Masahiko Yokoi

Elevations of AGE and vascular endothelial growth factor with decreased total antioxidant status in the vitreous fluid of diabetic patients with retinopathy

Background/aims: Advanced glycation end product (AGE) induces vascular endothelial growth factor (VEGF) expression in cell culture and animal models, being considered to be involved in development of diabetic retinopathy; oxidative stress also has a part in diabetic retinopathy. However, the interrelations between AGE, VEGF, and oxidative stress remain to be elucidated. In this study, vitreous AGE, VEGF, and total antioxidant levels in were determined in diabetic patients with retinopathy, and the relations among them investigated. Methods: ELISA (enzyme linked immunosorbent assay) was used to determine the vitreous levels of AGE and VEGF in 41 patients with diabetic retinopathy and 28 non-diabetic control subjects. Total antioxidant levels in vitreous of 20 diabetic patients and 18 controls were also analysed by ELISA. Results: The vitreous levels of AGE and VEGF were significantly higher in diabetic patients than in control subjects (p<0.01 for both). There was a significant correlation between the vitreous AGE and VEGF levels (p<0.001). Total antioxidant status was decreased in vitreous in patients with diabetes compared with the controls (p<0.01). Furthermore, both AGE and VEGF levels were inversely correlated with the total antioxidant status (p<0.01 and p<0.05, respectively). Conclusion: This study suggests that AGE and decreased total antioxidant status may contribute to the pathogenesis of diabetic retinopathy via induction of VEGF.

Increased Osteopontin Levels in the Vitreous of Patients with Diabetic Retinopathy

Purpose: Osteopontin (OPN) has diverse functions such as cell adhesion, chemoattraction, immunomodulation, and angiogenesis. The aim of this study is to analyze the OPN levels in vitreous fluid obtained from diabetic retinopathy (DR) and non-DR patients. Methods: Nineteen patients out of 11 with DR and 8 without DR underwent pars plana vitrectomy and vitreous fluid was obtained simultaneously. Two distinct sandwich enzyme-linked immunosorbent assay systems (systems 1 and 2) were applied, which have been developed in our laboratories to quantify the OPN concentrations in vitreous fluid. Results: The non-thrombin-cleaved full-length OPN levels in the vitreous fluid were 921.63 ± 45.38 ng/ml in DR and 632.80 ± 83.43 ng/ml in non-DR using system 1. Also, vitreous thrombin-cleaved and noncleaved OPN levels were increased to 2,109.22 ± 151.651 and 1,651.13 ± 229.82 ng/ml in patients with DR and non-DR using system 2. The vitreous OPN levels were significantly higher in DR than those in non-DR (p < 0.01 by system 1 and p < 0.05 by system 2). Conclusion: Thrombin-cleaved and noncleaved vitreous OPN levels in patients with DR were increased compared with control subjects, suggesting that OPN plays a potential role in the pathogenesis of diabetic retinal ischemia.

Expression of erythropoietin receptor in human epiretinal membrane of proliferative diabetic retinopathy

Purpose: It is widely accepted that intravitreous levels of erythropoietin (Epo) are elevated in patients with ischaemic retinal diseases such as proliferative diabetic retinopathy (PDR). The aim of this study was to examine the expression of Epo and the Epo receptor (EpoR) in epiretinal membranes with and without diabetes. Methods: Eighteen epiretinal membranes (PDR (n = 10), idiopathic epiretinal membranes (IERMs) without diabetes (n = 4) and inner limiting membranes (ILMs) (n = 4)) were obtained during pars plana vitrectomy. Formalin-fixed and paraffin-embedded tissues were examined by immunohistochemistry with anti-Epo and EpoR antibodies. Results: The histopathological findings demonstrated that PDR membranes consisted of a variety of endothelial cells forming a microvascular cavity with red blood cells and non-vascular stromal mononuclear cells. Membranous and cytoplasmic immunoreactivity for EpoR was strongly detected in endothelial cells and stromal cells in all PDR patients. Although microvessels were not observed in IERMs and ILMs, immunoreactivity for EpoR was noted in the cellular component of IERMs, and was weakly detected in ILMs. Epo was not expressed in any membrane. Conclusion: EpoR was strongly expressed in microvessels of all PDR membranes. The in vivo evidence in this study suggests that Epo in the vitreous binds to EpoR in PDR membranes, which subsequently leads to the proliferation of new retinal vessels. EpoR immunoreactivity in non-vascular stromal cells in PDR membranes, and IERMs and ILMs might be indirectly correlated with ischaemia.

Positive association of pigment epithelium-derived factor with total antioxidant capacity in the vitreous fluid of patients with proliferative diabetic retinopathy

Background: Pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, was recently found to inhibit advanced glycation end product (AGE)-induced retinal hyperpermeability and angiogenesis through its antioxidative properties, suggesting that it may exert beneficial effects on diabetic retinopathy by acting as an endogenous antioxidant. However, the inter-relationship between PEDF and total antioxidant capacity in the eye remains to be elucidated. Aims: To determine vitreous PEDF and total antioxidant levels in patients with proliferative diabetic retinopathy (PDR), and to investigate the relationship between them. Methods: Vitreous levels of PEDF and total antioxidant capacity were measured by an ELISA in 39 eyes of 36 patients with diabetes and PDR and in 29 eyes of 29 controls without diabetes. Results: Vitreous levels of total antioxidant capacity were significantly lower in patients with diabetes and PDR than in controls (mean (SD) 0.16 (0.05) vs 0.24 (0.09) mmol/l, respectively, p<0.001). PEDF levels correlated positively with total antioxidant status in the vitreous of patients with PDR (r = 0.37, p<0.05) and in controls (r = 0.41, p<0.05). Further, vitreous levels of PEDF in patients with PDR without vitreous haemorrhage (VH(−)) were significantly (p<0.05) decreased, compared with those in the controls or in patients with PDR with vitreous haemorrhage (VH(+); PDR VH(−), 4.5 (1.1) μg/ml; control, 7.4 (4.1) μg/ml; PDR VH(+) 8.5 (3.6) μg/ml). Conclusion: This study demonstrates that PEDF levels are associated with total antioxidant capacity of vitreous fluid in humans, and suggests that PEDF may act as an endogenous antioxidant in the eye and could play a protective role against PDR.

Retinal vasculitis due to secondary syphilis.

BackgroundRetinal vasculitis is one of the manifestations of ocular syphilis.CaseA 29-year-old man was referred to our hospital with the complaint of sudden visual loss in the left eye lasting more than three weeks.ObservationsOphthalmoscopic examination showed retinal hemorrhages, edema, and sheathing of large retinal arteries and veins. Fluorescein angiography revealed extensive occlusion of the affected retinal arteries, veins, and capillaries. Little evidence of uveitis or vitritis was observed. The fluorescent treponemal antibody-absorption test was positive, and the Treponema pallidum hemagglutination titer was 1 : 10 240. The treatment with penicillin was effective, leading to resolution of the retinal hemorrhages and edema, although occlusion of the retinal vessels persisted.ConclusionsVascular occlusion occurred simultaneously in large retinal arteries, arterioles, and capillaries as well as in segments of retinal veins, resulting in irreversible changes in the vascular walls. Jpn J Ophthalmol 2004;48:65–67

Epiretinal membrane formation in Terson syndrome

Clinical features of epiretinal membranes were examined in 22 eyes of 13 patients with Terson syndrome who were treated with pars plana vitrectomy. The shape and localization of the epiretinal membranes were intraoperatively evaluated and correlated with the presence or absence of posterior vitreous detachment (PVD). Patients with complete PVD, but with no membrane found during surgery, were followed postoperatively. Membrane formation ultimately developed in 13 of the 22 eyes. In eight eyes, PVD was incomplete and the epiretinal membrane was found at the optic disc or along the temporal vascular arcades, displaying retinal folds and vascular tortuosity. Three eyes had massive tractional retinal detachment; five of those with complete PVD developed a thin epiretinal membrane around the posterior pole that became more apparent during long-term follow-up. From these observations, we can classify epiretinal membrane formation in Terson syndrome into two groups: with complete, or with incomplete, PVD. It also appears that multiple pathological processes involving the vitreoretinal interface were responsible for the formation of epiretinal membranes.

Expression of glutamine synthetase and cell proliferation in human idiopathic epiretinal membrane

Background/aim: The mechanisms of the cellular origin and cell proliferation in the idiopathic epiretinal membrane (ERM) are unsolved. The aim of this study was to examine the expression of cell cycle related molecules and glutamine synthetase (GS), which is expressed in Müller cells and their processes, in ERM tissues. Methods: The ERMs were surgically removed using pars plana vitrectomy. Formalin fixed, paraffin embedded ERM tissues were analysed by immunohistochemistry with anti-cyclin D1, p27 (KIP1), proliferating cell nuclear antigen (PCNA), and GS antibodies. Results: The histopathological findings showed that all the ERMs consisted of oval or spindle mononuclear cells with thin collagen-like tissues. Immunoreactivity for GS was detected in collagen-like tissues of ERM, presenting a continuous, isodense pattern. GS immunopositive cells in all cases expressed PCNA in their nuclei. Nuclear immunoreactivity for cyclin D1 was noted in the ERM constituent cells, whereas p27 (KIP1) positive nuclei were not detected. Conclusion: Cyclin D1 and PCNA were expressed in the idiopathic ERM, which was mainly derived from Müller cells and extensions of their processes.

Development of central retinal vein occlusion in dural carotid-cavernous fistula.

We investigated a 46-year-old woman with central retinal vein occlusion complicating dural carotid-cavernous fistula, resulting in severe loss of visual acuity. Venous stasis retinopathy observed on the first examination progressed severely so that central retinal vein occlusion with retinal neovascularization developed 3 months later. A transvascular embolization discontinuing the feeders from the external carotid artery improved the retinal circulation and the visual acuity. These results indicate that the cause of the progression from venous stasis retinopathy to central retinal vein occlusion is the elevation of pressure in the cavernous sinus.

Positive correlation between vitreous levels of advanced glycation end products and vascular endothelial growth factor in patients with diabetic retinopathy sufficiently treated with photocoagulation.

We investigated whether vitreous levels of advanced glycation end products (AGEs) were positively correlated with vascular endothelial growth factor (VEGF) in patients with diabetic retinopathy patients sufficiently treated with retinal photocoagulation. Vitreous AGE and VEGF levels were significantly higher in patients with diabetes than in controls. Positive correlation between AGE and VEGF was found in patients with diabetic retinopathy sufficiently treated with retinal photocoagulation (r = 0.44, p<0.05), but not in those who were insufficiently treated (r = 0.26, p = 0.18). The present observations suggest that AGE may induce VEGF expression in an ischaemia-independent mechanism. AGE could be one of the important determinants of VEGF in diabetic retinopathy without obvious ischaemic regions. Vascular endothelial growth factor (VEGF) elicits retinal vascular hyperpermeability, thrombosis and angiogenesis, having a central role in the pathogenesis of diabetic retinopathy.1 Furthermore, vitreous VEGF levels are increased in proliferative diabetic retinopathy, whereas the levels are decreased after treatment with …

Retinal Angiography and Optical Coherence Tomography Disclose Focal Optic Disc Vascular Leakage and Lipid-rich Fluid Accumulation Within the Retina in a Patient With Leber Idiopathic Stellate Neuroretinitis

A 52-year-old woman with clinical features of Leber idiopathic stellate neuroretinitis (LISN) underwent retinal fluorescein and indocyanine green angiography that revealed lipid-containing fluid leakage from a single arteriole in the superficial nerve fiber layer of the optic disc. The fluid expanded gradually into the upper half of the optic disc and the adjacent peripapillary retina. Optical coherence tomography (OCT) demonstrated fluid accumulation in two separate subretinal spaces and in the outer nuclear-plexiform layer, which extended from the optic disc margin to the fovea. These angiographic and OCT findings support the hypothesis that LISN develops from focally increased permeability of an optic disc surface arteriole from which lipid-rich fluid flows through the outer nuclear-plexiform layer space to pool in these retinal areas.