Fumi Gomi

Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response.

Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer’s disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer’s disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

Intravitreal Bevacizumab to Treat Iris Neovascularization and Neovascular Glaucoma Secondary to Ischemic Retinal Diseases in 41 Consecutive Cases

PURPOSE To evaluate the biologic efficacy of intravitreal bevacizumab (IVB) for iris neovascularization (INV) or neovascular glaucoma (NVG) in patients with ischemic retinal disorders. DESIGN Retrospective, consecutive, interventional case series. PARTICIPANTS Thirty patients (41 eyes) with INV or NVG secondary to ischemic retinal disorders. METHODS Patients received IVB (1 mg) as the initial treatment for INV or NVG and were followed up for at least 6 months. Ophthalmic evaluations included measurement of visual acuity and intraocular pressure (IOP), a complete ophthalmic examination, and fluorescein angiography. Patients were divided into 3 subgroups: INV without elevated IOP (INV group), NVG with an open angle (O-NVG group), and NVG with angle closure (C-NVG group) for outcomes analysis. MAIN OUTCOME MEASURES The controllability of IOP by IVB, incidence of recurrence, and requirement for surgery to treat NVG. RESULTS No significant ocular or systemic adverse events developed during follow-up (range, 6-22 months; mean, 13.3 months). The mean IOP levels were 14.7, 31.2, and 44.9 mmHg at baseline in the INV, O-NVG, and C-NVG groups, respectively. In the INV group (9 eyes), the INV regressed or resolved after 1 injection. Iris neovascularization recurred in 4 eyes by 6 months and stabilized after repeated injections without IOP elevation. In the O-NVG group (17 eyes), rapid neovascular regression with successful IOP normalization (<or=21 mmHg) occurred in 12 eyes (71%) within 1 week after 1 injection. Five (29%) of the 17 eyes required surgery by 6 months despite repeated IVB injections, and a total of 7 eyes (41%) underwent surgery during follow-up. In the C-NVG group (15 eyes), IVB caused INV resolution but failed to lower the IOP. Fourteen (93%) of 15 eyes required surgery by 2 months after initial IVB and achieved IOP stabilization. The mean interval between IVB and surgery was significantly shorter in the C-NVG group than in the O-NVG group (P<0.001). CONCLUSIONS Intravitreal bevacizumab is well tolerated, effectively stabilized INV activity, and controlled IOP in patients with INV alone and early-stage NVG without angle closure. In advanced NVG, IVB cannot control IOP but may be used adjunctively to improve subsequent surgical results. Further evaluation in controlled randomized studies is warranted.

Intravitreal injection of bevacizumab for choroidal neovascularisation associated with pathological myopia

Aim: To assess the efficacy and safety of an intravitreal injection of bevacizumab (Avastin®) for myopic choroidal neovascularisation (mCNV). Methods: Intravitreal bevacizumab (1 mg) was injected into eight eyes of eight patients with mCNV in this non-randomised, interventional case series. The best-corrected visual acuity (BCVA) was measured and the optical coherence tomography (OCT) and fluorescein angiography findings were examined before and after treatment. The minimum follow-up time was 3 months. Results: The mean BCVA was 0.26 before treatment and 0.51 at the last visit (p = 0.009). The BCVA improved to two or more lines in six eyes (75%) and remained the same in two eyes (25%). Leakage from the mCNV on fluorescein angiography decreased in seven eyes (87.5%). The choroidal neovascularisation area on fluorescein angiography (p = 0.049) and the foveal thickness on OCT images decreased significantly (p = 0.027) after the treatment. No major complications developed. Conclusion: Intravitreal injection of bevacizumab seems to be an effective and safe treatment for mCNV.

Intravitreal Bevacizumab for Choroidal Neovascularization Attributable to Pathological Myopia: One-Year Results

PURPOSE To assess the potential effect of intravitreal bevacizumab (IVB) (Avastin) on retinal function and anatomic recovery in eyes with choroidal neovascularization attributable to pathological myopia (mCNV). DESIGN Retrospective case series. METHODS setting: Institutional. patient population: Sixty-three eyes of 63 patients were treated with IVB for mCNV. intervention procedure: 1 mg of bevacizumab was injected into the vitreous via the pars plana. IVB was repeated after two to three months if there was fluorescein leakage in fluorescein angiogram (FA), apparent subretinal fluid in optical coherence tomography (OCT) persisted, or both. main outcome measurement: Best-corrected visual acuity (BCVA) and CNV size measured on FA. RESULTS IVB was performed one to six times during the first 12 months (mean, 2.4 +/- 1.4 times). The size of the mCNV decreased and the BCVA improved significantly (P < .01 for both comparisons). The BCVA improved more than three lines in 25 eyes (40%), worsened more than three lines in three eyes (5%), and was unchanged in 35 (56%) eyes 12 months after. Fluorescein leakage from the mCNV ceased in 30 eyes (48%), diminished in 28 (44%), and was unchanged in five (8%) eyes. Stepwise analysis showed that the number of IVB (P < .01), macular atrophy associated with mCNV (P < .05), and myopic atrophy (P < .05) were significant predictive factors for BCVA at 12 months. CONCLUSIONS Although the current study lacked a control group, IVB seems to be an effective treatment for mCNV after a long-term. The absence of chorioretinal atrophy and that of recurrence and persistency of mCNV are positive predictive factors.

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.

Polypoidal choroidal vasculopathy and treatments

Purpose of review This review assesses the current knowledge of the clinical characteristics of polypoidal choroidal vasculopathy and treatments. Recent findings Polypoidal choroidal vasculopathy is a disease with characteristic choroidal vascular abnormalities. Indocyanine green angiography is essential for diagnosis. The prevalence is higher in Asian people than in Caucasians. Photodynamic therapy is efficacious for treating polypoidal choroidal vasculopathy; 1-year results have shown greater benefit of photodynamic therapy than choroidal neovascularization secondary to age-related macular degeneration. Recurrence, however, seriously affects vision long term during follow-up after photodynamic therapy. The lower efficacy of bevacizumab- a full-length antibody of vascular endothelial growth factor- has been shown for polypoidal choroidal vasculopathy. Summary Although the polypoidal choroidal vasculopathy and age-related macular degeneration have been known to share common genetic factors, its clinical characteristics including the different responses to photodynamic therapy suggest that polypoidal choroidal vasculopathy is a separate clinical entity from age-related macular degeneration. The results of photodynamic therapy for polypoidal choroidal vasculopathy are encouraging; however, recurrence may affect vision over time. Therapeutic modalities to inhibit development of the exudative choroidal vasculature of polypoidal choroidal vasculopathy are desirable.

Morphologic Changes in Acute Central Serous Chorioretinopathy Evaluated by Fourier-Domain Optical Coherence Tomography

OBJECTIVE To investigate morphologic alterations around fluorescein leakage sites using Fourier-domain optical coherence tomography (FD OCT) in acute central serous chorioretinopathy (CSC). DESIGN Observational case series. PARTICIPANTS Twenty-one eyes with acute CSC with subjective symptoms for under 3 months. METHODS Patients underwent measurement of visual acuity, fundus observations, and FD OCT examinations at every visit with the intervals of 2 to 4 weeks until subretinal fluid (SRF) resolved. Fluorescein angiography was performed at baseline to confirm dye leakage sites. Horizontal and vertical OCT scans (B-scans and consecutive raster scans) of the fovea and fluorescein leakage sites were obtained. MAIN OUTCOME MEASURES Morphologic changes in the retinal pigment epithelium (RPE), detached retina, and subretinal space around the leakage sites were evaluated repeatedly during follow-up. RESULTS The mean period between baseline and the final examination was 108 days (mean no. of examinations, 3.9). Among 23 leakage sites in 21 eyes, FD OCT showed RPE abnormalities in 22 (96%) sites (14 sites [61%] with a pigment epithelial detachment [PED] and 8 [35%] with a protruding or irregular RPE layer). Fibrinous exudates in the subretinal space and sagging/dipping of the posterior layer of the neurosensory retina above the leakage sites were seen at 12 (52%) and 10 (43%) leakage points, respectively. An RPE defect at the edge of or within the PED was observed in 5 leakage sites (22%); in 2 of these, a defect was detectable after the SRF decreased. The posterior surface of the detached retina was smooth in 17 eyes (81%) and granulated in 4 eyes (19%) (mean duration of subjective symptoms, 10 days and 42 days, respectively). The smooth posterior detached retina became granulated in the presence of residual SRF. A PED remained at the 5 leakage sites in 5 eyes (22%) despite SRF resolution. CONCLUSIONS Fourier-domain OCT examinations showed detailed morphologic changes in eyes with acute CSC including an RPE defect within the PED at a leakage site through which fluid might pass from the sub-RPE to the subretinal area. Fourier-domain OCT findings may offer new information to facilitate understanding of the mechanisms of acute CSC.

Optical coherence tomographic findings of Macular holes and retinal detachment after vitrectomy in highly myopic eyes

PURPOSE Macular holes cause retinal detachments in highly myopic eyes. Because degenerative macular changes often coexist, biomicroscopic evaluation of macular hole status after retinal reattachment is sometimes difficult. We studied macular holes with retinal detachment after vitrectomy using optical coherence tomography and evaluated the anatomic status of the hole and factors associated with anatomic success. DESIGN Retrospective, nonrandomized, comparative study. PATIENTS Sixteen eyes that underwent vitrectomy for retinal detachment associated with a macular hole were included. Internal limiting membrane peeling with indocyanine green was performed in 14 eyes; the epiretinal membrane was peeled with a diamond-dusted membrane scraper alone in two eyes. All retinas reattached postoperatively. The follow-up period at the optical coherence tomography examination was at least 6 months. METHODS Optical coherence tomography was performed vertically and horizontally, and the presence of a persistent macular hole was determined. Other information was obtained from patient records. RESULTS The macular holes closed in seven of 16 eyes (44%). Age, sex, axial length, preoperative best-corrected visual acuity, duration of symptoms, preoperative refractive error, and the preoperative area of the retinal detachment were not significantly correlated with hole closure. Improved postoperative best-corrected visual acuity (P <.05) was significantly associated with macular hole closure, and more frequent visual improvement (P =.06) was of borderline significance. CONCLUSIONS The success rate was lower than those obtained in eyes without myopia or in myopic macular holes without retinal detachments. Macular hole closure may predict improved visual outcome for patients with retinal detachment and macular holes. Optical coherence tomography detects persistent macular holes in highly myopic eyes with retinal detachment.

Retardation of Retinal Vascular Development in Apelin-Deficient Mice

Objective—Apelin is an endogenous ligand for the G protein–coupled receptor, APJ, and participates in multiple physiological processes. To identify the roles of endogenous apelin, we investigated the phenotype of apelin-deficient (apelin-KO) mice. Methods and Results—Apelin-KO mice showed impaired retinal vascularization and ocular development, which were analyzed by histology, immunohistochemistry, real-time polymerase chain reaction, and the mouse corneal micropocket assay. Apelin-KO mice showed significantly impaired retinal vascularization in the early postnatal period. Retinal apelin/APJ mRNAs were transiently upregulated during the first 2 postnatal weeks but were undetectable in adults. There were no differences in VEGF or FGF2 mRNA expression, or in the morphology and localization of GFAP-positive astrocytes, in the apelin-KO retinas at P5. The corneal pocket assay showed that angiogenic responses to VEGF and FGF2 were remarkably decreased in apelin-KO mice. The reduced responses to VEGF and FGF2 in apelin-KO mice were partially restored by apelin, but apelin alone did not induce angiogenesis. Conclusions—Our results suggest that spatiotemporally regulated apelin/APJ signaling participates in retinal vascularization in a cooperative manner with VEGF or FGF2, and contributes to normal ocular development.

Association Between the Efficacy of Photodynamic Therapy and Indocyanine Green Angiography Findings for Central Serous Chorioretinopathy

PURPOSE To determine the efficacy of photodynamic therapy (PDT) and indocyanine green angiography (ICGA) findings for treating chronic central serous chorioretinopathy (CSC). DESIGN Observational case series. METHODS Thirty-two eyes of 27 patients with chronic CSC and symptoms for at least 6 months were recruited. The minimum follow-up was 1 year. The total PDT energy was reduced to about 36 to 42 mJ/cm(2). The baseline middle-phase ICGA findings were classified as intense, intermediate, or no hyperfluorescence depending on the degree of hyperfluorescence. The resolution of the subretinal fluid and recurrence rates were assessed in relation to each ICGA finding at baseline. RESULTS ICGA before PDT showed intense hyperfluorescence in 23 eyes (72%), intermediate hyperfluorescence in 6 eyes (19%), and no hyperfluorescence in 3 eyes (9%). The subretinal fluid resolved completely 3 months after 1 application of PDT in 23 eyes (100%) with intense hyperfluorescence, 6 eyes (100%) with intermediate hyperfluorescence, and no eyes (0%) with no hyperfluorescence. In the last group, the subretinal fluid did not resolve throughout the follow-up period despite additional applications of PDT. The subretinal fluid recurred in 7 of 29 eyes (24%) in which the subretinal fluid resolved at 3 months; recurrence was frequent in eyes with intermediate hyperfluorescence (5 eyes; 83%). CONCLUSION The PDT success rate in eyes with chronic CSC depends on the degree of hyperpermeability on ICGA. PDT is not effective or the recurrence rate is predicted to be high in eyes without intense hyperfluorescence.