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PubMed2001

The effect of a growth hormone receptor antagonist drug on proliferative diabetic retinopathy.

OBJECTIVE: This study investigated whether the growth hormone receptor antagonist pegvisomant could produce regression of diabetic retinal neovascularization. DESIGN: A prospective, single-group, open-label, phase IIa multicenter trial was conducted. PARTICIPANTS: Twenty-five patients with diabetes mellitus (13 with type 1 and 12 with type 2) and proliferative diabetic retinopathy aged 21 years or older were enrolled. METHODS: Patients received an initial loading dose of 100 mg pegvisomant by subcutaneous injection, followed by self-administered injections of 20 mg daily for 12 weeks. The treatment period was followed by a 12-week period during which patients were observed off treatment. MAIN OUTCOME MEASURE: The effect of treatment on diabetic retinopathy was evaluated from fundus photographs that were graded at a central reading center. RESULTS: Regression of retinopathy was not observed in any patient. At the end of the treatment period, the extent of neovascularization in the study eye was unchanged in 16 patients (9 of 13 with type 1 and 7 of 12 with type 2) and had progressed in 9 patients (4 of 13 with type 1 and 5 of 12 with type 2). The maximum reduction from baseline per patient in the insulin-like growth factor-I (IGF-I) serum level averaged 55%; 17 (68%) of the 25 patients had a greater than 50% reduction in IGF-I. After treatment was discontinued, IGF-I levels returned to baseline. CONCLUSIONS: This study did not find evidence that pegvisomant could produce regression of diabetic retinal neovascularization.

Diabetes Mellitus, Type 1↗
PubMed1995

Hypoxia-induced expression of vascular endothelial growth factor by retinal glial cells promotes in vitro angiogenesis.

To determine whether retinal glial cells (RGCs) participate in the paracrine regulation of retinal neovascularization, we investigated whether cultured RGCs synthesize and release vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) under normoxic or hypoxic conditions. Northern blot analysis demonstrated that cultured RGCs transcribed both VEGF mRNA with two molecular bands approximately 3.9 and 4.3 kilobases (kb), and bFGF mRNA with approximately 3.7 and 6.0 kb. The expression of VEGF mRNA was greatly enhanced by hypoxic cultivation (2% oxygen) when compared with normoxic cultivation (20% oxygen), while the expression of bFGF mRNA by RGCs was not significantly affected by hypoxia. The effects of RGCs-conditioned media (CM) on tritiated-thymidine incorporation and in vitro angiogenesis by retinal capillary endothelial cells (RECs) in producing the formation of capillary-like tubes in type I collagen gels, were evident in the observation that RGCs-CM harvested after hypoxic cultivation significantly enhanced tritiated-thymidine incorporation (1.9 times, P < 0.01) and in vitro angiogenesis (2.4 times, P < 0.01) compared with the normoxic RGCs-CM. These enhancing effects of RGCs-CM at hypoxia were suppressed by anti-VEGF neutralizing antibody. Furthermore, RECs were shown to express mRNA encoding the VEGF receptor flt-1 by northern blot analysis. These results suggest that VEGF expressed by RGCs under hypoxic conditions plays an integral role in the initiation and progression of retinal neovascularization in a paracrine manner.

Animals↗
PubMedDate not supplied

Clinical and angiographic features in nasal branch retinal vein occlusion.

PURPOSE: To analyse the epidemiological and clinical characteristics of nasal branch retinal vein occlusion (NBRVO). METHODS: Patients affected by branch retinal vein occlusion observed in the out-patient departments of the Eye Clinic of Trieste between January 1995 and January 1999 were enrolled. RESULTS: Out of 144 patients with branch retinal vein occlusion, 128 (88.9%) were affected by temporal branch retinal vein occlusion (TBRVO), and 16 patients were affected by NBRVO (11.1%). The two groups did not differ as far as systemic hypertension, diabetes mellitus, glaucoma and ischaemic heart disease were regarded. NBRVO cases were characterized by better visual acuity and greater figures of capillary non-perfusion, retinal neovascularization and vitreous haemorrhage. CONCLUSIONS: NBRVO, even though infrequent, shares the same epidemiological characteristics as TBRVO. The higher prevalence of ischaemic cases in the NBRVO group could depend on a bias during the enrolment of patients, because especially symptomatic patients may have been examined in our out-patient departments. The relatively high percentage of epiretinal membrane formation after laser photocoagulation suggests particular caution, especially in cases presenting with vitreous haemorrhage.

Aged↗
PubMed2002

[Analysis of visual prognosis and correlative factors in retinal vein occlusion].

OBJECTIVE: To investigate the visual prognosis, risk factors, complications and the causes of visual deterioration in patients with various types of retinal vein occlusion (RVO). METHODS: Nine hundred and forty-four eyes of 913 patients with various types of RVO were analyzed. The age range of patients was 15 - 89 years (average 52.8 +/- 11.9), and the average follow-up was 20.7 months. The data of the patients were studied by SPSS software. RESULTS: (1) RVO was classified into central RVO (CRVO) in 406 eyes of 391 cases (43.0%), hemi-RVO (HRVO) in 60 eyes of 60 cases (6.4%) and branch RVO (BRVO) in 478 eyes of 462 cases (50.6%). (2) They were subdivided into ischemic type in 633 eyes (67.1%) and non-ischemic type in 311 eyes (32.9%). (3) The visual prognosis: the average initial visual acuity (VA) in CRVO, HRVO and BRVO was 0.36, 0.38 and 0.40 respectively. The average final VA was 0.40 in CRVO (P > 0.05), 0.50 in HRVO (P > 0.05) and 0.58 in BRVO (P < 0.05). (4) The initial VA and prognosis: there was close relationship between initial VA and visual prognosis. If the initial VA >/= 0.5, the final acuity maintained >/= 0.5 in 70.6% in CRVO, 75.0% in HRVO and 84.9% in BRVO. The patients with initial VA </= 0.l had final VA worse than 0.1 in 66.2% of CRVO, 35.7% of HRVO and 25.3% of BRVO (P < 0.01). (5) Low vision and the rate of blindness in RVO: Among the 205 eyes with low vision (21.7%), there were 27.6% with CRVO, 31.7% with HRVO and 17.2% with BRVO (P < 0.01). Among the 160 eyes with blindness (16.9%), There were 27.6% with CRVO, 11.7% with HRVO and 8.6% with BRVO (P < 0.01). (6) The visual prognostic comparison between ischemic type and non-ischemic type: there were 189 of 633 eyes with ischemic type (29.9%) and only l6 of 311 eyes with non-ischemic type (5.1%) had low vision. In the ischemic type, 157 eyes had blindness (25.1%) and 3 eyes with non-ischemic type (1.0%) had blindness (P < 0.01). (7) Risk factors of RVO were hypertension (57.8%), arteriosclerosis (67.4%), high blood viscosity (24.6%), diabetes (6.2%) and primary glaucoma (1.5%). (8) Complications of RVO: cystoid macular edema (CME) 46.7%, retinal neovascularization (RNV) 21.5%, vitreous hemorrhage 11.4% and neovascular glaucoma (NVG) 9.6% (39/406) in CRVO and 1.7% (1/60) in HRVO. (9) Low vision caused by CME was 37.9%, and RNV 29.9%; blindness in CME 19.5% and RNV 23.0%. In 40 eyes with NVG, the final VA was worse than 0.05 in 38 eyes (95.0%). CONCLUSION: The rate of blindness of RVO is high, and the visual prognosis of ischemic type is worse. There is close relationship between the level of initial VA and visual prognosis. CME, RNV and NVG are important causes of blindness.

Adolescent↗
PubMed1999

Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation.

OBJECTIVES: To examine the epidemiologic and clinical characteristics of the ocular manifestations of von Hippel-Lindau (VHL) disease and to detect phenotype-genotype relationships of disease severity. DESIGN: A cross-sectional clinical and molecular genetic study. PATIENTS AND METHODS: One hundred eighty-three affected VHL gene carriers from 81 unrelated pedigrees were interviewed and examined; clinical data were also obtained from 12 living and 39 deceased affected relatives. DNA extracted from venous blood was used to identify mutations in the VHL gene. RESULTS: The prevalence of ocular angiomatosis (hemangioblastomas) in von Hippel-Lindau disease was 67.8% (124/183), and the mean number of angiomas in gene carriers was 1.85 (range, 0-15). Neither prevalence nor angioma count increased with age. Severe vision loss in 1 or both eyes was associated with presentation at a young age. The cumulative probability of incurring vision loss by age 50 years was 35% in all gene carriers, 55% in those with angiomatosis, and significantly worse in those coming to us with symptoms. Angiomas were nonrandomly distributed in the fundus, occurring rarely at the posterior pole (1% of retinal tumors) and commonly on the optic disc (8% of eyes) and supratemporal retina. Complications of ocular angiomatosis included disc and retinal neovascularization; secondary angioma formation; retinal detachment, exudation, and membrane; and retinal and vitreous hemorrhage. Germ-line VHL mutations were detected in 161 of 183 patients and 69 (85%) of 81 pedigrees and included deletions (n= 16), missense (mutations causing amino acid substitutions; n = 24), nonsense (premature stop codons; n = 15), frameshift (n = 13), and splice-site (n = 1) mutations. There was no association between the type or position of mutation and the severity of ocular angiomatosis. CONCLUSIONS: A systematic clinical description of a large cohort of VHL gene carriers further defines the ocular phenotype. There is no general influence of germline mutation on severity of ocular disease in VHL. CLINICAL RELEVANCE: The ophthalmic and molecular genetic description of patients with VHL disease.

Adolescent↗
PubMed1998

Retrovirus-mediated gene transfer targeted to retinal photocoagulation sites.

Diabetic retinopathy is a major cause of acquired blindness due to the development of retinal neovascularization and associated traction retinal detachment. It is commonly treated with retinal photocoagulation therapy; however, progression to blindness remains a significant problem. To determine the feasibility of adjunctive anti-angiogenic gene therapy, we evaluated the capability of retroviral vectors, which transfer exogenous genes only into dividing cells, to transfer and express a beta-galactosidase gene selectively into photocoagulation sites. Thirty-five rabbits received 30 retinal photocoagulation burns in the right eye followed 2 days later by beta-galactosidase (G1nBgSvNa) or control (G1XSvNa) vector injection into the subretinal space. Beta-galactosidase expression was observed in the photocoagulation sites from 5 days after vector administration (31.7+/-7.0%) to 12 weeks (6.7+/-3.4%). Immunohistochemical studies of the treated retinas using antibody Ber-MAC3 and anti-cytokeratin antibodies revealed that transduced cells were macrophages and retinal pigment epithelial cells. To determine feasibility in a primate, two monkeys received 10 laser burns in the macula superior to the fovea followed 2 days later by G1nBgSvNa vector. beta-galactosidase expression was found in photocoagulation sites and foveal retina was well preserved. We conclude that gene transfer to retinal photocoagulation sites provides stable expression of the transduced gene with relatively high efficiency. This feasibility study suggests the possibility of transferring genes encoding for anti-angiogenic factors into photocoagulation sites to improve the efficacy of laser photocoagulation therapy.

Angiography↗
PubMed2005

Human retinal epithelium produces and responds to placenta growth factor.

BACKGROUND: Placenta growth factor (PlGF) is an important co-factor in retinal neovascularization. To examine whether retinal pigment epithelial (RPE) cells may represent a source for PlGF during retinopathy, we determined whether human RPE cells in vitro produce and respond to PlGF. In addition, we determined whether the cells express receptors for PlGF, i.e. flt-1 and neuropilins. METHODS: Cultured human RPE cells of passages 3-5 were used. The regulation of the PlGF gene and protein expression by growth factors and cytokines was evaluated by quantitative PCR and ELISA. Proliferation rates and chemotaxis were determined by a bromodeoxyuridine and a Boyden chamber assay. RESULTS: Human RPE cells express mRNAs for various members of the vascular endothelial growth factor family and for their receptors, including mRNAs for PlGF, flt-1, KDR, and neuropilins-1 and -2. The expression levels of the mRNAs for neuropilins-1 and -2 were significantly higher than those for flt-1 and KDR. Members of the transforming growth factor (TGF)-beta superfamily of growth factors (BMP-4, TGF-beta1, and beta2) were strong inducers of PlGF gene expression, and evoked secretion of PlGF-2 protein by RPE cells. Exogenous PlGF-2 induced chemotaxis in RPE cells and reduced slightly the cell proliferation at high concentrations. CONCLUSION: The findings that RPE cells produce and respond to PlGF indicate that the factor exerts an autocrine/paracrine action on these cells. It is suggested that increased expression of TGF-beta-related growth factors during diabetic retinopathy may cause PlGF secretion by RPE cells contributing to the stimulation of cell migration as a critical component of the progression of fibrovascular membranes.

Blotting, Western↗
PubMed1991

Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy.

Between 1979 and 1989, I examined 106 patients (16 pedigrees) with signs of familial exudative vitreoretinopathy. Of these patients, 101 had familial exudative vitreoretinopathy, and five had a sporadic manifestation. The complications of familial exudative vitreoretinopathy, deformation of the posterior retina, vitreous hemorrhage, amblyopia, and retinal detachment, caused diminished visual acuity. Of 170 eyes, retinal neovascularization was observed in 18 eyes (11%), and retinal exudates were observed in 16 eyes (9%). Several forms of retinal detachment occurred in 37 of 180 eyes (21%), which often took an unfavorable course. A falciform retinal fold was observed in 14 eyes (8%). Retinal surgery was performed in 14 eyes; reattachment of the retina was successful in only seven eyes. Platelet aggregation studies disclosed no significant differences between seven patients with familial exudative vitreoretinopathy and ten control subjects. The pathogenesis of the disease is based on a premature arrest of the vascular development of the retina.

Adolescent↗
PubMed1987

Krypton red laser photocoagulation for branch retinal vein occlusion.

Krypton red (647 nm) laser photocoagulation may offer distinct advantages in the treatment of branch retinal vein occlusion (BRVO), particularly in eyes with extensive intraretinal hemorrhage or in the presence of media opacities such as vitreous hemorrhage or cataract. Twenty-three eyes were followed for a minimum of 6 months (range, 6-38). Of 19 eyes treated for macular edema, 17 (89%) had complete resolution of their edema, one (5%) had reduction of its edema, and one (5%) was unchanged. Of five eyes treated for retinal neovascularization of the disc or retina, all eyes had complete elimination of neovascularization. The authors were unable to demonstrate any statistical correlation between final visual acuity and the following factors: duration of symptoms, cystoid macular edema (CME), degree of paramacular nonperfusion, and contiguous intraretinal hemorrhage extending into the foveal avascular zone (FAZ).

Edema↗
PubMedDate not supplied

Growth factors in proliferative diabetic retinopathy.

Many growth factors are implicated in the pathogenesis of proliferative diabetic retinopathy. Alteration of growth factors and their receptors in diabetes has been shown in both experimental and clinical studies. Sustained hyperglycemia resulting from long-standing diabetes leads to several biochemical abnormalities that consequently result in retinal hypoxia. Retinal oxygenation state regulates various growth factors that promote angiogenesis in order to meet the oxygen demands of the tissue. However, unregulated expression of these growth factors and induction of complex cascades leading to augmentation of other proangiogenic factors, which may not be regulated by tissue oxygenation, leads to uncontrolled retinal neovascularization and blindness in diabetic patients.

Animals↗
PubMed2000

Missense mutations in norrie disease gene are not associated with advanced stages of retinopathy of prematurity in Kuwaiti arabs.

Retinopathy of prematurity (ROP) is a disease characterized by retinal neovascularization, possibly leading to retinal detachment and finally blindness. In a proportion of ROP cases, the disease progresses to advanced stages despite rigorous intervention. Missense mutations of the Norrie disease (ND) gene have been associated with progression of the disease in ROP cases from the USA. We have investigated the presence of ND gene mutations in 102 premature newborns of Kuwaiti Arab origin to replicate this finding in a different population/racial group. 56 (55%) of these newborns had normal eyes and served as controls. In 35 (34%) cases, the ROP regressed spontaneously during stage 1-3. In 11 (11%) cases, ROP progressed to advanced stages. A PCR-RFLP method was used to detect the mutations in exon 3 of the ND gene and confirmed the DNA sequence by direct sequencing of the PCR product. The [R121W] mutation of the ND gene was not detected in the premature newborns screened from our Kuwaiti population/group. For the second mutation [L108P], a genotype (PP) was present in 98% of the premature newborns screened and only in 1 of 56 normal infants was the (LL) genotype detected. Our population is genetically homogenous in that genotype (PP) was detected at codon 108 in almost all controls and ROP cases. We did not find an association between the presence or absence of missense mutations of the ND gene and the risk of severe ROP.

Deoxyribonuclease HpaII↗
PubMedDate not supplied

[Retinal vasculitis in Behçet's disease].

Behçet's disease (BD) is a multisystemic disorder characterized by primary vasculitis of unknown etiology. We studied retinal vasculitis in 35 patients with ocular form of BD. All patients fulfilled the International Study Group criteria for BD. Mean age was 30.8 +/- 6.5 years (19-45 years, mean follow-up period 4.1 +/- 1.29 years (3-10 years. The disease occurred 3.3 times more often in men than in women (p = 0.0003). Retinal vasculitis was diagnosed in 26 (74.3%) of 35 patients with ocular form of BD. Retinal vascular changes characteristic of BD were bilateral in 96.1% cases and involved both arteries and veins. The earliest changes were detectable only by fluorescent angiography. Diffuse capillary leakage was observed in all cases during the active period of disease, involving the posterior pole. The disk and macular capillaries were involved most of all. Late staining of vasculature was observed in 68.6% patients. No ruptures of retinal vessels, retinal neovascularization, or areas of retinal nonperfusion were observed (except one case with occlusion of a branch of the central retinal vein), which are usually seen in other types of retinal vasculitis. Visual acuity was significantly decreased in patients with retinal occlusive vasculitis in comparison with patients without it (0.04 +/- 0.09 vs. 0.3 +/- 0.3, p = 0.029).

Adult↗
PubMed1982

Ocular findings in the intravenous drug abuser.

Two patients with talc emboli of the retinal vasculature, both of them intravenous drug abusers, are described. One underwent a pars plana vitrectomy for removal of the vascularized vitreous mass that obscured the retina. The vitreous mass was presumably a result of retinal neovascularization secondary to the talc embolic. Other ocular findings that may be observed in the intravenous drug abuser are described.

Adult↗
PubMed1997

[Expression of basic fibroblast growth factor and fibroblast growth factor receptor 1 in the experimental retinal vein occlusion model].

Retinal ischemia promotes retinal neovascularization. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are important growth factors for neovascularization. We did experimental retinal vein occlusion (RVO) and examined the expression of basic FGF and FGF receptor 1(one of the basic FGF receptors) by in situ hybridization. We used adult pigmented rats (Brown-Norway strain). Dye laser photocoagulation (577 nm) was applied to the retinal arteries and veins within two disc diameters of the optic nerve head to injure the retinal vessels. After one week, laser photocoagulation was applied to only the retinal veins to occlude them (RVO model). As a control, laser photocoagulation was applied to the posterior retina avoiding the retinal vessels. After treatment, the eyes were removed and 10 microns thick cryostat-cut chorioretinal section were used for in situ hybridization with probes as mentioned above. In the RVO model, expression of messenger RNA of basic FGF (b-FGF) and FGF receptor 1 increased in the inner nuclear layer and the inner segment of the photoreceptors, and appeared in the retinal vessel wall in the early stage. This shows that b-FGF and FGF receptor 1 increased in the ischemic retina, and were produced on the retinal vessel wall. This suggests that b-FGF may be involved in protection, regeneration, and proliferation of the retinal vascular endothelial cells in retinal circulatory disturbance.

Animals↗