronic inflammation, better therapeutical management of a variety a sight-threatening diseases.     

Kringle结构及其在眼部新生血管性疾病中的应用

以异常新生血管形成为主要病理变化的新生血管性眼病是l临床常见、治疗棘手的致盲性眼病，一旦发生往往难以逆转，将导致严重的视力损害。近年来研究发现体内多种内源性蛋白所包含的带双硫键三环蛋白结构区的kringle结构具有抑制新生血管的作用，因此kringle结构域被认为是具有抑制新生血管作用的独立保守结构和功能单位。就近年来发现的具有抑制新生血管作用的kringle结构及其抑制眼部新生血管的作用进行综述，以期对研究新生血管抑制剂有所提示。     

Progression of eye disease in "cured" leprosy patients: implications for understanding the pathophysiology of ocular disease and for addressing eyecare needs

BACKGROUND: Ocular damage in leprosy is due either to nerve damage or infiltration by mycobacteria. There is currently little information about the magnitude and nature of incident ocular pathology in cured leprosy patients. This information would increase our understanding of the pathophysiology of ocular involvement in leprosy and help in developing programmes to address the eyecare needs of leprosy patients who have been released from treatment. The cumulative incidence of leprosy related ocular pathology and cataract was measured during an 11 year follow up period in cured leprosy patients released from treatment in Korea. METHODS: In 1988 standardised eye examinations were performed on 501 patients in eight resettlement villages in central South Korea. In May 1999 standardised eye examinations were repeated in this population. RESULTS: Among the patients in whom there was no sight threatening leprosy related ocular disease (lagophthalmos, posterior synechia, or keratitis) in 1988, 14.7% developed one or more of these conditions. Overall, among those with no vision reducing cataract in 1988, 26.4% had developed a vision reducing lens opacity in at least one eye. Among patients examined in both 1988 and 1999, 14.3% developed visual impairment and 5.7% developed blindness. CONCLUSION: This study demonstrates that leprosy related ocular pathology progresses in some patients even after they are cured mycobiologically. The progressive leprosy related lesions are the result of chronic nerve damage; ocular lesions due to infiltration by Mycobacterium leprae did not develop. Based on the factors found to be associated with development of the most visually significant findings (posterior synechia, keratitis, and cataract) certain patients should be targeted at discharge for active follow up eye care. We suggest that patients with lagophthalmos (even in gentle closure), trichiasis, small pupils, and posterior synechiae should be screened regularly for the development of lagophthalmos in forced closure, keratitis, and cataract.     

Nematode infections of the eye: toxocariasis and diffuse unilateral subacute neuroretinitis.

In many parts of the world, parasitic infections of the eye are a major cause of blindness. The parasites Toxocara canis, Onchocerca volvulus, Taenia solium, Ancylostoma caninum, and Cysticercus celulosae all have been responsible for blinding ocular infections. The nematodes T. canis and Toxocara cati are parasitic roundworms that infect dogs (toxocarosis), other canidae, and cats. Ocular toxocariasis is an uncommon worldwide infection caused by the nematode larvae of T. canis, commonly found in dogs. Human transmission is usually via geophagia, the ingestion of food contaminated with Toxocara eggs, or contact with infected puppies, often resulting in devastating ocular or systemic effects. Ocular toxocariasis is typically a monocular disease of young children, and its clinical findings include posterior and peripheral retinochoroiditis, optic papillitis, and endophthalmitis. The inflammatory response created by ocular involvement may result in epiretinal membrane formation, traction retinal detachment, and combined traction-rhegmatogenous retinal detachment. Diffuse unilateral subacute neuroretinitis is another ocular parasitic infection that usually results in severe visual loss. Evidence suggests that diffuse unilateral subacute neuroretinitis is caused by a solitary unidentified nematode of two different sizes, but to date, only a small number of nematodes have been recovered from eyes affected with the infection. Diffuse unilateral subacute neuroretinitis occasionally can affect the fellow eye.     

A new era of uveitis: impact of polymerase chain reaction in intraocular inflammatory diseases

Uveitis is a sight-threatening intraocular inflammatory disorder which may occur from both infectious and non-infectious or autoimmune causes. The frequency of infectious uveitis and autoimmune uveitis varies depending on countries and regions. According to a nationwide survey conducted by the Japanese Ocular Inflammation Society, infectious and non-infectious uveitis accounted for 16.4 and 50.1% of new patients, respectively while the remaining 33.5% of new uveitis cases were not classified or were idiopathic uveitis. Infectious uveitis is particularly important because it causes tissue damage to the eye and may result in blindness unless treated. However, it can be treated if the pathogenic microorganisms are identified promptly and accurately. Remarkable advancements in molecular and immunological technologies have been made in the last decade, and the diagnosis of infectious uveitis has been greatly improved by the application of molecular and immunological investigations, particularly polymerase chain reaction (PCR). PCR performed on a small amount of ocular samples provides a prompt, sensitive, and specific molecular diagnosis of pathogenic microorganisms in the eye. This technology has opened a new era in the diagnosis and treatment of uveitis, enabling physicians to establish new clinical entities of uveitis caused by infectious microorganisms, identify pathogens in the eyes of many patients with uveitis, and determine prompt diagnosis and appropriate therapy. Here we review the PCR process, new PCR tests specialized for ocular diseases, microorganisms detected by the PCR tests, diseases in the eye caused by these microorganisms, and the clinical characteristics, diagnosis, and therapy of uveitis.     

Ocular neovascularization with retinal vascular occlusion-III. Incidence of ocular neovascularization with retinal vein occlusion

A prospective natural history study was conducted in 721 eyes with various types of retinal vein occlusion (RVO) to determine the incidence of various types of ocular neovascularization (NV) and the factors that influence the development of ocular NV. The material was 360 eyes with central retinal vein occlusion (CRVO), 97 eyes with hemi-CRVO, and 264 eyes with branch retinal vein occlusion (BRVO); these cases were further subdivided into six groups for logical data analysis: nonischemic CRVO (venous stasis retinopathy-VSR, 282 eyes), ischemic CRVO (hemorrhagic retinopathy-HR, 78 eyes), hemi-VSR (66 eyes), hemi-HR (31 eyes), major BRVO (191 eyes) and macular BRVO (73 eyes). Ocular NV attributable to RVO was seen only in HR, hemi-HR, and major BRVO. In HR the anterior segment was the major site of NV, with iris and angle NV and neovascular glaucoma (NVG), while in hemi-HR and major BRVO the retina and optic disc were the major sites of NV. The principal factor influencing the development of ocular NV in RVO seems to be the severity and extent of retinal ischemia, while duration of follow-up since onset also plays an important role in determining the incidence of ocular NV. The findings and subject of ocular NV in RVO are discussed in detail along with a review of the pertinent literature.     

儿童眼外伤165例分析

目的研究儿童眼外伤的有关特点。方法对165例儿童眼外伤的相关因素进行统计分析。结果儿童眼外伤有其特点:男性儿童多发,眼部伤情重,并发症多,农村多发,致盲率高等。结论儿童眼外伤是主要的致盲原因之一,重在预防。     

Genetic diseases of the eye

The eye has always provided a diagnostic window for hereditary and acquired systemic diseases. Of the more than 6,000 known hereditary diseases, many are associated with changes of the visual system. Some are isolated genetic diseases of the eye, others are associated with additional ocular or systemic disorders (syndromes). In recent years, the recognition of genetic diseases as a leading cause of severe visual impairment in adults and in children has led to efforts to determine the underlying defects as well as to develop diagnostic and therapeutic molecular genetic tools. Also, education of ophthalmologists about these diseases will foster the prevention of and therapeutic approaches for genetic blindness. In this article, current knowledge on the clinical manifestations, aetiology and management of genetic diseases of the eye has been summarised.     

长非编码RNA在视网膜发育和眼部病变中的作用

长非编码RNA(lncRNA)是一类长度大于200个核苷酸,不具有编码蛋白功能的转录本,在哺乳动物细胞转录本中占很大比例.近年来,旨在阐明lncRNA在发育和疾病中功能的研究急剧增加.已经证实这类非编码RNA可以在表观遗传、转录和转录后水平调控基因表达.视网膜的发育依赖于复杂而精确的转录作用和转录调控.在这些调节机制中,lncRNA起到了重要的作用.现已知或预测lncRNA参与视网膜细胞亚型的分化和发育,并与若干眼部疾病相关.虽然,大部分lncRNA的分子机制还不清楚,但是它们很可能是决定视网膜细胞命运的重要组成部分.在视网膜发育中,lncRNA可诱导细胞分化、影响细胞周期并调控X染色体失活.在无眼畸形、糖尿病视网膜病变和脊髓小脑运动失调7型等眼部疾病中,lncRNA也发挥了重要作用.本文综述lncRNA在视网膜发育及眼部疾病中作用的最新研究进展及存在的问题,对基础和临床研究及药物靶点开发具有重要意义.     

眼部新生血管与抗血管内皮生长因子治疗

眼部新生血管性病变是致盲的主要原因之一,可见于多种眼底疾病,其确切的发病机制尚不完全清楚.大量的研究证据表明血管内皮生长因子(VEGF)是新生血管形成的关键调控因子.本文对VEGF的特性、VEGF在眼部新生血管形成中的作用和抗VEGF治疗进行综述.