A Recurrent Case of Full-Thickness Macular Hole After Successful Closure With Primary Vitrectomy and Epiretinal Proliferation Embedding.

Epiretinal proliferation (EP) is thought to be glial cell proliferation arising from the inner retina, seen in cases of lamellar or full-thickness macular holes (FTMH). Embedding EP within the macular hole is considered supportive for FTMH closure and functional recovery. We report a recurrent case of FTMH that was successfully closed after primary vitrectomy with the EP embedding technique. In the primary surgery, internal limiting membrane (ILM) peeling was avoided to reduce the potential risk of retinal nerve fiber layer damage associated with glaucoma. The FTMH was successfully closed, with complete recovery of macular layer structures. However, over one year later, the FTMH reopened, slightly dislocated from the position of the embedded EP scar. The reopened FTMH was closed again after the second surgery using the ILM inverted flap technique. This case indicates that macular hole closure with EP might not sufficiently support the tissue repair of FTMH as a new hole can form if tangential traction of the ILM remains.

Intraocular kinetics of pathological ATP after photoreceptor damage in rhegmatogenous retinal detachment.

PURPOSE: Extracellular Adenosine triphosphate (ATP) released by dying cells may cause a secondary cell death in neighboring cells in retinal degeneration. We investigated intraocular ATP kinetics to gain mechanical insights into the pathology in rhegmatogenous retinal detachment (RRD). STUDY DESIGN: Retrospective clinical study. METHODS: Vitreous or subretinal fluids (SRF) were obtained from patients with RRD (n=75), macular hole (MH; n=20), and epiretinal membrane (ERM; n=35) during vitrectomy. ATP levels in those samples were measured by luciferase assay. RESULTS: Mean ATP levels in the vitreous from RRD patients were significantly higher compared to those from MH and ERM patients (2.3 and 0.3 nM, respectively. P<0.01). Mean ATP levels in the SRF from RRD (11.7 nM) were higher than those in the vitreous from RRD (P<0.01). Mean ATP levels in the vitreous with short durations (1-8 days) of RRD were higher compared to those with long durations (>8 days) (3.2 and 1.4 nM, respectively. P<0.05). Similarly, ATP in SRF with short durations were higher than those with long durations (23.8 and 3.6 nM, respectively. P<0.05). Furthermore, the concentrations of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), a major ATP degradative enzyme, in the vitreous from RRD were higher than those from MH/ERM (1.2 and 0.2 ng/ml, respectively. P<0.01). ENTPD1 expression was localized in the cytoplasm of CD11b-positive infiltrating cells in the vitreous and retinal cells. CONCLUSION: ATP increased in the vitreous and SRF in RRD and decreased over time with an upregulation of ENTPD1. The kinetics indicate the pathological mechanism of the excessive extracellular ATP after RRD.

The factors associated with retinal pigment epithelium tear development in the early phase after treatment initiation for age-related macular degeneration.

PURPOSE: This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). METHODS: Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3 months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3 months of starting anti-VEGF therapy was examined. RESULTS: This study included 244 eyes (230 patients; mean age 75.0 years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3 months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100 µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07-2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22-7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12-850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). CONCLUSIONS: Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs.

Clinical Characteristics of Eyes with Neovascular Age-Related Macular Degeneration and Retinal Pigment Epithelium Tears.

BACKGROUND: Although anti-vascular endothelial growth factor (anti-VEGF) therapy is the first choice of treatment for eyes with neovascular age-related macular degeneration (AMD), it sometimes results in retinal pigment epithelium (RPE) tears. This study presents the detailed clinical characteristics of RPE tears to help predict their occurrence before anti-VEGF therapy initiation. METHODS: This study retrospectively analyzed neovascular age-related macular degeneration (nAMD) patients who visited the Kyushu University Hospital and started anti-VEGF therapy between April 2013 and June 2020. Using medical records, we collected the clinical data of patients with RPE tears, including age, sex, best-corrected visual acuity (BCVA), number of anti-VEGF drug injections and the type and size of pigment epithelial detachment (PED). RESULTS: RPE tears occurred in 16 (1.50%) eyes of 16 patients in all 1068 nAMD eyes of 987 patients. The mean age of these patients with RPE tear was 81.7 ± 8.7 years. Fifteen eyes had typical AMD and one eye had polypoidal choroidal vasculopathy. The mean number of anti-VEGF drug injections before RPE tears was 5.0 ± 5.1. All patients experienced PED before the RPE tear (hemorrhagic, 4 eyes; serous vascular, 2 eyes; fibrovascular, 10 eyes). The average PED height and area were 615.7 ± 175.3 µm and 21.0 ± 7.2 mm2, respectively. The sub-RPE cleft was observed in 10 eyes. The logMAR BCVA immediately after the RPE tear (0.73 ± 0.40) at 6 months (0.86 ± 0.51) and 12 months (0.84 ± 0.43) after the RPE tear were significantly worse than that before the RPE tear (0.58 ± 0.31; p < 0.05). The BCVA of patients with RPE tears that spread to the fovea was poorer than that of patients without RPE tears. CONCLUSIONS: In patients with nAMD, RPE tears tended to occur in typical AMD eyes with high or large PEDs, and sub-RPE clefts. The visual prognosis depended on whether the RPE tear included the fovea.

Differences in Central and Peripheral Choroidal Thickness among the Subtypes of Age-Related Macular Degeneration in an Asian Population.

Age-related macular degeneration (AMD) causes visual impairment in individuals who are >50 years of age. However, no study has investigated AMD when using ultra-wide-field swept-source optical coherence tomography (UWF SS-OCT). We aimed to evaluate central and peripheral choroidal thicknesses using UWF SS-OCT, and to compare these across the AMD subtypes. We included 75 eyes of patients with typical AMD (tAMD), 56 with polypoidal choroidal vasculopathy (PCV), 29 with pachychoroid neovasculopathy (PNV), and 12 with retinal angiomatous proliferation (RAP). To compare choroidal thicknesses in the central and peripheral choroids, we established subfields of <3 mm, <9 mm, and 9-18 mm from the fovea. PNV patients were significantly younger than those with tAMD (p = 0.01). The choroidal thicknesses of PNV were significantly greater than that of tAMD in all subfields (p < 0.01), and choroidal thickness significantly correlated with age and axial length in all subfields (p < 0.05). Even after adjusting for age and axial length, the choroidal thickness in PNV was significantly greater than that in tAMD (p < 0.05). In addition, the ratio of the posterior <9 mm to a peripheral 9-18 mm choroidal thickness in PNV was significantly greater than that in tAMD (p < 0.01). A thickened choroid in PNV was more pronounced in the posterior choroid than in the periphery.

Characteristics of retinal pigment epithelium elevations preceding exudative age-related macular degeneration in Japanese.

INTRODUCTION: Drusen and pigmentary abnormality are found as the hallmark to predict progression of age-related macular degeneration (AMD). In Asian populations, exudative AMD often appears in the absence of drusen but are rather accompanied by pigmentary abnormality. Recently, shallow irregular retinal-pigment-epithelium (RPE) elevations (SIRE) has been shown as a sign of subclinical non-exudative macular neovascularization. In this study, we aimed to investigate the characteristics of optical coherence tomography (OCT) findings including SIRE before the appearance of exudative AMD. METHODS: We retrospective reviewed 32 cases of exudative AMD that occurred in the fellow eye within the 5-years-observation period. Color fundus photography, OCT, and fluorescein/indocyanine green angiography at the beginning of observation and at the time when exudative AMD appeared were examined to diagnose SIRE and the subtype of exudative AMD. RESULTS: Exudative AMD were found in 19 eyes with large drusen and 13 eyes without large drusen. Mean sub-foveal choroidal thickness without large drusen were significantly thicker than those with large drusen (336 ± 109 and 220 ± 96 µm, respectively; mean± SD). Six eyes with pachychoroid neovasculopathy, 4 eyes with Type 1 macular neovascularization, and 3 eyes with PCV had occurred in the fellow eye without large drusen. Among those, 6 eyes had been accompanied by SIRE with a greatest transverse linear dimension of 1 mm or more at the beginning of observation-period. Besides, small RPE elevations with a longest diameter of less than 1 mm had been observed in other 5 eyes. Three cases of polypoidal choroidal vasculopathy had originated from small RPE elevations. Moreover, pachyvessels, choriocapillaris thinning, or choroidal hyperpermeability were observed with SIRE or small RPE elevation. CONCLUSIONS: There is a non-drusen type of exudative AMD that originates from small RPE elevations as well as SIRE.

A Case of Bullous Central Serous Chorioretinopathy Treated with Surgical Removal of Submacular Fibrin and Subsequent Photodynamic Therapy under Silicone Oil.

Bullous retinal detachment is a rare complication in the chronic phase of central serous chorioretinopathy (CSC). Only a small subset of eyes with chronic CSC develops into the bullous variant of CSC (bCSC). In patients with bCSC, the elevated concentration of fibrin in the subretinal space leads to persistent retinal detachment and eventually, severe vision loss. We experienced a case of unilateral bCSC with a massive accumulation of subretinal fibrin. Multiple leakage points and dilated choroidal veins were also observed. The patient underwent surgical removal of subretinal fibrin and silicone oil injection followed by photodynamic therapy (PDT). After this treatment, the retina was successfully reattached, and the affected eye was free from recurrent exudative changes for more than 18 months. Massive subretinal fibrin could be surgically removed to prevent the formation of subretinal fibrosis and retinal fold, and PDT under silicone oil can control the underlying exudative changes in bCSC.

Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçet's disease and sarcoidosis.

PURPOSE: Uveitis accounts for 10-15% of all cases of blindness in the developed world. Uveitic macular edema (UME) is a primary cause of permanent visual impairment in patients with uveitis. Because proinflammatory mediators elicit inflammation and lead to UME, we determined the profiles of proinflammatory mediators associated with complications, such as ME, in the vitreous humor of patients with panuveitis related to Behçet's disease (BD) and sarcoidosis. METHODS: In this retrospective study, we enrolled 21 patients with uveitis, including 6 with BD and 15 with sarcoidosis, and 15 patients with idiopathic epiretinal membrane (iERM) at the Department of Ophthalmology, Kyushu University Hospital, between January 2008 and April 2016. Vitreous concentrations of 32 proinflammatory mediators, including cytokines and soluble receptors of tumor necrosis factor (TNF) and interleukin (IL)-6 families, were assessed using a bead-based multiplex assay and their association with clinical data was examined. RESULTS: The levels of proinflammatory mediators, including a proliferation-inducing ligand (APRIL), B cell activating factor belonging to the TNF family (BAFF), soluble cluster of differentiation 30 (sCD30), soluble TNF receptor-1 (sTNFR1), sTNFR2, TNF-α, IL-6, and soluble IL-6 receptor-α (sIL-6Rα), were significantly higher in patients with uveitis. With regard to clinical parameters in patients with uveitis, vitreous levels of BAFF and sIL-6Rα were prominently elevated in patients with UME compared to in those without UME (P < 0.01, respectively). CONCLUSIONS: Our results suggest that elevated vitreous levels of BAFF and sIL-6Rα are associated with the pathogenesis of UME in patients with panuveitis related to BD and sarcoidosis.

TNFRSF10A downregulation induces retinal pigment epithelium degeneration during the pathogenesis of age-related macular degeneration and central serous chorioretinopathy.

Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common diseases that can cause vision loss in older and younger populations. These diseases share pathophysiological conditions derived from retinal pigment epithelium (RPE) dysfunction. Tumor necrosis factor receptor superfamily 10A (TNFRSF10A)-LOC389641 with the same lead single-nucleotide polymorphism (SNP) (rs13278062) is the only overlapped susceptibility locus found in both AMD and CSC through genome-wide association studies. This lead SNP has been reported to alter the transcriptional activity of TNFRSF10A. This study aimed to elucidate the function of TNFRSF10A in RPE degeneration using human primary RPE cells and Tnfrsf10 knockout (Tnfrsf10-/-) mice. TNFRSF10A was found to be localized in human RPE. In vitro assays revealed that a T allele of rs13278062, the risk allele for AMD and CSC, downregulated TNFRSF10A transcription in RPE, leading to decreased cell viability and increased apoptosis through protein kinase C-α (PKCA) downregulation. Treatment with phorbol 12-myristate 13-acetate, a PKC activator, rescued the cell viability. Morphological RPE abnormality was found in the retina of Tnfrsf10-/- mice. Our data suggest that downregulation of TNFRSF10A expression inactivates PKCA signaling and causes cellular vulnerability of the RPE, which may contribute to the pathogenesis of AMD and CSC.

One-year efficacy of "rescue photodynamic therapy" for patients with typical age-related macular degeneration, polypoidal choroidal vasculopathy, and pachychoroid neovasculopathy refractory to anti-vascular endothelial growth factor therapy.

PURPOSE: This study aimed to evaluate the one-year outcomes of photodynamic therapy (PDT) as a rescue treatment for age-related macular degeneration (AMD) refractory to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Patients with AMD refractory to anti-VEGF therapy, treated with "rescue-PDT" were retrospectively investigated. The time of PDT was defined as the baseline value. Baseline characteristics including sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), and foveal choroidal thickness (FCT) were examined. The changes in BCVA, CMT, and recurrence were also assessed at the 1-year follow-up. The logMAR VA change of 0.3 or more was defined as "improved" or "declined." RESULTS: Twenty-three consecutive eyes (typical AMD: 10 eyes, polypoidal choroidal vasculopathy: 10 eyes, and pachychoroid neovasculopathy: 3 eyes), which underwent "rescue-PDT," were analyzed in this study. The BCVA was improved in three patients and maintained in 20 patients at 12 months after PDT (mean BCVA change: 0.11 ± 0.19). The CMT improved in 19 patients (82.6%), and the mean CMT changed from 318.5 ± 93.7 µm to 225.9 ± 51.6 µm (p < 0.01) 12 months after PDT. "Retreatment" of anti-VEGF drug injections was considered if the retinal fluid or retinal hemorrhage recurred after PDT. The baseline FCT of the "retreatment group (15 eyes)" was significantly lower than that of the "no retreatment group (8 eyes)" (206.3 ± 50.7 µm vs 293.9 ± 85.7 µm: p = 0.033). CONCLUSIONS: PDT could be an effective treatment option for anti-VEGF refractory AMD to maintain visual acuity and control retinal fluid for up to 12 months.

Surgical Outcomes of Contrast Sensitivity and Visual Acuity in Uveitis-Associated Cataract.

PURPOSE: To evaluate the pre- and post-operative outcomes of phacoemulsification in patients with uveitis-associated cataract in remission, such as conventional visual acuity (VA), photopic and mesopic contrast visual acuity (CVA), and flares in the anterior chamber objectively assessed as intraocular inflammation. PATIENTS AND METHODS: This prospective study included 26 eyes of 19 patients with uveitis and 45 eyes of 26 controls who underwent cataract surgery at the Kyushu University Hospital and Kyushu Medical Center in Fukuoka, Japan, from October 2016 to December 2018. Conventional VA and flare values in the anterior chamber were evaluated preoperatively and 1 and 3 months postoperatively. Photopic and mesopic CVAs were assessed preoperatively and 3 months postoperatively. RESULTS: The best-corrected VA (BCVA) was improved significantly from baseline to 1 and 3 months postoperatively in both groups (P < 0.01 in both groups). The mean preoperative 100% and 10% CVAs under the photopic condition were significantly lower in the uveitis group than in the control group (P < 0.05 for both CVA), whereas the mean preoperative 100% CVA under the mesopic condition was comparable between the two groups. Although the mean preoperative 100% and 10% CVAs improved significantly from baseline under both photopic and mesopic conditions in both groups (P < 0.01 in both groups), the postoperative contrast sensitivities under both photopic and mesopic conditions remained lower in the uveitis group than in the control group (P < 0.01 for both conditions). The postoperative complications included recurrence of active inflammation in five eyes and cystoid macular edema in one eye and were managed by topical steroid therapy alone. CONCLUSION: Cataract surgery for uveitis-associated cataracts during remission is well tolerated. However, the present results suggest that amelioration of hemeralopia and/or nyctalopia is not as good as expected after cataract surgery in patients with uveitis.

Drusen and pigment abnormality predict the development of neovascular age-related macular degeneration in Japanese patients.

Drusen are known to be the important hallmark to predict the development of age-related macular degeneration (AMD). The prevalence of drusen is lower in Asians compared with Caucasians so that the role of signs constituting early AMD is not well established in Asian populations as in Western countries. In this study, we retrospectively investigated clinical characteristics and 5-year incidence of neovascular AMD (nAMD) in the fellow eye of unilateral nAMD patients. Of 296 consecutive unilateral nAMD patients who had been followed up more than 5 years, 170 typical AMD, 119 polypoidal choroidal vasculopathy, and 7 retinal angiomatous proliferation were included. To examine factors associated with nAMD occurrence in the fellow eye, drusen and pigmentary abnormality in the fellow eye were classified into 4 categories; Category 1: no or small drusen < 63 µm (37.2%), Category 2: 63-125 µm medium drusen or pigmentary abnormality (22.2%), Category 3: large drusen > 125 µm (25.0%), Category P: pachydrusen (15.5%). The mean sub-foveal choroidal thickness (SFCT) was Category 1: 276 µm, Category 2: 308 µm, Category 3: 246 µm, and Category P: 302 µm, respectively. Of note, SFCT in Category 2 and Category P was significantly larger than those of Category 3. Finally, the 5-year incidence of nAMD in the fellow eye was 32/296 (10.8%); Category 1: 0/110 (0%), Category 2: 12/66 (18.2%), Category 3: 20/74 (27.0%), and Category P: 0/46 (0%). Thus, signs of intermediate AMD (large drusen) as well as those of early AMD, especially the pigmentary abnormality, may contribute to development of bilateral nAMD in Japanese patients.

Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells.

RATIONALE: Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells. METHODS: ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis. RESULTS: Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine's effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it's action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn't prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3. CONCLUSIONS: Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases.

Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.

RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4-activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.

Atorvastatin Promotes Phagocytosis and Attenuates Pro-Inflammatory Response in Human Retinal Pigment Epithelial Cells.

Phagocytosis of daily shed photoreceptor outer segments is an important function of the retinal pigment epithelium (RPE) and it is essential for retinal homeostasis. RPE dysfunction, especially impairment of its phagocytic ability, plays an essential role in the pathogenesis of age-related macular degeneration (AMD). Statins, or HMG CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, are drugs with multiple properties that have been extensively used to treat hyperlipidemia. However, their effect on RPE cells has not been fully elucidated. Here we report that high dose atorvastatin increased the phagocytic function of ARPE-19 cells, as well as rescue the cells from the phagocytic dysfunction induced by cholesterol crystals and oxidized low-density lipoproteins (ox-LDL), potentially by increasing the cellular membrane fluidity. Similar effects were observed when evaluating two other hydrophobic statins, lovastatin and simvastatin. Furthermore, atorvastatin was able to block the induction of interleukins IL-6 and IL-8 triggered by pathologic stimuli relevant to AMD, such as cholesterol crystals and ox-LDL. Our study shows that statins, a well-tolerated class of drugs with rare serious adverse effects, help preserve the phagocytic function of the RPE while also exhibiting anti-inflammatory properties. Both characteristics make statins a potential effective medication for the prevention and treatment of AMD.

Verteporfin-induced formation of protein cross-linked oligomers and high molecular weight complexes is mediated by light and leads to cell toxicity.

Verteporfin (VP) was first used in Photodynamic therapy, where a non-thermal laser light (689 nm) in the presence of oxygen activates the drug to produce highly reactive oxygen radicals, resulting in local cell and tissue damage. However, it has also been shown that Verteporfin can have non-photoactivated effects such as interference with the YAP-TEAD complex of the HIPPO pathway, resulting in growth inhibition of several neoplasias. More recently, it was proposed that, another non-light mediated effect of VP is the formation of cross-linked oligomers and high molecular weight protein complexes (HMWC) that are hypothesized to interfere with autophagy and cell growth. Here, in a series of experiments, using human uveal melanoma cells (MEL 270), human embryonic kidney cells (HEK) and breast cancer cells (MCF7) we showed that Verteporfin-induced HMWC require the presence of light. Furthermore, we showed that the mechanism of this cross-linking, which involves both singlet oxygen and radical generation, can occur very efficiently even after lysis of the cells, if the lysate is not protected from ambient light. This work offers a better understanding regarding VP's mechanisms of action and suggests caution when one studies the non-light mediated actions of this drug.

Long-term Surgical Outcomes of Epiretinal Membrane in Patients with Retinitis Pigmentosa.

Macular complications such as an epiretinal membrane (ERM), a cystoid macular edema and a macular hole lead to unexpected central vision impairment especially for patients with retinitis pigmentosa (RP). To evaluate the long-term surgical outcomes of pars plana vitrectomy (PPV) for ERM in patients with RP, we retrospectively reviewed the charts of a consecutive series of 10 RP patients who underwent PPV for ERM at Kyushu University Hospital. Visual acuity (VA) testing, a fundus examination, and an optical coherence tomography (OCT) analysis were conducted. The standard PPV using three sclerotomies was performed for ERM. PPV was performed in 12 eyes of 10 patients. One eye was excluded from the outcome assessment due to short period observation (18 months). There was no significantly deleterious change from the baseline to final VA between the operation eyes and the fellow eyes (P = 0.19). Moreover, morphological improvement was obtained in 9 of 11 eyes based on OCT. Our present data suggest that PPV may be tolerable in the management for ERM in RP patients over the long-term. Furthermore, the appearance of the ellipsoid zone was an important factor in the prediction of visual outcome and determination of surgical indication.

Vitreous cysts in patients with retinitis pigmentosa.

PURPOSE: To determine the prevalence of vitreous cysts in patients with retinitis pigmentosa (RP). METHODS: We retrospectively reviewed the charts of 435 consecutive patients diagnosed as having typical RP. RESULTS: Vitreous cysts were diagnosed in 37 eyes of 28 patients with RP (13 males and 15 females; mean age 47.0 ± 19.8 years; range 15-79 years), for an overall prevalence of 6.4%. The cysts were observed bilaterally in nine of the patients (32.1%). Among these 28 patients, 11 (39.3%) were younger than 40 years. In all, 81.8% of the vitreous cysts were detected around the optic nerve head. CONCLUSIONS: We demonstrated that the prevalence of vitreous cysts was 6.4% in patients with RP. These cysts were considered to be asymptomatic.

Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa.

PURPOSE: To investigate the factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, observational study. PARTICIPANTS: We retrospectively reviewed the charts of a consecutive series of 40 patients with RP who underwent cataract surgery. METHODS: The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were measured. We investigated the relation between preoperative mean deviation (MD) value on the Humphrey Field Analyzer (HFA: the central 10-2 program; Humphrey Instruments, Inc, San Leandro, CA) and final BCVA. We also investigated the relationship between preoperative ellipsoid zone (EZ; also called the inner/outer segment junction) conditions and final BCVA. In addition, we showed the prevalence of macular complications and capsule complications. MAIN OUTCOME MEASURES: The BCVA, slit-lamp biomicroscopic analysis, visual field, and optical coherence tomography (OCT) were obtained. RESULTS: The mean of the BCVA significantly improved after cataract surgery from 0.76 (range, -0.08 to 2.30) to 0.45 (range, -0.18 to 2.00) (P < 0.005). However, final BCVA did not improve in 30 eyes (53.6%). The preoperative MD value and the final BCVA were significantly correlated, and the final BCVA significantly improved in the less advanced RP group (MD was ≥-15 decibels [dB]). The final BCVA was significantly better in the group in which preoperative OCT showed a normal EZ than in the groups in which the EZ was abnormal or not visible. Posterior capsular opacification was observed in 47 eyes (83.9%), and 23 eyes (41.1%) underwent YAG laser capsulotomy within a mean follow-up time of 3 years. CONCLUSIONS: Final BCVA in approximately half of the eyes improved after cataract surgery in patients with RP. The preoperative ophthalmic examinations that may reflect macular (or foveal) function, such as HFA 10-2 program and OCT, are important parameters to assess postoperative visual outcome.