HIF-1α-dependent upregulation of angiogenic factors by mechanical stimulation in retinal pigment epithelial cells.

Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the underlying molecular mechanisms remain unclear. We investigated and characterized the effects of mechanical stimulation on the expression of angiogenic factors in RPE cells both in vitro and in a mouse model. Mechanical stimulation increased the expression of vascular endothelial growth factor (VEGF, encoded by VEGFA) and other angiogenesis-related genes in cultured RPE1 cells. The presence of hypoxia-inducible factor 1α (HIF-1α, encoded by HIF1A) was also increased, and both knockdown of HIF-1α and treatment with the HIF-1α inhibitor CAY10585 attenuated the effect of mechanical stimulation on angiogenesis factor gene expression. Signaling by the tyrosine kinase SRC and p38 mitogen-activated protein kinase was involved in HIF-1α activation and consequent angiogenesis-related gene expression induced by mechanical stimulation. Our results suggest that SRC-p38 and HIF-1α signaling are involved in the upregulation of angiogenic factors in RPE cells by mechanical stimulation. Such in vivo suppression of upregulated expression of angiogenesis-related genes by pharmacological inhibitors of HIF-1α suggests a new potential approach to the treatment of age-related macular degeneration.

Treatment of Failure of Macular Hole Closure due to Post-Vitrectomy Macular Edema Using Sub-Tenon Triamcinolone Acetonide Injection: A Case Report.

Introduction: Post-vitrectomy cystoid macular edema (CME) can lead to failure of macular hole (MH) closure. We report 2 cases of failure of MH closure due to post-vitrectomy CME, which were successfully treated using sub-Tenon triamcinolone acetonide (STTA) injection. Case Presentations: Case 1 involved a 72-year-old male patient with a Gass Stage 3 MH in the right eye. He underwent pars plana vitrectomy (PPV), internal limiting membrane translocation, and sulfur hexafluoride (SF6) gas injection with cataract surgery in his right eye. The MH did not close postoperatively; further, CME developed at the edge of the MH. Accordingly, the patient underwent an STTA injection. Approximately 2 weeks after the STTA injection, the CME disappeared and the MH closed, which has remained closed 1 year after PPV. Case 2 involved a 78-year-old female patient with Gass Stage 3 MH in the left eye. The patient underwent the same surgical procedure as that performed in case 1. Further, she presented with failure of MH closure caused by CME; therefore, an STTA injection was performed. Approximately 6 weeks after STTA injection, the CME disappeared and the MH closed; further, there was maintained improvement of best-corrected visual acuity for 6 months. Conclusions: STTA injection could be considered before reoperation in cases involving failure of MH closure due to postoperative CME.

Exacerbation of Diabetic Retinopathy following Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor Administration: A Case Report.

Introduction: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, used in the treatment of renal anemia, hold the potential to increase the production of vascular endothelial growth factors. Therefore, HIF-PH inhibitors may exacerbate retinal hemorrhage in diseases such as diabetic retinopathy. Here, we present a case involving the administration of an HIF-PH inhibitor, resulting in the exacerbation of retinal hemorrhage in a patient with diabetic retinopathy. Case Presentation: A 32-year-old man with diabetes mellitus and renal anemia caused by diabetic nephropathy was referred to our department for ophthalmic examination, revealing diabetic retinopathy with scattered retinal hemorrhages, exudates, and diabetic maculopathy in both eyes. Darbepoetin alfa was initially administered and switched to the HIF-PH inhibitor roxadustat on day 74. By day 88, fresh retinal hemorrhage was observed in the right eye. On day 132, the retinal hemorrhage had further worsened, with new preretinal hemorrhage in both eyes. Roxadustat was discontinued, replaced with darbepoetin alfa, resulting in retinal hemorrhage improvement by day 181 (49 days post-roxadustat cessation). On day 201, fundus hemorrhage further improved, optical coherence tomography showed no macular edema or subretinal fluid, and the retina was thinning. Fluorescein angiography showed neovascular vessels, active fluorescein leakage, and extensive avascular areas in both eyes, prompting pan-retinal photocoagulation. Visual acuity remained stable throughout treatment. Conclusion: Patients with advanced diabetic retinopathy taking HIF-PH inhibitors should be aware of retinal hemorrhage exacerbations. If observed, the treatment plan, including discontinuation of the HIF-PH inhibitor or switching to another agent, should be discussed with a diabetologist, nephrologist, and ophthalmologist.

Use of Ranibizumab for evaluating focal laser combination therapy for refractory diabetic macular edema patients: an exploratory study on the RELAND trials.

Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for diabetic macular edema (DME), but is less effective in some patients. We conducted a prospective study to determine whether laser combination therapy with anti-VEGF was more effective than Ranibizumab monotherapy in anti-VEGF-resistant DME patients. There was no significant difference in the improvement of the best-corrected visual acuity (BCVA) between the laser combination therapy and Ranibizumab monotherapy groups (3.2 letters and -7.5 letters, p = 0.165). BCVA did not significantly change between visits 1 and 7 (the laser combination group, 64.3 letters 70.3 letters, respectively, p = 0.537; the Ranibizumab monotherapy group, 72.3 letters and 64.8 letters, respectively, p = 0.554), with no significant improvements in central foveal retinal thickness (the laser combination therapy group, 9.3%: the Ranibizumab monotherapy groups, - 7.3%; p = 0.926). There was no significant difference in the number of Ranibizumab intravitreal therapy (IVT) sessions between the groups (laser combination therapy, 5.2; ranibizumab monotherapy, 6.0; p = 0.237). This study did not show that laser combination therapy was significantly more effective for anti-VEGF-resistant DME than anti-VEGF monotherapy alone. Therefore, for anti-VEGF-resistant DME, alternative therapeutic approaches beyond combined laser therapy may be considered.

Anti-VEGF Treatment Strategies for 3 Subtypes of Neovascular Age-Related Macular Degeneration in a Clinical Setting: A Multicenter Cohort Study in Japan.

PURPOSE: Neovascular age-related macular degeneration (nAMD) is classified into typical AMD (tAMD), polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP). This study investigated clinical features of the 3 subtypes and visual outcome associated with treatment regimens in a large cohort of patients with nAMD in a clinical setting. DESIGN: Retrospective multicenter cohort study. PARTICIPANTS: Five hundred patients with treatment-naive nAMD (268 tAMD, 200 PCV, and 32 RAP) initiated with anti-VEGF agents and followed for 1 year. METHODS: Medical records were reviewed to extract demographic data, best-corrected visual acuity at baseline and 1 year after treatment initiation, spectral-domain OCT findings, baseline fellow eye condition, systemic factors, treatment strategies, and number of intravitreal injections in the first year. MAIN OUTCOME MEASURES: Primary outcome measures were anti-VEGF treatment strategy (ranibizumab or aflibercept, anti-VEGF regimen, concomitant photodynamic therapy, drug switch), best-corrected visual acuity at 1 year, and factors associated with visual acuity. RESULTS: Patients with RAP were significantly older, were more commonly women, and had more macular lesions in fellow eye than patients with tAMD and PCV. Smoking history and diabetes prevalence were not different among the 3 subtypes. Frequencies of subretinal fluid were higher and intraretinal fluid were lower in tAMD and PCV than in RAP, whereas serous pigment epithelial detachment and subretinal hemorrhage were higher in PCV than in tAMD and RAP. Choice of anti-VEGF agents and treatment regimens did not differ among 3 subtypes. The aflibercept-to-ranibizumab ratio was approximately 7:3. The mean number of injections in 1 year was 5.3 ± 2.4 in nAMD overall, which was significantly less in pro re nata (PRN) than in treat and extend (TAE) regardless of the anti-VEGF agent. Best-corrected visual acuity improved in all 3 subtypes, although it was not significant in patients with RAP. CONCLUSIONS: This clinical study demonstrates that treatment regimens were similar in 3 subtypes and aflibercept was used in 70% of all patients. Approximately 5 injections were given in the first year regardless of the anti-VEGF agent, which was significantly less in PRN regimen than in TAE. Visual acuity improvement was observed after 1-year anti-VEGF therapy in all 3 subtypes, but was not significant in RAP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy of ripasudil in reducing intraocular pressure and medication score for ocular hypertension with inflammation and corticosteroid.

AIM: To investigate the efficacy of ripasudil, a Rho kinase inhibitor, in reducing intraocular pressure (IOP) and medication scores of anti-glaucoma drugs in patients with ocular hypertension with inflammation and corticosteroid. METHODS: The study included 11 patients diagnosed with ocular hypertension with inflammation and corticosteroid, all of whom were prescribed ripasudil eye drops and followed up for at least 2y after the initiation of treatment. IOP was measured using a non-contact tonometer before enrollment and at each follow-up visit. The medication score of glaucoma eye drops was calculated for each patient. RESULTS: The mean IOP (26.4±2.9 mm Hg before treatment) significantly decreased after ripasudil therapy (13.7±3.3 mm Hg at 3mo) and remained stable in the low-teens during the 2-year follow-up period (P<0.0001). A significant decrease in the medication score was observed at 12mo or later after the initiation of ripasudil therapy (P<0.05). Both baseline medication scores and glaucomatous optic disc change rates were significantly higher in the five eyes that required glaucoma surgery during the 2-year observation period than the 10 eyes that did not require surgery. CONCLUSION: Our results demonstrate the efficacy of ripasudil, in reducing IOP and the medication score over a 2-year treatment period in patients with ocular hypertension with inflammation and corticosteroid. Our findings also suggest that ripasudil could reduce the IOP in uveitic glaucoma patients with both lower baseline medication score and lower glaucomatous optic disc change rate.

Evaluation of microaneurysms as predictors of therapeutic response to anti-VEGF therapy in patients with DME.

Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Evaluation of corneal hysteresis after pars plana vitrectomy combined phacoemulsification and intraocular lens implantation.

We evaluated the early effects of pars plana vitrectomy (PPV) on corneal biomechanics by comparing corneal hysteresis (CH) after cataract surgery (phacoemulsification and aspiration with intraocular lens implantation; PEA + IOL) alone and PPV combined with cataract surgery. This study included 20 eyes (18 patients), who underwent cataract surgery alone (PEA + IOL group), and 28 eyes (27 patients) who underwent PPV combined with cataract surgery (PPV triple group). The CH was 11.1 ± 1.1, 10.4 ± 1.1, and 11.0 ± 1.0 mmHg in the PEA + IOL group and 11.0 ± 1.4, 9.8 ± 1.4, and 10.6 ± 1.6 mmHg in the PPV triple group, preoperatively, at 2 weeks, and 3 months after surgery, respectively. The CH was not significantly different after surgery in the PEA + IOL group, but decreased significantly in the PPV triple group 2 weeks following surgery (p < 0.01). Intraocular pressure (IOP) and central corneal thickness (CCT) did not change significantly after surgery in either group. Preoperatively, there was a positive correlation between CH and CCT in the PPV triple group, but the correlation disappeared postoperatively. In PPV combined with cataract surgery, CH temporarily decreased postoperatively, independent of IOP and CCT. Removal of the vitreous may reduce the elasticity and rigidity of the entire eye.

Surgical resection of intraorbital metastasis of a gastrointestinal stromal tumor resistant to chemotherapy.

PURPOSE: We present a case of a gastrointestinal stromal tumor (GIST) metastasis of the rectal primary resisting chemotherapy to the right orbit 15 years after excision of the primary lesion. OBSERVATIONS: A 79-year-old man was diagnosed with rectal GIST at the age of 65 years and underwent rectal amputation. He underwent hepatectomy for GIST liver metastases at the age of 69 years and pericardiectomy for GIST pericardial metastases at 72 years of age. At the age of 79 years, positron emission tomography-computed tomography revealed the possibility of liver metastasis and metastasis to the right orbit of 10 mm in size. Magnetic resonance imaging revealed a well-circumscribed mass of 10 mm × 12 mm in the deep medial rectus muscle of the right orbit, which was referred to our department for ophthalmic examination. The latter revealed only mild abduction disorder in the right eye. Although chemotherapy was initiated, the tumor gradually increased, causing exophthalmos in the right eye, visual field impairment due to optic nerve exclusion, and decreased visual acuity. Due to repeated multiple metastases, the patient underwent right orbital exenteration and free flap reconstruction at the age of 83 years for radical cure. Pathological examination revealed c-Kit positive, CD34 positive, S100 protein minority positive, MIB-1 positive rate of 10% or more, and α-SMA negative, and the diagnosis was intraorbital metastasis of GIST. CONCLUSIONS AND IMPORTANCE: Orbital metastases in GISTs are extremely rare, and there is no established standard treatment. Therefore, a comprehensive decision must be made based on the final treatment goal and the patient's background when selecting treatment.

Retinal Pigment Epithelial Detachment Associated with Immunoglobulin A Nephropathy: A Case Report.

Uveitis and scleritis are eye diseases associated with immunoglobulin A (IgA) nephropathy, but reports on retinal pigment epithelial detachment (PED) in relation to IgA nephropathy are scarce. We have experienced a case of PED associated with IgA nephropathy that was improved by pulse steroid treatment. A 68-year-old woman underwent examination for visual loss in the right eye. Her corrected visual acuity was 20/20 on both sides, and serous PED was observed in both eyes. One month later, the PED improved in both eyes but recurred 3 months later. Results of blood examination raised suspicion of IgA nephropathy, and she was referred to a nephrologist. Two weeks later, the PED in both eyes worsened, and a retinal pigment epithelium (RPE) tear appeared in the right eye. A sub-Tenon's injection of triamcinolone acetonide was performed to address the PED, but it was not effective; thus, pulse steroid therapy was performed twice. The PED disappeared from both eyes, and the visual acuity in her left eye was maintained at 20/20, but it decreased to 20/200 in her right eye due to macular atrophy after the RPE tear. The PED had not recurred despite having no improvement in renal function. In conclusion, in IgA nephropathy, deposition of immune complexes on the RPE causes its inflammation, which may lead to PED. In cases of unexplained PED, the possibility of a systemic disease as the cause should be considered.

Intravitreal Tissue Plasminogen Activator Injection for Treatment-Resistant Diabetic Macular Edema of the Vitrectomized Eye.

Diabetic macular edema (DME) is the main cause of visual loss in patients with diabetic retinopathy. DME has been treated using intravitreal anti-vascular endothelial growth factor (VEGF) drugs, steroids, laser photocoagulation, vitreoretinal surgery, and their combinations. These modalities are generally effective in preserving vision, but they sometimes produce only limited responses in patients with persistent or refractory DME. The levels of various inflammatory factors, including cytokines, chemokines, and extracellular matrices, as well as VEGF in the vitreous fluid, are increased in patients with DME. Excessive fibrinogen/fibrin levels in the vitreous fluid or fibrin deposition in the retina also contribute to DME pathogenesis. Tissue plasminogen activator (t-PA) promotes the degradation of fibrinogen or fibrin. Intravitreal t-PA injection is a commonly used treatment for subretinal hemorrhage secondary to age-related macular degeneration. Intravitreal t-PA injections have previously been used to restore vision by inducing posterior vitreous detachment in patients with DME. Herein, we describe the visual outcomes of intravitreal t-PA injection in a 78-year-old woman with treatment-resistant DME in her vitrectomized eye after several previous treatments. Before the injection, her best-corrected visual acuity (BCVA) was 0.7 logMAR and central foveal retinal thickness (CRT) was 735 µm. At 1 month after the injection, her BCVA was 0.8 logMAR and CRT was 558 µm, and 3 months later, her BCVA was 0.8 logMAR and CRT was 207 µm. Her BCVA was sustained, and CRT showed gradual improvements. These findings suggested the effectiveness of intravitreal t-PA injections for DME in the vitrectomized eye.

Benzalkonium chloride-induced myofibroblastic transdifferentiation of Tenon's capsule fibroblasts is inhibited by coculture with corneal epithelial cells or by interleukin-10.

Benzalkonium chloride (BAC) is used as a preservative in eyedrops but induces subconjunctival fibrosis that can result in failure of glaucoma surgery. Tenon's capsule fibroblasts in subconjunctival tissue interact with the corneal epithelium through tear fluid. With the use of a coculture system, we have now investigated the effect of human corneal epithelial (HCE) cells on myofibroblastic transdifferentiation of human Tenon fibroblasts (HTFs) induced by BAC (5 × 10-6%). Immunofluorescence and immunoblot analyses revealed that the BAC-induced expression of α smooth muscle actin (αSMA) in HTFs was suppressed by coculture of these cells with HCE cells (p < 0.01). The concentration of interleukin-10 (IL-10) in culture supernatants of BAC-treated HTFs was increased by coculture with HCE cells (17.26-fold, vs. coculure, p < 0.001). Immunofluorescence and immunoblot analyses also showed that exogenous IL-10 (300 pg/ml) suppressed the BAC-induced expression of αSMA by 43.65% (p < 0.05) as well as the nuclear translocation of myocardin-related transcription factor-A (MRTF-A) by 39.32% (p < 0.01) in HTFs cultured alone. Our findings suggest that corneal epithelial cells may protect against subconjunctival fibrosis by maintaining IL-10 levels and preventing the MRTF-A-dependent transdifferentiation of HTFs into myofibroblasts.

Inhibition of epithelial-mesenchymal transition in retinal pigment epithelial cells by a retinoic acid receptor-α agonist.

Epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a key role in proliferative retinal diseases such as age-related macular degeneration by contributing to subretinal fibrosis. To investigate the potential role of retinoic acid receptor-α (RAR-α) signaling in this process, we have now examined the effects of the RAR-α agonist Am580 on EMT induced by transforming growth factor-ß2 (TGF-ß2) in primary mouse RPE cells cultured in a three-dimensional type I collagen gel as well as on subretinal fibrosis in a mouse model. We found that Am580 inhibited TGF-ß2-induced collagen gel contraction mediated by RPE cells. It also attenuated the TGF-ß2-induced expression of the mesenchymal markers α-smooth muscle actin, fibronectin, and collagen type I; production of pro-matrix metalloproteinase 2 and interleukin-6; expression of the focal adhesion protein paxillin; and phosphorylation of SMAD2 in the cultured RPE cells. Finally, immunofluorescence analysis showed that Am580 suppressed both the TGF-ß2-induced translocation of myocardin-related transcription factor-A (MRTF-A) from the cytoplasm to the nucleus of cultured RPE cells as well as subretinal fibrosis triggered by laser-induced photocoagulation in a mouse model. Our observations thus suggest that RAR-α signaling inhibits EMT in RPE cells and might attenuate the development of fibrosis associated with proliferative retinal diseases.

A Trinity regimen with aflibercept for treatment-naïve neovascular age-related macular degeneration: 2-year outcomes.

PURPOSE: To evaluate the advantages of the Trinity regimen for treatment-naïve neovascular age-related macular degeneration (nAMD). METHODS: Thirty-one treatment-naïve nAMD eyes were treated using the Trinity regimen with an intravitreal aflibercept injection (IVA) and evaluated after 24 months. Three treatment methods, pro re nata (PRN), treat and extend (TAE), and fixed regimen were changed depending on recurrence frequency. After the initial treatment, PRN or TAE (started for 4 or 8 weeks) was selected as per the recurrence interval. Subsequently, the recurrence interval became constant, transitioning from a TAE to fixed regimen. When the recurrence frequency became irregular, the treatment regimen was changed to TAE. RESULTS: After the initial treatment, 15 eyes (48.4%) were allocated to the PRN group, 12 (38.7%) to the TAE 8-week group, and 4 (12.9%) to the TAE 4-week group. Mean logMAR significantly improved in all cases, 0.53 ± 0.40 at baseline to 0.36 ± 0.34 at 24 months (p < 0.01), in the PRN group (0.63 ± 0.46 to 0.42 ± 0.43, p < 0.01), and the TAE 8-week group (0.44 ± 0.29 to 0.27 ± 0.19, p < 0.05). LogMAR in the TAE 4-week group was maintained. The mean number of injections for all and in the PRN, TAE 8-week, and TAE 4-week groups were 9.7, 5.3, 13.1, and 15.8, respectively, with the PRN group being significantly less (p < 0.01). CONCLUSION: The Trinity regimen delivered the benefits of the PRN, TAE, and FIXED regimens while minimizing injections during the early treatment phase without visual loss. TRIAL REGISTRATION: This trial was registered with the University Hospital Medical Information Network (UMIN ID: 000038335).

Indocyanine green angiography findings of cystoid macular edema secondary to paclitaxel therapy.

PURPOSE: To report 2 cases of paclitaxel-related maculopathy manifesting as cystoid macular edema (CME) with late petaloid hyperfluorescence on indocyanine green angiography (IA). CASES: A 74-year-old man (patient 1) undergoing paclitaxel chemotherapy for gastric and metastatic liver cancer and a 69-year-old man (patient 2) receiving paclitaxel for hypopharyngeal cancer presented with anorthopia in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed macular edema in both eyes of each patient. Fluorescein angiography showed weak petaloid pooling around the fovea in the late phase. IA revealed CME with petaloid hyperfluorescence that matched the region of macular edema detected by SD-OCT. The CME was attenuated in the right eye but not in the left eye of patient 1 at 2 weeks after discontinuation of paclitaxel treatment, whereas it was no longer apparent in either eye at 3 months. The CME was no longer detected in either eye of patient 2 at 3 months after discontinuation of paclitaxel. CONCLUSION: These cases suggest that paclitaxel-induced CME may result from intraretinal accumulation of intracellular fluid and minimal impairment of the blood retinal barrier.

Safety and Efficacy of Benzalkonium Chloride-optimized Tafluprost in Japanese Glaucoma Patients With Existing Superficial Punctate Keratitis.

PURPOSE: To evaluate the safety and efficacy of benzalkonium chloride (BAK)-optimized tafluprost (with a BAK concentration reduced from 0.01% to 0.001%) in glaucoma patients with existing superficial punctate keratitis (SPK). PATIENTS AND METHODS: A prospective, multicenter, open-label study was designed to compare BAK-optimized tafluprost administered over 12 weeks relative to other preserved prostaglandin analogs previously administered in Japanese glaucoma patients. Thirty patients with SPK graded at <6 points by area density (AD) scoring in 1 eye were recruited. The primary outcome measure was change in AD score at 12 weeks after the switch in treatment compared with that at baseline. Secondary outcome measures included changes in tear film breakup time (TBUT), hyperemia score, and intraocular pressure (IOP). Four patients were excluded from analysis because of treatment discontinuation. RESULTS: Mean AD score±SD decreased significantly from 3.4±0.9 to 1.8±1.8 after the switch (P<0.0001). Mean TBUT increased significantly from 6.3±3.3 to 8.0±4.2 seconds (P<0.01). Mean hyperemia score remained unchanged, whereas mean IOP decreased significantly from 15.6±2.6 to 14.4±2.0 mm Hg (P<0.01). For patients previously treated with BAK-preserved latanoprost (n=17) or bimatoprost (n=2), mean AD score decreased significantly from 3.4±0.9 to 1.8±1.8 (P<0.01) and mean TBUT increased significantly from 6.4±3.6 to 8.2±4.3 seconds (P<0.01); no such changes were apparent for patients previously treated with sofZia-preserved travoprost (n=7). CONCLUSIONS: BAK-optimized tafluprost is a treatment option to improve the condition of the ocular surface and to maintain IOP control in glaucoma patients with existing SPK who have been previously treated with other BAK-preserved prostaglandin analogs.

Inhibition by female sex hormones of collagen gel contraction mediated by retinal pigment epithelial cells.

PURPOSE: Collagen contraction mediated by retinal pigment epithelial (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR). We examined the effects of sex hormones on this process. METHODS: Mouse RPE cells were cultured in a type I collagen gel and exposed to 17ß-estradiol, progesterone, or dehydro-epiandrosterone. Collagen contraction induced by transforming growth factor-ß2 (TGF-ß2) was determined by measurement of gel diameter. Expression of α-smooth muscle actin (α-SMA), as well as phosphorylation of Smad2 and myosin light chain (MLC), was examined by immunoblot analysis. Matrix metalloproteinase (MMP) release was evaluated by gelatin zymography. Fibronectin and interleukin-6 secretion was measured with immunoassays. RESULTS: The female sex hormones 17ß-estradiol and progesterone inhibited TGF-ß2-induced collagen contraction mediated by RPE cells, whereas the male sex hormone dehydro-epiandrosterone had no such effect. The TGF-ß2-induced release of MMP-2 and MMP-9 from RPE cells was also inhibited by 17ß-estradiol and progesterone, and the MMP inhibitor GM6001 attenuated TGF-ß2-induced collagen contraction. Expression of the mesenchymal markers α-SMA and fibronectin, interleukin-6 release, and Smad2 and MLC phosphorylation induced by TGF-ß2 were all inhibited by 17ß-estradiol and progesterone. Immunohistochemical analysis also detected nuclear immunoreactivity for estrogen and progesterone receptors in proliferative fibrocellular membranes of PVR patients. CONCLUSIONS: Female sex hormones inhibited TGF-ß2-induced collagen contraction mediated by RPE cells. This action appeared to be mediated through inhibition both of MMP, α-SMA, and fibronectin expression as well as of Smad2 and MLC phosphorylation. Female sex hormones might thus prove effective for the treatment of PVR.

Noninvasive direct detection of ocular mucositis by in vivo confocal microscopy in patients treated with S-1.

PURPOSE: S-1 is an oral antineoplastic agent that contains a prodrug of 5-fluorouracil and has adverse effects on skin, alimentary tract mucosa, and the ocular surface. We investigated the effects of S-1 on the corneal epithelium by in vivo confocal microscopy and histopathologic analysis. METHODS: Twelve patients with eye problems related to S-1 treatment participated in the study. Twenty eyes of ten subjects were evaluated by laser-scanning confocal microscopy. Corneal epithelial debridement as a diagnostic therapy and histopathologic analysis were performed for five eyes of three subjects affected in the pupillary zone of the cornea. RESULTS: Slitlamp examination revealed a local limbal abnormality characterized by epithelial invasion toward the center of the cornea in all 24 eyes. In vivo confocal microscopy revealed an altered structure of the corneal epithelium with abnormal epithelial cells and inflammation. One of five specimens subjected to cytologic diagnosis showed moderate dysplasia. Hematoxylin and eosin staining showed that each abnormal epithelial sheet lacked the stratified structure of the normal corneal epithelium. Immunofluorescence analysis revealed the presence of cells positive for one, both, or neither of cytokeratins 12 and 4 in each lesion. CONCLUSIONS: S-1 can induce ocular mucositis with dysplasia, likely affecting cellular functions, including differentiation, of the corneal epithelium. In vivo confocal microscopy allowed the noninvasive detection of cellular changes in the cornea as an adverse effect of S-1 administration.

In vivo biopsy by laser confocal microscopy for evaluation of traumatic recurrent corneal erosion.

PURPOSE: Laser in vivo confocal microscopy noninvasively provides images that are equivalent to high quality histology. We have now applied this technique to identify pathological characteristics of traumatic recurrent corneal erosion (RCE). METHODS: Six eyes of six patients with traumatic RCE were studied. Corneas were examined with a slit lamp biomicroscope and with a laser in vivo confocal microscope (Heidelberg Retina Tomograph II-Rostock Cornea Module or HRTII-RCM) at various times after the onset of the most recent recurrence of corneal erosion. RESULTS: Brightly reflective granular structures were detected by the HRTII-RCM system in the basal and wing cell layers of the corneal epithelium in all eyes affected by recurrent erosion. Activated keratocytes and scattered fine particles were also apparent in the shallow stroma of five of the six affected eyes. These features were not observed in the normal cornea. CONCLUSIONS: The HRTII-RCM system allows detection of characteristic abnormal structures in the cornea of individuals with traumatic RCE. The presence of granular structures in the corneal epithelium as well as persistent inflammation in the shallow stroma may contribute to the deterioration of the corneal epithelial cell alignment and to the weakening of adhesion between the basal epithelial cells and the basement membrane in RCE lesions.