Search

PURPOSE To determine choroidal vascular abnormalities in eyes with internal carotid artery obstruction (ICO). METHODS We examined eight eyes with ICO with wide-angle indocyanine green (ICG) video-angiography beginning in the posterior fundus. Another angiography was performed in three eyes to observe the arterial phase of the temporal peripheral fundus. ICG angiography was done until the late choroidal venous phase or for more than 10 minutes. RESULTS Slow dye filling in the choroidal arteries and delayed filling of the posterior watershed zone occurred in all eyes. Delayed perfusion or multiple patchy occlusions of choriocapillaris was seen in all eyes. There were delayed perfusion and/or occlusion in the peripheral watershed zone in the examined three eyes. The super-late-phase angiograms showed hyperfluorescent lines corresponding to choroidal veins. CONCLUSION Elongated arm-to-choroid circulation and delayed intrachoroidal circulation times suggest severe choroidal hypoperfusion. Choroidal hypoperfusion resulted in multiple occlusions of the choriocapillaris and attenuated choroidal vessels. Slow filling or nonperfusion of the peripheral watershed zone was another characteristic finding. Linear hyperfluorescence may reflect severely damaged choroidal venous walls. These findings are useful to understand choroidal angiopathy in ICO or high-grade stenosis, and to diagnose ocular ischemic syndrome.

PURPOSE. The purpose of this study was to investigate the effect of the von Hippel-Lindau (VHL) protein on VEGF gene expression in vitro and to determine whether adenovirus-mediated VHL intraocular gene transfer inhibits the development of angiogenesis in a monkey model of multiple branch retinal vein occlusion (BRVO). METHODS. A recombinant adenovirus vector adVHL was constructed to deliver the human VHL gene. Total RNA prepared from various kinds of cells transduced with adLacZ (control) or adVHL under normoxic or hypoxic conditions was subjected to Northern blot analyses. Either adLacZ or adVHL was delivered by preretinal injection in monkeys. The effects of adLacZ or adVHL on ocular neovascularization in laser-induced multiple BRVO was evaluated in color photographs and with fluorescein angiography (FA). RESULTS. VHL expression in adVHL-transduced cells was confirmed at the transcript and protein levels. VHL overexpression significantly decreased the levels of VEGF transcripts in human aortic endothelial cells (HAECs); retinal pigment epithelium (RPE) cells; and RCC 786-O cells, renal carcinoma cells lacking VHL expression under normoxia. In contrast, VHL had no effect on the hypoxia-mediated increase in VEGF expression in these cells, although basal levels of VEGF expression were substantially reduced. Color photographs and FA revealed that retinal neovascularization and iris rubeosis accompanied by multiple BRVO in a monkey model were obviously suppressed by VHL, overexpression. Northern blot analysis and immunostaining for VHL and VEGF indicated that VHL transfer obviously suppressed VEGF gene expression in VHL-transduced tissues such as retina or RPE. CONCLUSIONS. The results showed that adenovirus expressing VHL led to a significant reduction in VEGF expression in vitro under normoxic or hypoxic conditions. adVHL effectively inhibited angiogenesis in retina and iris in laser-induced multiple BRVO in monkey eyes. These data suggest that gene therapy based on VHL gene delivery has potential in the treatment of human ocular neovascularization.

Vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) have been implicated as important stimulatory factors for retinal neovascularization. In this study, we used intraocular gene transfer with gutless adenoviral (AGV) vectors to determine the effect of increased intraocular expression of VEGF, IGF-1, or sphingosine kinase (SPK), which produces sphingosine-1-phosphate, another angiogenic factor. Retinal neovascularization did not occur from intravitreous AGV-vectored VEGF, IGF-1, SPK, or combined VEGF and IGF-1, except occasionally adjacent to the retinal penetration site from the injection. However, corneal and iris neovascularization occurred after 2 weeks in all eyes injected with AGV.VEGF, but not those injected with only AGV.IGF-1 or AGV.SPK. These data suggest that the superficial capillary bed of the retina is relatively insensitive to VEGF, IGF-1, or SPK in adult mice, except when combined with retinal trauma. However, AGV-vectored VEGF is sufficient to consistently cause severe corneal and iris neovascularization. This provides a model for anterior segment neovascularization, which unlike previous models is relatively inexpensive and is not plagued by spontaneous regression, and therefore, may be useful for identification of new treatments.

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF-TRAP(R1R2), in models for these disease processes. VEGF-TRAP(R1R2) is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF-TRAP(R1R2) strongly suppressed choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane. Subcutaneous injection of VEGF-TRAP(R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF-induced breakdown of the blood-retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF-TRAP(R1R2) significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF-TRAP(R1R2) may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

Breakdown of the blood-retinal barrier (BRB) occurs in several retinal diseases and is a major cause of visual loss. Vascular endothelial growth factor (VEGF) has been implicated as a cause of BRB breakdown in diabetic retinopathy and other ischemic retinopathies, and there is evidence to suggest that other vasopermeability factors may act indirectly through VEGF. In this study, we investigated the effect of several receptor kinase inhibitors on BRB breakdown resulting from VEGF, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), insulin-like growth factor-1 (IGF-1), prostaglandin E1 (PGE(1)), or PGE(2). Inhibitors of VEGF receptor kinase, including PKC412, PTK787, and SU1498, decreased VEGF-induced breakdown of the BRB. None of the inhibitors blocked leakage caused by TNF-alpha, IL-1beta, or IGF-1 and only PKC412, an inhibitor of protein kinase C (PKC) as well as VEGF and platelet-derived growth factor (PDGF) receptor kinases, decreased leakage caused by prostaglandins. Since the other inhibitors of VEGF and/or PDGF receptor kinases that do not also inhibit PKC had no effect on prostaglandin-induced breakdown of the BRB, these data implicate PKC in retinal vascular leakage caused by prostaglandins. PKC412 may be useful for treatment of post-operative and inflammatory macular edema, in which prostaglandins play a role, as well as macular edema associated with ischemic retinopathies.

PURPOSE: To evaluate the choroidal drainage route after scleral buckling for retinal detachment. METHODS: We performed wide-angle indocyanine green angiography with a scanning laser ophthalmoscope in 22 eyes of 22 patients with rhegmatogenous retinal detachment that had been treated with scleral buckling and cryopexy. The 22 eyes had at least one retinal break located posterior to the equator where vortex veins were present. The period between angiography and retinal detachment surgery was less than 3 months in 10 eyes, 3 to 12 months in five eyes, and more than 1 year in seven eyes. RESULTS: At the site of the silicone exoplant and cryopexy for retinal breaks, one vortex vein was occluded in seven eyes and two in five eyes. Choroidal veins were congested in the quadrant of the occluded vortex vein in two of 12 eyes that had angiography less than 3 months after retinal detachment surgery. In 10 of 12 eyes that had angiography 3 months or more after retinal detachment surgery, new drainage routes developed that connected the sector of the occluded vortex veins to that of the intact vortex veins with venovenous anastomoses. No venous congestion was found in the areas of the occluded vortex veins in the 10 eyes. Venous collaterals formed between the superior and inferior vortex in all 10 eyes and between the temporal and nasal vortex in two eyes. CONCLUSIONS: New venous drainage routes, which were connected to the intact vortex veins, formed in eyes with occluded vortex veins resulting from scleral buckling surgery and compensated for choroidal venous congestion. The choroidal veins have a great deal of plasticity that enables remodeling of the drainage routes, depending on the pressure gradient.

To report four cases of branch retinal vein occlusion (BRVO) with the complication of serous retinal detachment (SRD).We retrospectively studied four eyes of four patients with macular edema and macular hard exudates associated with midperipheral BRVO. Visual acuity, ophthalmoscopy, fluorescein angiography, and optical coherence tomography findings were evaluated. Three of the four eyes underwent laser photocoagulation in the BRVO area 1 month after the initial visit.Macular edema consisted of SRD without cystoid macular edema in all eyes. Late-phase fluorescein angiography showed extensive dye leakage in the BRVO area. When SRD was resolved 4 months after the initial examination, hard exudates had increased in the macular area. Although macular hard exudates decreased 1 year after the initial examination, visual acuity remained under 20/20 because of macular atrophy.SRD is one type of macular edema observed in BRVO. In macula-spared midperipheral BRVO, the SRD originates from a vascular leaking area, and there is a high risk that massive macular hard exudates will develop, which may affect visual recovery.

In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.

Purpose: To evaluate the angioarchitecture and the hemodynamics in the peripheral choroid in humans. Methods: Choroidal circulation was examined in 23 normal eyes and in 7 with equatorial lattice degeneration by wide-angle indocyanine green (ICG) angiography using a scanning laser ophthalmoscope. A hand-held 30-diopter lens was placed in front of the eye to expand the observation angle from the original 40° to 70°. The peripheral temporal Choroid and ora serrata thus could be seen in one frame. Results: An arterial watershed zone was identified in the temporal peripheral choroid in 21 of 30 eyes. This watershed zone was located in a sectorial region posterior to the ora serrata. It did not form a circular belt along the equator. The area anterior to the watershed zone was supplied by peripheral retrograde choroidal arteries. Inflow of dye into the peripheral retrograde choroidal arteries was consistently later than into the more posterior choroid via short posterior ciliary arteries. The terminal branches of peripheral and short posterior ciliary arteries did not form functional anastomoses. Peripheral retrograde choroidal arteries showed wide variations in number and distribution. These arteries originated from recurrent branches of long posterior ciliary arteries in 18 of 21 eyes and from anterior ciliary arteries in 3 eyes. There was no correlation between the watershed zone and equatorial lattice degeneration in location and extent. Conclusion: A peripheral watershed zone is a regular feature in the far temporal sector of the choroid. The far peripheral choroid anterior to the watershed zone was perfused by peripheral retrograde choroidal arteries which originated from the long posterior ciliary arteries and/or the anterior ciliary arteries.

Background Carotid cavernous sinus fistula may induce drastic changes in choroidal circulation secondary to elevated orbital venous pressure. Cases and methods Three patients affected by spontaneous carotid cavernous sinus fistula were studied for 3-15 months. The angioarchitecture and hemodynamics of the choroid were evaluated repeatedly by indocyanine green angiography using a montage panoramic technique. Results Choroidal vessels underwent drastic restructuring including patchy nonperfusion of the choriocapillaris, attenuation of vortex veins, preferential venous dilatations, and drainage into outflow channels near the optic disc or into anterior ciliary veins. Conclusions Choroidal veins were very versatile in remodelling their structure and hemodynamics after sustained elevation of orbital venous pressure. The presence of numerous anastomoses between choroidal veins appeared to be a major underlying cause of this versatility. The observed remodelling of choroidal vessels seemed to be guided by the principle that the venous blood flowed toward sites of lesser pressure resistance.

Survival and population proportion of ice nucleation-active (INA) bacteria on mulberry tree and in an insect, mulberry pyralid, were investigated. Two groups of epiphytic bacteria, Pseudomonas syringae and Erwinia herbicola group bacteria formed dominant bacterial floras on mulberry leaves. E. herbicola group bacteria also distributed in most larvae of mulberry pyralid, but P. syringae was detectable in only some of them. Population frequency of INA P. syringae against total P. syringae in mulberry trees was very high (48.1%), whereas that of E. herbicola group bacteria was low (0.5%). Two group of INA bacteria were identified as P. syringae pv. mori and as Erwinia ananas which has not been detected from mulberry. These two species of INA bacteria were also first found in the insect, mulberry pyralid. A relationship between population of the INA bacteria and frost damage of mulberry trees was discussed.

The 11CaO.89ZrO2 (in mol%) fibers were fabricated by the sol-gel method using Zr(O-n-C3H7)4 and Ca(CH3COO)2.H2O or Ca(NO3)2.4H2O. The maximum tensile strength of 1000°C-treated fibers was 0.8–1.0 GPa at diameters of 10–15 μm. However, the strength of the alkoxide/acetate-derived fibers decreased with increasing diameter at a greater rate than that of the alkoxide/nitrate-derived fibers. This was associated with the sudden removal of acetate groups at a unique temperature, and was explained by the increased difficulty in the removal of acetate groups through the oxide matrix without forming microcracks in the fibres having increased diameters. For the CeO2-ZrO2 fibers made from Zr(O-n-C3H7)4 and Ce(NO3)3.6H2O, a maximum tensile strength of 1.0–1.2 GPa was attained at diameters of 10–15 μm. The addition of a small amount of CuO as a sintering aid much improved the mechanical properties of the fibers, resulting in fibers with tensile strength as high as 1.8–2.0 GPa.

To report optical coherence tomography (OCT) findings of macular edema secondary to retinal arterial macroaneurysms. Six eyes with retinal arterial macroaneurysms were retrospectively examined by OCT. All eyes had macular edema without massive macular hemorrhage. Fluorescein angiography was performed in six eyes, and indocyanine green angiography was done in four eyes. Five eyes underwent direct laser photocoagulation to the retinal arterial macroaneurysms. The foveal thickness, height of the serous macular detachment, and visual acuity (VA) were evaluated from the initial examination until the macular edema resolved. In all six eyes, the macular edema secondary to retinal arterial macroaneurysms comprised a serous macular detachment with retinal swelling. No cystoid macular edema was observed in any eyes. Dye leakage occurred only from the macroaneurysms in all eyes. OCT showed complete resolution of the serous macular detachment and retinal swelling 1 to 4 months after the initial examination. Macular hard exudates developed during absorption of the serous macular detachment in all eyes. VA improved more than two lines in all eyes after the macular edema resolved. Retinal arterial macroaneurysms may leak extravasated fluid into the subretinal space, which may result in a serous macular detachment. Jpn J Ophthalmol 2006;50:460–464 © Japanese Ophthalmological Society 2006

To report frequency, clinical characteristics, treatment, and the complications of branch retinal vein occlusion (BRVO) with serous macular detachment.We retrospectively studied 22 eyes of 22 patients in 111 eyes with acute BRVO, whose eyes had serous macular detachment that was detected by optical coherence tomography (OCT). Fluorescein angiography was conducted in 19 of the 22 eyes. Fourteen of the 22 eyes underwent scatter laser photocoagulation of the BRVO area. We observed serial OCT findings before and after treatment.Approximately 20% of the BRVO eyes had serous macular detachment. The superotemporal vein was occluded in 15 eyes and the inferotemporal vein was involved in 7 eyes. Four eyes were ischemic and 15 eyes were not ischemic. Extensive dye leakage was observed in the BRVO area in all examined eyes (19 eyes). The occlusion area of perifoveal capillary network ranged from 5 to 60%, with an average of 40%. OCT demonstrated pure serous macular detachment in 13 eyes and the remaining 9 eyes had both serous macular detachment and cystoid macular edema(CME). The occlusion area of perifoveal capillaries in these 9 eyes was more than 20%. Serous macular detachment was resolved in 11 of 14 eyes (80%) 6 months after laser treatment. The average period for resolution of macular detachment was 3.4 months after treatment. Visual acuity was improved more than 2 lines in 8 of the treated 11 eyes (73%). Hard exudates appeared in the posterior fundus in 13 of 14 treated eyes (93%) and in 16 of the total of 22 eyes (73%) in the follow-up period. Massive macular hard exudates and ensuing macular atrophy resulted in poor visual outcome.Serous macular detachment is one of the patterns of macular edema in BRVO. OCT is an essential tool to detect it. Leakage from the entire BRVO area seems to travel via subretinal space by gravity or other factors and may form serous detachment in the macular area. Laser photocoagulation is indicated for early resolution of serous macular detachment. The major complication of serous detachment is the deposit of macular hard exudates, which may result in poor visual outcome.

In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.

PURPOSE. Topical nepafenac readily penetrates the cornea and is metabolized to amfenac, a potent cyclooxygenase (COX)-1 and COX-2 inhibitor. In this study, we tested the effect of topical nepafenac in three murine models of ocular neovascularization (NV). METHODS. A masked trial was performed to compare the topical effects of vehicle with one of several concentrations of nepafenac (0.01%, 0.03%, 0.1%, or 0.5%), 0.1% diclofenac, or 0.5% ketorolac tromethamine in mice with oxygen-induced ischemic retinopathy, mice with choroidal NV (CNV) due to laserinduced rupture of Bruch’s membrane, or transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF transgenic mice). RESULTS. Mice treated with 0.1% or 0.5% nepafenac had significantly less CNV and significant less ischemia-induced retinal NV than did vehicle-treated mice. Nepafenac also blunted the increase in VEGF mRNA in the retina induced by ischemia. In rho/VEGF transgenic mice, nepafenac failed to inhibit neovascularization. In additional studies, compared with vehicletreated mice, mice treated with 0.1% or 0.03% nepafenac had significantly less CNV, whereas eyes treated with 0.1% diclofenac showed no significant difference. Mice treated with 0.5% ketorolac tromethamine for 14 days had high mortality, but when evaluated after 7 days of treatment showed no difference from mice treated with vehicle for 7 days. CONCLUSIONS. Topical nepafenac inhibits CNV and ischemiainduced retinal neovascularization by decreasing production of VEGF. The absence of effect in rho/VEGF transgenic mice is consistent with this mechanism. Topical nepafenac may provide an effective new treatment for ocular neovascularization. The excellent corneal penetration of nepafenac certainly plays an important role in this effect. It is possible that other antiangiogenic agents are also amenable to topical application after formulations are identified that maximize their corneal penetration. Because of the many advantages of the topical route of delivery, this is a possible topic for exploration. (Invest Ophthalmol Vis Sci. 2003;44:409 – 415) DOI:10.1167/iovs.02-0346

Human immunodeficiency viral (HIV) vectors mediate long-term transduction of many types of nondividing cells in vivo. Bovine immunodeficiency virus (BIV) is a lentivirus that shares many characteristics with HIV, but does not cause human disease. In this study, we investigated the potential of BIV vectors for ocular gene therapy. An enhanced green fluorescent protein (eGFP)-encoding reporter gene was packaged in recombinant BIV vector (BIV. eGFP). Adult C57BL/6 mice were given an intravitreous (5 3 10 4 or 5 3 10 5 transducing units [TU]) or subretinal (5 3 10 5 TU) injection of BIV. eGFP and then GFP expression was assessed at several time points. In vivo examinations of mice showed that subretinal injection of BIV. eGFP resulted in strong expression of GFP from the first examination at 1 week through the final examination at 20 weeks. Only a few mice that received intravitreous injection of BIV. eGFP showed GFP expression by ocular examinations until 11‐ 12 weeks, when most showed small areas of expression. Postmortem examinations showed prominent GFP expression in retinal pigmented epithelial (RPE) cells throughout the region of subretinal injection of vector, although occasional negatively staining RPE cells were scattered among the much more numerous, brilliantly staining cells. Ciliary epithelial cells frequently expressed GFP, as did occasional Mu ller cells and rarely other retinal cells. The expression was stable from the first time point (2 weeks) to the last (20 weeks). Postmortem examination of eyes given an intravitreous injection of BIV. eGFP showed transduction of cells in the corneal endothelium and a few scattered retinal cells. There was no evidence of inflammation or toxicity in any eyes. These data show that BIV vectors mediate rapid and sustained transduction of RPE cells, suggesting that they may be useful for ocular gene therapy targeting RPE cells.

Nitric oxide (NO) has been shown to have proangiogenic or antiangiogenic effects depending upon the setting. In this study, we used mice with targeted deletion of one of the three isoforms of nitric oxide synthase (NOS) to investigate the effects of NO in ocular neovascularization. In transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors, deficiency of any of the three isoforms caused a significant decrease in subretinal neovascularization, but no alteration of VEGF expression. In mice with laser-induced rupture of Bruch's membrane, deficiency of inducible NOS (iNOS) or neuronal NOS (nNOS), but not endothelial NOS (eNOS), caused a significant decrease in choroidal neovascularization. In mice with oxygen-induced ischemic retinopathy, deficiency of eNOS, but not iNOS or nNOS caused a significant decrease in retinal neovascularization and decreased expression of VEGF. These data suggest that NO contributes to both retinal and choroidal neovascularization and that different isoforms of NOS are involved in different settings and different disease processes. A broad spectrum NOS inhibitor may have therapeutic potential for treatment of both retinal and choroidal neovascularization.

Background: To report the ocular manifestations of neuro-Behcet's disease. Cases: A 34-year-old woman had recurrent meningitis. She developed diplopia, headache, and ataxia, and was diagnosed as having neuro-Behcet's disease. Observations: Imaging revealed two infarct foci in the transitional midbrain and pons. After treatment with prednisolone and colchicine, the diplopia resolved. Two years later, a scotoma developed in the right eye, in which the best-corrected visual acuity was 4/200. Papillitis and a prepapillary vitreous opacity were seen in the right fundus. These findings disappeared 11 days after subconjunctival steroid injections and increased colchicine. Her vision gradually improved to 20/20 two months later. Conclusion: Neuro-Behcet's disease may manifest with transient optic neuritis and prepapillary vitreous opacity.

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon alpha2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin kappa-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch's membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had approximately 10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.

In this study, we investigated whether overexpression of pigment epithelium-derived factor (PEDF) by gene transfer can inhibit neovascularization by testing its effect in three different models of ocular neovascularization. Intravitreous injection of an adenoviral vector encoding PEDF resulted in expression of PEDF mRNA in the eye measured by RT-PCR and increased immunohistochemical staining for PEDF protein throughout the retina. In mice with laser-induced rupture of Bruch's membrane, choroidal neovascularization was significantly reduced after intravitreous injection of PEDF vector compared to injection of null vector or no injection. Subretinal injection of the PEDF vector resulted in prominent staining for PEDF in retinal pigmented epithelial cells and strong inhibition of choroidal neovascularization. In two models of retinal neovascularization (transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors and mice with oxygen-induced ischemic retinopathy), intravitreous injection of null vector resulted in decreased neovascularization compared to no injection, but intravitreous injection of PEDF vector resulted in further inhibition of neovascularization that was statistically significant. These data suggest that sustained increased intraocular expression of PEDF by gene therapy might provide a promising approach for treatment of ocular neovascularization.

Background: It has been shown, by indocyanine green (ICG) videoangiography, that the prepapillary vascular loops in chronic central retinal vein occlusion (CRVO) serve as an anastomosis between the retina and the choroidal venous systems. Similar vascular loops may develop in hemi-central retinal vein occlusion (hemi-CRVO). Cases and Methods: I performed indocyanine green and fluorescein angiography using a scanning laser ophthalmoscope in 8 eyes of 8 patients with hemi-CRVO to evaluate the angioarchitecture and hemodynamics of the retinochoroidal circulation. All eyes had a prepapillary vascular loop and were identified as ischemic. The patients' ages ranged from 28 to 77 years (mean, 57 years). The interval between onset of hemi-CRVO and angiography ranged from 2 to 42 months (mean, 13 months). Scattered laser photocoagulation had been applied to the affected area in all 8 eyes and vitreous surgery in one eye. Results: Delayed dye flow in the affected retinal veins was present in all 8 eyes. The blood in the affected retinal veins drained through the prepapillary vascular loop into the branch or trunk of the intact central retinal vein. No anastomoses were seen between the vascular loop and the choroidal veins. The prepapillary vascular loop became more dilated during follow-up in one eye. Conclusions: The prepapillary vascular loop in hemi-CRVO served as a collateral from the affected into intact retinal veins and not into the choroidal venous system. (J Jpn Ophthalmol Soc 103:404–408, 1999)

PURPOSE: To demonstrate the reperfusion of nonperfused capillary beds in diabetic retinopathy. METHODS: In a retrospective study, we reviewed 292 fluorescein angiograms of 94 eyes of 74 patients (mean age, 52 years; range, 20 to 68 years) with diabetic retinopathy. Fluorescein angiography was performed repeatedly (mean, three times; range, two to eight times) during a mean follow-up period of 2 years (range, 3 months to 12 years). None of the 94 eyes received laser photocoagulation. RESULTS: Reperfusion of occluded capillary beds was observed in 65 (69%) of 94 eyes. Reperfusion was characterized by recanalization in 22 (34%) of the 65 eyes or by intraretinal neovascularization in 54 (83%) of the 65 eyes. The former took place in small nonperfused areas and the latter in larger nonperfused areas. Reperfusion occurred throughout the entire fundus in six of 94 eyes, resulting in resolution of diabetic retinopathy. Reperfused capillary beds with intraretinal neovascularization left vascular remodeling, which was seen as twisted or kinked abnormal vessels. CONCLUSIONS: In diabetic retinopathy, occluded capillary beds may be reperfused. Twisted abnormal vessels may represent the reperfusion process through intraretinal neovascularization.

Purpose: To demonstrate the drainage routes that compensate the venous congestion in central retinal vein occlusion. Methods: Indocyanine green angiography was performed in 13 eyes of 13 patients with central retinal vein occlusion at the involutional stage using a scanning laser ophthalmoscope. The interval between onset of central retinal vein occlusion and indocyanine green angiography ranged from 1.0 to 9.3 years (mean, 3.6 years). Panoramic indocyanine green angiograms that covered the entire choroidal vasculature were produced by composing regional angiograms. Results: Retinochoroidal collateral routes were found in 10 eyes that had papillary vascular loops. They were not observed in three eyes that did not have the vascular loops. Papillary vascular loops served as the collaterals to connect retinal veins and choroidal veins. The blood in the retinal veins was drained through the papillary vascular loops into the choroidal veins. These choroidal veins were selectively dilated and acted as drainage routes to the vortex veins. Nasal vortex veins served as extraocular exits of the drainage routes in all 10 eyes, and temporal vortex veins served as extraocular exits of the drainage routes in three of the 10 eyes. Conclusions: In central retinal vein occlusion with papillary loops, blood in the retinal veins ultimately drained into the vortex veins through the retinochoroidal collaterals.

Purpose To describe a case of radiation choroidopathy manifesting drastic remodeling of choroidal drainage routes. Method Case report. A 34-year-old man who had received radiation treatment for a tumor in the upper eyelid of his right eye 15 years earlier had floating black spots. He was examined ophthalmologically, including with indocyanine green angiography using a scanning laser ophthalmoscope. Results The right eye manifested classic features of radiation retinopathy in the superior fundus. Indocyanine green angiography showed vaso-occlusion of choroidal arteries, capillaries, and veins in a wider area than that affected by radiation retinopathy. The superotemporal vortex vein was obliterated, resulting in a remodeling of the choroidal veins in the same quadrant. The blood in this quadrant drained into the inferotemporal vortex vein through collateral venovenous drainage routes. Conclusion The diagnosis in this eye was radiation retinopathy and radiation choroidopathy. Choroidal vascular lesions were more pronounced and involved a wider area than retinal vascular lesions did. This case illustrates that the choroidal veins may manifest a vast plasticity to remodel the drainage route after obliteration of a major vortex vein.

Objective To investigate pazopanib hydrochloride, a multitargeted kinase inhibitor, for treatment of choroidal neovascularization (CNV). Methods Choroidal neovascularization was induced in mice by rupture of Bruch membrane with laser photocoagulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured. Results Twice-daily gavage of pazopanib, 100 mg/kg, suppressed the development of CNV by 93%. Treatment of established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazopanib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quantifiable concentration of 129.6 and 752.0 μg • h/mL, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng/mL and levels in the retina/choroid were 4800, 28 800, and 38 000 ng/g of tissue. Conclusions Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV. Clinical Relevance Pazopanib may be useful for treatment of CNV in humans.

PURPOSE. Platelet-derived growth factor (PDGF) is an important stimulatory factor for proliferative retinopathies. Expression of PDGF-B in the retinas of transgenic mice (hemizygous rho/ PDGF-B mice) results in rapid-onset retinal detachment caused by proliferation of glial cells, endothelial cells, and pericytes, whereas expression of PDGF-AA (homozygous rho/PDGF-A or PDGF-AA mice) causes slowly progressive retinal detachment from proliferation of glial cells. In this study, we investigated the effect in rho/PDGF-B and rho/PDGF-AA mice of several different receptor kinase inhibitors. METHODS. Hemizygous rhoPDGF-B or homozygous rho/PDGF-A mice were treated orally with PKC412 (an inhibitor of PDGF, VEGF, and c-kit receptor kinases and several isoforms of PKC), PTK787 (an inhibitor of PDGF, VEGF, and c-kit receptor kinases), SU1498 (an inhibitor of VEGF receptor kinases), imatinib mesylate (an inhibitor of PDGF, c-kit, and v-abl receptor kinases), or vehicle, and at appropriate time points epiretinal membrane (ERM) formation and retinal detachment were quantified. RESULTS. In either rho/PDGF-B or rho/PDGF-A mice, oral administration of PKC412 or PTK787, but not SU1498 or imatinib mesylate, significantly reduced ERM formation. PKC412 reduced the incidence of severe retinal detachments in both models and PTK787 did so in homozygous rho/PDGF-A mice. CONCLUSIONS. These data indicate that PKC412 (and possibly PTK787) has appropriate activity and sufficient intraocular bioavailability after oral administration to prevent retinal detachment in models of proliferative retinopathy. PKC412 should be considered for treatment of vascular and nonvascular proliferative retinopathies in humans.

症例は28才.生後3カ月にクレチン症と診断され,舌根部甲状腺を有していた. TBG異常は無く,サイロキシン(l-T4)100μg/日の内服で甲状腺ホルモンレベルは正常に保たれ妊娠した.血中TSHは妊娠経過と共に上昇し, 26週には121μU/mlに達し, l-T4200μg/日への増量で正常値に向かい,満期正常分娩を迎えた.妊娠経過中,血中T3,フリーT3はやや低値を呈し, T4,フリーT4はl-T4 200μg/日投与以降に高値を持続した.本症例を通じて,クレチン症妊娠時の甲状腺薬補充量決定の指標にはTSH値が最も有用と考えられた.現在までにクレチン症における妊娠中の甲状腺ホルモン値の経時的変動や治療の報告は少なく,貴重な症例と考え,報告した.