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Inhibitory mechanism of vascular endothelial growth factor (VEGF) by bucillamine.

1. Vascular endothelial growth factor (VEGF) plays an important role in the neovascularization of ischaemic retinal diseases such as proliferative diabetic retinopathy. We determined that bucillamine, an anti-rheumatic drug, inhibits the VEGF production induced by hypoxia in bovine retinal microcapillary endothelial cells (BREC). To further clarify the inhibitory mechanism, we investigated the possible mechanism by which bucillamine exerts this inhibitory effect. 2. Bucillamine (100 micro M) decreased the hypoxia-induced increase of VEGF mRNA by 54.5% (P<0.001). Bucillamine (100 micro M) reduced the hypoxia-induced VEGF content in culture media by 29.0% (P<0.001), while monosulfydryl drugs, N-acetylcysteine and D-penicillamine, did not. 3. Bucillamine (100 micro M) did not affect VEGF mRNA half-life (hypoxia, 4.3 h; hypoxia+bucillamine, 3.9 h; normoxia, 2.7 h; normoxia+bucillamine, 2.7 h). 4. Reporter gene studies revealed that bucillamine reduced transcriptional activity in the 5'-flanking region of the VEGF gene by 74.0%. Hypoxia stimulated binding activity of BREC nuclear protein to a hypoxia responsive element (HRE), which was decreased by bucillamine. 5. Bucillamine inhibited hypoxic-induction of HIF-1alpha mRNA by 73.1% (P<0.001). Bucillamine also inhibited spontaneous VEGF mRNA expression by 26.6%. Furthermore, it inhibited activity of VEGF promoter and decreased binding activity to Sp1 and HRE, but did not alter AP1 and AP2 activity in normoxia. 6. These data suggest that bucillamine inhibits hypoxic induction of VEGF through inhibition of HIF-1 induction and binding activity in BREC. Bucillamine also inhibits the spontaneous expression of VEGF mRNA by its effect on Sp1 and HRE binding.

Animals↗

Management and outcome of sight-threatening diabetic retinopathy in pregnancy.

AIMS: To report the management and outcomes of sight-threatening diabetic retinopathy in pregnancy. METHODS: A retrospective review of 8 diabetic females who developed pregnancy related sight-threatening diabetic retinopathy requiring treatment over a 12-year period. RESULTS: In total, 16 eyes of eight patients were included in this series. The mean age of the patients at presentation was 30.75 years +/-3.8 SD and the mean duration of diabetes was 21.0 years +/-5.1 SD. The mean follow-up period was 46.75 months +/-47.2 SD. A total of 87.5% of patients showed progression of diabetic retinopathy during pregnancy, 71% of which were in the sight-threatening proliferative category. In the postpartum period, 81% of patients continued to progress to proliferative diabetic retinopathy, requiring panretinal photocoagulation and multiple other surgical procedures. In all, 69% of eyes retained visual acuity equal to or better than 0.3 logMAR units (6/12). CONCLUSION: Sight-threatening diabetic retinopathy in pregnancy is a rare disease, but it can have devastating consequences for mother and child. Laser photocoagulation should be considered for pregnant women with severe preproliferative diabetic retinopathy. Proliferative diabetic retinopathy may not regress postpartum. Close followup should be extended in the postpartum period in this group of patients until the retinopathy is stabilised. The presence of combined rhegmatogenous and tractional retinal detachment and neovascular glaucoma were associated with the worst outcome.

Adult↗

Senile macular degeneration: review of epidemiologic features.

Senile macular degeneration is a leading cause of visual loss in the United States, England, and probably many other industrialized countries. The clinical manifestations of this disease include: drusen, atrophy of the retinal pigment epithelium, serous detachment of the retinal pigment epithelium, subretinal neovascularization, and disciform scars. Standardized techniques for defining these manifestations of senile macular degeneration are necessary for epidemiologic study of this disease. Such standardization is facilitated by the use of fundus photographs. If a visual acuity deficit is included in the definition of senile macular degeneration, care must be taken to assure that senile macular degeneration is responsible for the decreased vision. The Framingham Eye Study provides the best senile macular degeneration prevalence data. The rapid increase in prevalence of senile macular degeneration after the fifth decade is demonstrated in this study and is consistent with other studies. In fact, increasing age has the strongest association with senile macular degeneration of any of the risk factors considered to date. Many other possible risk factors have been identified but further investigation is necessary to verify these associations.

Aged↗

Sequelae of intravitreal phagocytic activity in response to microparticles.

Cynomolgus monkeys were injected intravitreally with a colloidal suspension of carbon microparticles (size 20-70 nm) under aseptic surgical conditions. An intravitreal cellular proliferation occurred, inducing retinal detachment and neovascularization that started from the optic nerve head, ciliary body and ora serrata. Transmission electron microscopy revealed the features of the intravitreal cellular response to be inflammatory cells, mononuclear phagocytes (the predominant cell type), and fibroblasts. Newly-formed collagen fibrils (banding 70 nm) were found in the vitreous. The newly-formed vasculature generally showed continuous endothelial lining, but some intravitreal cellular proliferation is primarily a macrophagic response. We suggest that mononuclear phagocytes play a major role by triggering the collagen formation and neovascularization in the vitreous.

Animals↗

Production and accumulation of thrombospondin-1 in human retinal pigment epithelial cells.

PURPOSE: To investigate the production and release of thrombospondin-1 (TSP-1), a natural inhibitor of angiogenesis, by human retinal pigment epithelial (RPE) cells to clarify the possible role of TSP-1 in maintaining intraocular angiogenesis. METHODS: Human RPE cells were isolated from a human cadaveric eye and cultured in medium with 5% newborn calf serum. TSP-1 messages in the purified RNA of RPE cells were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Intracellular TSP-1 peptides were detected by cytofluorographic analysis. TSP-1 peptides in the culture medium on RPE cells were measured by sandwich enzyme-linked immunosorbent assay (ELISA). TSP-1 specific immunofluorescent staining was tested in RPE cells cultured on glass slides and in a human retinal tissue specimen. RESULTS: mRNA specific for TSP-1 was found in RT-PCR products from RPE cells, and it showed a time-dependent increase from the beginning of the culture. Intracellular staining for TSP-1 was identified by flow cytometry. The sandwich ELISA identified a time-dependent increase of TSP-1 peptides in the culture medium of RPE cells. Immunostaining for TSP-1 was observed in the cytoplasm of RPE cells cultured on glass slides. Positive immunostaining of TSP-1 was observed in the cytoplasm of the RPE layer in the human retinal tissue specimen. CONCLUSIONS: RPE cells can produce and release TSP-1 in vitro, and TSP-1 accumulates in the cytoplasm of RPE cells in vivo as well as in vitro. The production of TSP-1 by RPE cells is influenced by the state of proliferation and/or cell density. TSP-1 appears to be an important control factor in retinal and choroidal neovascularization.

Antibodies, Monoclonal↗

The challenge of preventing vision loss from diabetic retinopathy.

Diabetes is present in 7% of Missourians. Another 52% are at risk. Periodic eye examinations are key to averting vision loss from diabetic retinopathy. Signs of diabetic retinopathy are evident long before vision loss and include microaneurysms, retinal hemorrhage, microvascular and venous caliber abnormalities and neovascularization. Loss of vascular integrity can lead to retinal edema and neovascular growth. Laser ablation of the peripheral retina can curb neovascular growth. It can also help stabilize macular edema.

Blindness↗

[Analysis of the clinical effectiveness of vitrum vision in the tired eye syndrome and senile macular degeneration].

The paper evaluates the clinical effectiveness of Vitrum Vision ("Unifarm") that contains a complex of carotenoids, vitamins, and trace elements, which is adapted to ocular tissue metabolic features, in the tired eye syndrome and senile macular degeneration. The use of Vitrum Vision in patients with the tired eye syndrome improved the basic parameters of photosensitivity and increased the reserve of relative accommodation and in those with myopia enhanced uncorrectable visual acuity, ameliorated the magnitude of subjective visual and ocular symptoms, and increased the duration of a visual load until sensations of eye tiredness appeared. The administration of the drug in all clinical forms of senile macular degeneration increased visual acuity, improved the basic parameters of photosensitivity, enhanced the functional activity of neurons in the central portions of the retina (as shown by electrophysiological studies) while that in the subretinal neovascular membrane diminished retinal edema, improved the patients' general condition, far vision, and increased comfort on reading.

Accommodation, Ocular↗

[Cataract surgery and implantation in diabetics. Apropos of 92 eyes].

We examined 92 eyes (63 patients) who underwent extracapsular cataract extraction with implantation of a posterior chamber intraocular lens. Visual acuity improved by two lines or more in 65% of cases. Follow-up examination (6 months and 2 years) showed posterior capsule opacification in 30% of cases. Progression of diabetic retinopathy was mild but cystoid macular edema was present in 70% of cases with non proliferative retinopathy. Proliferative retinopathy was treated postoperative by pan retinal photocoagulation. One neovascular glaucoma occurred, secondary to a ruptured capsule.

Aged↗

Retrolental fibroplasia: further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infant.

To further evaluate the efficacy of oral vitamin E in preventing the development of severe retrolental fibroplasia (RLF) in very low-birth-weight infants, 100 infants treated with 100 mg/kg/d of vitamin E (dl-alpha-tocopheryl acetate) were compared with 75 infants treated with 5 mg/kg/d of vitamin E (dl-alpha-tocopherol) in the same nursery during the previous year. All 175 infants weighed less than or equal to 1,500 g at birth and required supplemental oxygen. A total of 120 infants (69 treatment; 51 control) survived greater than or equal to 10 weeks. Multivariate analysis of the control population identified five risk factors (P less than or equal to .10): gestational age, level and duration of oxygen administration, intraventricular hemorrhage, sepsis, and birth weight. When multivariate analysis was applied to both control and treatment groups, the severity of RLF was found to be significantly reduced in infants given the treatment dose of vitamin E (P = .003). Ultrastructural analyses of 58 pairs of whole-eye donations from high-risk infants surviving less than 10 weeks suggest that the initial morphologic event is gap junction increases between the plasma membranes of adjacent spindle cells of the van-guard retina. Such extensively gap junction-linked spindle cells are apparently removed from the vasoformative process as early as 4 days of life, forming a barrier to further normal vascular development and triggering retinal and vitreal neovascularizations approximately 8 weeks later. These events are maximally suppressed by elevated plasma vitamin E levels in infants greater than or equal to 27 weeks gestational age.

Cell Membrane↗

Carbon dioxide-induced retinopathy in the neonatal rat.

PURPOSE: Hypercarbia has been suggested as a risk factor for retinopathy of prematurity (ROP). We investigated the effect of hypercarbia on the retinal vasculature of the neonatal rat to determine whether hypercarbia alone could induce preretinal neovascularization analogous to ROP. METHODS: In a preliminary blood gas study, 8-11-day-old rats were exposed to specific levels of inspired O2 and either 0.2% CO2 or 10% CO2. Arterial blood gases were obtained, and a level of inspired O2 was determined that, when combined with inspired 10% CO2, would produce a PaO2 equivalent to room air (pure hypercarbia). In the formal retinopathy study, 300 newborn rats raised in 12 expanded litters (n = 25 each) were exposed for 7 days to either room air, 10% CO2 in 21% O2 and nitrogen (high-inspired CO2 group) or 10% CO2 in 12.5% O2 and nitrogen (pure-hypercarbia group). Each type of exposure was followed by recovery in room air for 5 days. Animals were sacrificed on day 13 and retinae were analyzed, using fluorescein perfusion and ADPase staining techniques. RESULTS: Neovascularization occurred in 19% of rats in the high-inspired CO2 group, and 14% of rats in the pure-hypercarbia group, compared to 0% of rats exposed to room air alone (p = 0.001, Chi square). CONCLUSIONS: In the neonatal rat model, exposure to hypercarbia alone, followed by room air recovery, results in preretinal neovascularization similar to that seen in oxygen-induced retinopathy. Our results support the suggestion that hypercarbia may be a risk factor for retinopathy of prematurity.

Animals↗

Vascular leakage, neovascularization, and vitreous hemorrhage in senile bullous retinoschisis.

Retinal detachment is the primary complication of bullous retinoschisis, a benign abnormality of the peripheral retina. We examined three patients (all women, 43, 55, and 56 years old) with typical bullous retinoschisis who had vitreous hemorrhage. In each case, there were sclerotic retinal vessels over the surface of the schisis cavity along with neovascularization above the central portion of the cyst. In one case there was also neovascularization of the peripheral retina in an area distant from the schisis. These findings were confirmed by fluorescein angiography in one case; the other two cases demonstrated similar changes by fluorescein angioscopy. Fluorescein angiography, also demonstrated intraretinal dye leakage from vessels along the posterior extent of the schisis, as well as from an adjacent area of white without pressure.

Female↗

[Fluorescein angiography findings after retinotomy and retinectomy].

Drainage-retinotomies and relaxing retinectomies are helpful techniques in extreme vitreoretinal surgery. They have become established as a surgical instrument, but their possible pathophysiologic effects on the retina, pigment epithelium and choroid have not been investigated as yet. 30 Patients with retinotomies or retinectomies after vitrectomy with silicone oil filling for advanced proliferative vitreoretinopathy were studied angiographically. Fluorescein angiographic findings revealed 1. a predominant effect of endophotocoagulation in the area of the retinotomy/retinectomy with occlusion of the choriocapillaris and hyperpigmentation and window effects of the retinal pigment epithelium, but sometimes there was a localized traction effect with retinal and choroidal folds, 2. that retinal perfusion is unaffected in untreated and coagulated areas without evidence for a breakdown of the blood-retina-barrier or retinal ischemia, 3. an intact blood-retinal-barrier in areas of uncovered retinal pigment epithelium, 4. no evidence for significant reproliferations in the areas of retinotomies and retinectomies, 5. choroidal neovascular membranes which may occur postoperatively at the retinotomy site probably as a complication for intraoperative injury of Bruch's membrane, 6. a cystoid macular edema, an optic atrophy, pigment-fallout, depigmented tracks and choroidal folds as unspecific findings post retinal detachment surgery. The angiographic data support the clinical impression, that retinotomies and retinectomies performed in otherwise untreatable cases cause no significant damage in the attached retina.

Drainage↗

Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium.

BACKGROUND: Choroidal neovascularization (CNV) causes loss of vision in age-related macular degeneration (AMD). In CNV, choroidal capillaries penetrate Bruch's membrane and the retinal pigment epithelium (RPE). Angiogenic factors produced by RPE cells are suspected as major contributors to CNV development. We therefore studied the differential expression of angioregulatory factors in normal and CNV-derived RPE. METHODS: Cultures of normal (ARPE-19) and CNV-derived RPE (CNV-RPE) were compared by quantitative PCR. Differential expression was verified on the protein level by immunohistochemistry in tissue samples. RESULTS: The angioregulatory factors VEGF-A, VEGF-B, VEGF-C, Angiopoietin-1 (Ang-1) and Angiopoietin-2, Semaphorin-3A, PEDF, HIF-1, FGF-2, and the receptors VEGF-R2, Neuropilin-1 and Neuropilin-2 were detected in both, ARPE-19 and CNV-RPE. Transcription of PEDF, FGF-2, Neuropilin-2, Ang-1 and Ang-2 was significantly upregulated in CNV-RPE. EphA7, VEGF-R1 and leptin were transcribed exclusively in CNV-RPE and Eph-A7 and VEGF-R1 proteins were present exclusively in CNV specimens. CONCLUSIONS: A set of common factors controlling angiogenesis was detected in both, ARPE-19 cells and CNV-RPE cells. Surprisingly, PEDF and other factors inhibiting angiogenesis are strongly upregulated in CNV-RPE; thus, at least in later stages, the RPE has a potential to control angiogenesis in age-related macular degeneration.

Angiogenic Proteins↗

Subretinal neovascularization as a complication of drainage of subretinal fluid.

Four cases of subretinal choroidal neovascularization that developed at the sight of breaks in Bruch's membrane were made for the drainage of subretinal fluid during retinal reattachment surgery. This neovascularization can occur in both young and older patients. All drainage sights were posterior to the equator, which may indicate a higher risk of the development of this complication from posterior drainage sights. Unless the fovea is threatened, there is no urgency to treat this choroidal neovascularization. It is unclear why this complication is so rare, considering the frequency of surgical perforation of the choroid and Bruch's membrane during drainage of subretinal fluid in retinal reattachment surgery.

Adolescent↗

Findings on retinal topography and thickness mapping in age-related macular degeneration.

PURPOSE: To report alterations in the retinal topography and thickness in typical cases of age-related macular degeneration (ARMD). METHODS: An optical imaging system was applied to patients with ARMD with alterations in the retinal structures. The system generates a series of 20 optical section images that encompass a 2 mm x 2 mm retinal area. The optical sections are digitized and analyzed to provide topographic maps of the vitreo-retinal and chorio-retinal surfaces and the retinal thickness. RESULTS: Retinal topography and thickness mapping in a normal eye corresponded to normal anatomy. Topographic mapping in a patient with confluent drusen indicated elevation of the vitreo-retinal surface. Retinal topography in a patient with retinal pigment epithelium detachment displayed localized elevation of the chorio-retinal surface. The thickness map in a patient with geographic atrophy of the retinal pigment epithelium revealed retinal thinning. In the patients with choroidal neovascularization, the vitreoretinal and chorio-retinal surfaces were elevated. The chorio-retinal surface map in a patient with evolving disciform scar displayed topographic variations corresponding to the fibrovascular tissue underlying the serous detachment. CONCLUSION: Retinal topography and thickness mapping is useful for visualization and evaluation of pathologic alterations in retinal structures due to ARMD.

Adult↗

A new staging system for idiopathic retinal periphlebitis.

PURPOSE: To develop and standardize a universally acceptable new staging system for idiopathic retinal periphlebitis (Eales disease). METHODS: A new staging system was established and standardized based on standard terminology and features. Idiopathic retinal periphlebitis was classified as peripheral and central types. Peripheral disease consisted of four stages. Stage 1 is periphlebitis of small (1a) and large (1b) caliber vessels with superficial retinal hemorrhages. Stage 2a denotes capillary nonperfusion and 2b neovascularization elsewhere/of the disc. Stage 3a is classified as fibrovascular proliferation and 3b vitreous hemorrhage. Stage 4a is traction/combined rhegmatogenous retinal detachment whereas 4b is rubeosis iridis, neovascular glaucoma, complicated cataract, and optic atrophy. A total of 253 cases of idiopathic retinal periphlebitis (mean age, 24.7 +/- 4.7 years, all male) presenting at this tertiary care center were classified prospectively according to the new staging system, by two independent observers (interobserver correlation = 0.7). RESULTS: The new staging system was consistent, simple, and easy to recall. Peripheral and central types of idiopathic retinal periphlebitis were found in 94.07% and 5.93% of cases, respectively. The new staging system also defined the severity of the disease. Vitreous hemorrhage was found to be the commonest presenting feature (51.68%), whereas traction/combined rhegmatogenous detachment was found in 5.88% of cases. CONCLUSIONS: The new staging system is useful in classifying and assessing the severity of disease. Management strategy can also be defined according to the stage of the disease. It is designed to promote the use of standard assessment with applications to clinical management and research.

Adolescent↗

[A morphological study of experimental intravitreal proliferative tissues].

Experimental tractional retinal detachments in rabbits' eyes was produced several weeks following aspiration of vitreous gels through a posterior small window of the eye wall. Histological examination showed that intravitreal proliferative tissues contained many fibroblasts, derived from the optic disc a small amount of migrated RPE, macrophages and other cells associated with proliferative tissues, Glial cells also grew especially at the epi-retina, causing shrinkage of the sensory retina. Vitreous neovascularization deriving from the retinal vessels was also found in these proliferative tissues. Our experimental data indicated that the extent of proliferative tissues mainly depend upon the amount of vitreous loss and vitreous hemorrhage, and the duration of retinal detachment. This experiment may be useful as an animal model of vitreous neovascularization.

Animals↗