Efficacy and safety of 1% and 2% rebamipide clear solution in dry eye disease: a multicenter randomized trial.

BACKGROUND: To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED). METHODS: Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment. RESULTS: The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups. CONCLUSIONS: 1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED.

Inflammation Confers Healing Advantage to Corneal Epithelium Following Subsequent Injury.

Recent evidence shows that epithelial stem/progenitor cells in barrier tissues such as the skin, airways and intestines retain a memory of previous injuries, which enables tissues to accelerate barrier restoration after subsequent injuries. The corneal epithelium, the outermost layer of the cornea, is the frontline barrier for the eye and is maintained by epithelial stem/progenitor cells in the limbus. Herein, we provide evidence that inflammatory memory also exists in the cornea. In mice, eyes that had been exposed to corneal epithelial injury exhibited faster re-epithelialization of the cornea and lower levels of inflammatory cytokines following subsequent injury (either the same or a different type of injury) relative to naïve eyes without previous injury. In ocular Sjögren's syndrome patients, corneal punctate epithelial erosions were significantly reduced after experiencing infectious injury compared with before. These results demonstrate that previous exposure of the corneal epithelium to inflammatory stimuli enhances corneal wound healing in response to a secondary assault, a phenomenon which points to the presence of nonspecific inflammatory memory in the cornea.

Matrix metalloproteinase 9 is associated with conjunctival microbiota culture positivity in Korean patients with chronic Stevens-Johnson syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS) is an abnormal immune-response causing extensive exfoliation of the mucocutaneous tissue including conjunctiva. While several factors are associated with the alteration of conjunctival microbiota, the conjunctiva of SJS patients are found to harbor a different microbiota compared to healthy subjects. We investigated the conjunctival microbiota of Korean SJS patients, and identified factors associated with the conjunctival microbiota and its positive culture. METHODS: Medical records were retrospectively reviewed in 30 chronic SJS patients who had undergone conjunctival swab culture sampling. Demographic factors, chronic ocular surface complications score (COCS), tear break-up time (TBUT), tear secretion, tear matrix metalloproteinase 9 (MMP9), and results of conjunctival swab culture were assessed. RESULTS: Positive culture was seen in 58.1%. Gram positive bacteria was most commonly isolated, among which Coagulase-negative Staphylococci (45.5%) and Corynebacterium species (40.9%) were predominantly observed. Tear MMP9 positivity was observed significantly more in the positive culture group (100%) compared to the negative culture group (70%) (P = 0.041). Topical cyclosporine and corticosteroid were not associated with repetitive positive cultures. No significant differences in COCS, TBUT, and tear secretion were found between culture-positive and culture-negative groups. CONCLUSION: Our study suggests that tear MMP9 positivity may be related with the presence of an abnormal ocular surface microbiota in chronic SJS patients.

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study.

BACKGROUND: While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice. RESULTS: Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, ß-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity. CONCLUSIONS: Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice.

Clinical outcomes in post-epikeratophakic eyes after removal of epikeratoplasty lenticule.

BACKGROUND: Assessment of the optical outcome and adverse events in post-epikeratopathic eyes after removal of the epikeratoplasty lenticule (EKPL). METHODS: This was a retrospective case-series study of patients who underwent EKPL removal between 2002 and 2020. Ten eyes were included in the analysis. We compared the clinical characteristics of the patients before surgery, 6 months after surgery, before lenticular removal, and after removal, and reported optical or ocular surface complications. RESULTS: We removed EKPL due to the lenticular opacity in five eyes (50%), intraocular lens (IOL) insertion (n = 4, 40%) after cataract surgery (n = 3) or in aphakic eyes (n = 1), and lenticule-induced irregular astigmatism in one eye (10%). After EKPL removal, the mean refractive power of the cornea (Km) revealed a tendency to increase. Out of nine cases, six cases showed corneal steepening and three cases revealed corneal flattening. When the keratometric readings of pre-epikeratoplasty and post-lenticular removal were compared within the same case, the average difference was 5.1 D ± 4.0 (n = 8). Complications were observed in 3 of 10 cases (excessive corneal flatness, ectatic change, and abnormal epithelial cell ingrowth) after removal. CONCLUSIONS: The surgeon should expect the corneal refractive power to steepen or flatten in some cases with abnormal astigmatism and irregularity. Epikeratophakic eyes may exhibit serious ectatic changes, and abnormal epithelial cell ingrowth after removal of epikeratophakic lenticules.

Comparison of ocular biometric measurements in patients with cataract using three swept-source optical coherence tomography devices.

BACKGROUND: Precise measurement of ocular biometry is critical for determining intraocular lens power. Newly developed swept-source optical coherence tomography (SS-OCT) - based ocular biometric devices, ANTERION and CASIA2 provide ocular biometric measurements as IOLMaster 700. This study aimed to assess agreement between three devices. METHODS: This retrospective comparative study includes patients with cataract who underwent ocular biometric measurements with three devices, ANTERION, CASIA2, and IOLMaster 700, at Seoul National University Hospital, in April 2020. Anterior keratometry, total keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were the main parameters for the comparison. To assess the agreement between the devices, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used. RESULTS: A total of 47 eyes of 29 patients were measured with three devices. Average anterior keratometry showed excellent agreement (ICC ≥ 0.989), and the mean difference was less than 0.1 D. However, the ICC of the total average keratometry ranged from 0.808 to 0.952, and the difference was more than 0.43 D. The AL measured by ANTERION and IOLMaster 700 showed excellent agreement (ICC = 0.999), and the mean difference was 0.005 mm. The ANTERION and IOLMaster 700 did not obtain AL in six (12.8%) and three (6.4%) cases, respectively (P = 0.001 by Fisher's exact test). The CCT, ACD, and LT also showed excellent agreement (ICC > 0.9). CONCLUSIONS: The new SS-OCT-based devices, ANTERION, and CASIA2 showed a good agreement with IOLMaster 700 in measuring ocular biometry except for the total keratometry. The AL of ANTERION and IOLMaster 700 showed excellent agreement.

Improved accuracy of intraocular lens power calculation by preoperative management of dry eye disease.

BACKGROUND: To evaluate the effects of pretreatment for dry eye disease (DED) on the accuracy of intraocular lens (IOL) power calculation. METHODS: Patients who underwent uneventful cataract surgery were included in the study. IOL power was determined using the SRK/T and Barrett Universal II (Barrett) formulas. The patients were divided into non-pretreatment and pretreatment groups, and those in the pretreatment group were treated with topical 0.5% loteprednol etabonate and 0.05% cyclosporin A for 2 weeks prior to cataract surgery. Ocular biometry was performed in all groups within 2 days before surgery. The mean prediction error, mean absolute error (MAE), and proportions of refractive surprise were compared between the non-pretreatment and pretreatment groups at 1 month postoperatively. Refractive surprise was defined as MAE ≥ 0.75D. RESULTS: In a total of 105 patients, 52 (52 eyes) were in the non-pretreatment group and 53 (53 eyes) in the pretreatment group. The MAE was 0.42 ± 0.33, 0.38 ± 0.34 (SRK/T, Barrett) and 0.23 ± 0.19, 0.24 ± 0.19 in the non-pretreatment and pretreatment groups, respectively (p < 0.001/=0.008). The number of refractive surprises was also significantly lower in the pretreatment group. [non-pretreatment/pretreatment: 9/2 (SRK/T); 8/1 (Barrett); p = 0.024/0.016]. Pretreatment of DED was related to a reduction in postoperative refractive surprise. [SRK/T/Barrett: OR = 0.18/0.17 (95% CI: 0.05-0.71/0.05-0.60), p = 0.014/0.006]. CONCLUSIONS: The accuracy of IOL power prediction can be increased by actively treating DED prior to cataract surgery.

Inhibition of mTOR by Rapamycin Aggravates Corneal Epithelial Stem Cell Deficiency by Upregulating Inflammatory Response.

The mammalian target of rapamycin (mTOR) signaling is critical to the regulation of stem cell maintenance and function in a cell-type and context-dependent manner. However, the effects of mTOR signaling on corneal epithelial stem cells (CESCs) under inflammatory conditions are not clear. Here, we demonstrate that mTOR inhibition with rapamycin promotes apoptosis of CESCs in a mouse model of sterile inflammation-induced CESC deficiency, and thereby aggravates the disease. Apoptosis induction in CESCs by rapamycin is not due to direct effect of rapamycin on the cells, but mediated by increase in neutrophilic inflammation. The interleukin (IL)-10/signal transducer and activator of transcription 3 anti-inflammatory pathway was downregulated in a Toll-like receptor 2-independent manner after rapamycin treatment and IL-10 replenishment abrogated the effects of rapamycin on inflammation and CESC apoptosis. Hence, our data reveal that the mTOR signaling is implicated in the control of the pro-inflammatory and anti-inflammatory balance in the cornea and that mTOR inhibition with rapamycin is detrimental to CESCs by accelerating inflammation-induced collateral damage to the cells. Stem Cells 2019;37:1212-1222.

Long-term survival of full-thickness corneal xenografts from α1,3-galactosyltransferase gene-knockout miniature pigs in non-human primates.

BACKGROUND: We aimed to investigate (a) the long-term survival of corneal grafts from α1,3-galactosyltransferase gene-knockout miniature (GTKOm) pigs in non-human primates as a primary outcome and (b) the effect of anti-CD20 antibody on the survival of corneal grafts from GTKOm pigs as a secondary outcome. METHODS: Nine rhesus macaques undergoing full-thickness corneal xenotransplantation using GTKOm pigs were systemically administered steroid, basiliximab, intravenous immunoglobulin, and tacrolimus with (CD20 group) or without (control group) anti-CD20 antibody. RESULTS: Graft survival was significantly longer (P = .008) in the CD20 group (>375, >187, >187, >83 days) than control group (165, 91, 72, 55, 37 days). When we compared the graft survival time between older (>7- month-old) and younger (≤7-month-old) aged donor recipients, there was no significant difference. Activated B cells were lower in the CD20 group than control group (P = .026). Aqueous humor complement C3a was increased in the control group at last examination (P = .043) and was higher than that in the CD20 group (P = .014). Anti-αGal IgG/M levels were unchanged in both groups. At last examination, anti-non-Gal IgG was increased in the control group alone (P = .013). CONCLUSIONS: The GTKOm pig corneal graft achieved long-term survival when combined with anti-CD20 antibody treatment. Inhibition of activated B cells and complement is imperative even when using GTKO pig corneas.

Spontaneous regression of congenital corneal opacity.

PURPOSE: To determine the incidence of spontaneous regression of congenital corneal opacity (CCO) and identify clinical factors associated with the regression. METHODS: Medical records and anterior segment photographs were reviewed of 57 eyes in 35 patients with CCO that were not related to congenital glaucoma, tumors, infection, trauma, or metabolic disorders and were followed up without corneal transplantation for longer than one year at Seoul National University Hospital. Spontaneous regression of corneal opacity was defined as a decrease in corneal opacity significant enough for visual axis clearance. Data on demographics, systemic, and ocular characteristics were collected and compared between patients who had spontaneous regression of CCO and those who did not. RESULTS: Spontaneous regression of corneal opacity developed in 32 eyes (22 patients, 56.1%) out of 57 CCO eyes (35 patients) at the mean 8.2 ± 5.4 months of age (the median 6.7 months). Absence of combined ocular anomalies such as iris anomaly, lens opacity, and peripheral corneal vascularization was significantly associated with the regression of opacity. CONCLUSIONS: Corneal opacity can spontaneously regress in 56.1% of eyes with CCO during the first year of life. Careful follow-up with amblyopia management can be one of treatment options for CCO.

Comparative effects of various types of toric intraocular lenses on astigmatism correction.

BACKGROUND: Currently, various types of toric intraocular lenses (IOL) have been manufactured and can be divided into three types according to the location of correction component; front-toric IOL (correction on anterior IOL surface), back-toric IOL (correction on posterior IOL surface), and bi-toric IOL (correction on both anterior and posterior IOL surfaces). In this study, we aimed to investigate the effectiveness of reducing corneal astigmatism of either normal or post-penetrating keratoplasty (PKP) corneas according to the type of implanted toric IOLs. METHODS: Medical records were retrospectively reviewed in 370 patients who had undergone phacoemulsification with posterior chamber toric IOL insertion (front-toric IOL, back-toric IOL or bi-toric IOL). Subjects were divided into 2 groups; subjects who had no history of corneal disease with corneal astigmatism more than 1.00 diopters (D) (G1) and subjects who received previous PKP with all corneal sutures removed and had corneal astigmatism more than 1.25 D (G2). Preoperatively intended target from SRK/T was evaluated. Refractive astigmatism and its vector analysis (J0, J45), mean numerical error (MNE) and mean absolute error (MAE) were assessed at least a month after cataract surgery. RESULTS: Mean preoperative corneal astigmatisms were 2.2 D and 4.0 D in G1 and G2, respectively. There was significant reduction of mean postoperative refractive astigmatism to 0.89 D in G1 and to 2.33 D in G2. In G1, bi-toric IOL showed significantly more improved refractive astigmatism than back-toric IOL. In G2, no difference in refractive astigmatism according to toric IOL type was observed. While G2 showed no difference in MNE among toric IOLs, in G1, bi-toric IOL showed significant hyperopic shift compared to back-toric IOL. In both groups, there was no significant difference in MAE according to type of IOL. No postoperative complications were observed. CONCLUSION: Our study suggests that all types of toric IOL are beneficial in correcting astigmatism of normal and post-PKP corneas. Noticeably, bi-toric IOL showed significantly better results in refractive astigmatism than back-toric IOL in normal cornea. However, bi-toric IOL showed a more hyperopic shift compared to back-toric IOL. Among post-PKP corneas, all types of toric IOL showed similar results.

Retraction Note: Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

An amendment to this paper has been published and can be accessed via the original article.

Can Gut Microbiota Affect Dry Eye Syndrome?

Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren's syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation of autoimmune dry eye with gut microbiota. Herein, we review the current knowledge of how the gut microbiota interact with the immune system in homeostasis as well as its influence on rheumatic and ocular autoimmune diseases, and compare their characteristics with SS. Both rodent and human studies regarding gut microbiota in SS and environmental dry eye are explored, and the effects of prebiotics and probiotics on dry eye are discussed. Recent clinical studies have commonly observed a correlation between gut dysbiosis and clinical manifestations of SS, while environmental dry eye portrays characteristics in between normal and autoimmune. Moreover, a decrease in both the Firmicutes/Bacteroidetes ratio and genus Faecalibacterium have most commonly been observed in SS subjects. The presumable pathways forming the "gut dysbiosis-ocular surface-lacrimal gland axis" are introduced. This review may provide perspectives into the link between the gut microbiome and dry eye, enhance our understanding of the pathogenesis in autoimmune dry eye, and be useful in the development of future interventions.

Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model.

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

Effects of topical autologous serum on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs.

PURPOSE: To investigate the effects of topical autologous serum application on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs. METHODS: The patients who had corneal epitheliopathy because of preservative-containing anti-glaucoma eye drops were prospectively enrolled. The epitheliopathy was refractory to preservative-free artificial tear treatment. The patients topically applied 20% autologous serum to the eye eight times per day for 1 month. Baseline and one-month change in symptoms and signs were assessed by the Ocular Surface Disease Index (OSDI) questionnaire, tear film break-up time (TFBUT), Schirmer I values, corneoconjunctival staining scores, corneal sensitivity, InflammaDry® tear immunoassay, and tear cytokine profiles using a bead-based multiplex assay. RESULTS: A total of ten consecutive patients were enrolled between January and August 2018 and evaluated after one-month treatment with 20% autologous serum eye drops. Significant improvement was observed in symptoms (OSDI scores from 25.5 ± 20.9 to 10.5 ± 12.0; P = .039), TFBUT (from 3.1 ± 1.8 s to 5.4 ± 2.3 s; P = .025), corneoconjunctival staining scores (from 7.7 ± 1.8 to 1.8 ± 1.9 NEI scale; P = .005), corneal sensitivity (from 4.6 ± .9 cm to 5.8 ± .5 cm; P = .013), and metalloproteinase-9 levels (P = .013). There were no significant changes in Schirmer I values and tear cytokine levels on multiplex assays. Treatment-related side effects were not detected. CONCLUSIONS: Topical instillation of 20% autologous serum is an effective treatment for toxic corneal epitheliopathy associated with anti-glaucoma eye drops. TRIAL REGISTRATION NUMBER: KCT0003827.

Predictive biomarkers for graft rejection in pig-to-non-human primate corneal xenotransplantation.

We investigated the predictive biomarkers for graft rejection in pig-to-non-human primate (NHP) full-thickness corneal xenotransplantation (n = 34). The graft score (0-12) was calculated based on opacity, edema, and vascularization. Scores ≥ 6 were defined as rejection. NHPs were divided into two groups: (a) graft rejection within 6 months; and (b) graft survival until 6 months. In the evaluation of 2-week biomarkers, none of the NHPs showed rejection within 2 weeks and the 34 NHPs were divided into two groups: (a) entire rejection group (n = 16); and (b) survival group (n = 18). In the evaluation of 4-week biomarkers, four NHPs showing rejection within 4 weeks were excluded and the remaining 30 NHPs were divided into two groups: (a) late rejection group (n = 12); and (b) survival group (n = 18). Analysis of biomarker candidates included T/B-cell subsets, levels of anti-αGal IgG/M, donor-specific IgG/M from blood, and C3a from plasma and aqueous humor (AH). CD8+ IFNγ+ cells at week 2 and AH C3a at week 4 were significantly elevated in the rejection group. Receiver operating characteristic areas under the curve was highest for AH C3a (0.847) followed by CD8+ IFNγ+ cells (both the concentration and percentage: 0.715), indicating excellent or acceptable discrimination ability, which suggests that CD8+ IFNγ+ cells at week 2 and AH C3a at week 4 are reliable biomarkers for predicting rejection in pig-to-NHP corneal xenotransplantation.

Protocol for the first clinical trial to investigate safety and efficacy of corneal xenotransplantation in patients with corneal opacity, corneal perforation, or impending corneal perforation.

BACKGROUND: Xenotransplantation using fresh porcine corneas has been suggested as a feasible alternative to overcome the shortage of human donor corneas. Successful long-term survival of grafts without evidence of xenozoonosis in clinically applicable pig-to-non-human primate corneal transplantation model has brought researchers close to human clinical trials. Accordingly, we aimed to prepare a clinical trial protocol to conduct the first corneal xenotransplantation. METHODS: We developed the clinical trial protocol based on international consensus statement on conditions for undertaking clinical trials of corneal xenotransplantation developed by the International Xenotransplantation Society. Detailed contents of the protocol have been modified with reference to comments provided by ophthalmologists and multidisciplinary experts, including an infectionist, an organ transplantation specialist, a clinical pharmacologist, a neuropsychiatrist, a laboratory medicine doctor, and a microbiologist. RESULTS: Two patients with bilateral legal corneal blindness (best-corrected visual acuity ≤20/200 in the better eye and ≤20/1000 in the candidate eye) or with (impending) corneal perforation will be enrolled. During the screening period, participants and their family members will have two separate deep consideration periods before signing informed consent forms. Each patient will undergo corneal xenotransplantation using fresh corneas from Seoul National University miniature pigs. Commercially available immunosuppressants will be administered and systemic infection prophylaxis will be performed according to the program schedule. After transplantation, each patient will be monitored at a specialized clinic to investigate safety up to 2 years and efficacy up to 1 year. CONCLUSIONS: A detailed clinical trial protocol for the first corneal xenotransplantation reflecting the global guidelines is provided.

Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner.

The cornea is a transparent tissue devoid of blood and lymphatic vessels. However, various inflammatory conditions can cause hemangiogenesis and lymphangiogenesis in the cornea, compromising transparency and visual acuity. Mesenchymal stem/stromal cells (MSCs) have therapeutic potentials in a variety of diseases because of anti-inflammatory properties. Herein, we investigated the effects of MSCs on corneal angiogenesis using a model of suture-induced inflammatory corneal neovascularization. Data demonstrated that an intravenous administration of MSCs suppressed corneal inflammation and neovascularization, inhibiting both hemangiogenesis and lymphangiogenesis. MSCs reduced the levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, Tek, MRC1, and MRC2 in the cornea, which are expressed by pro-angiogenic macrophages. Moreover, the number of CD11b+ monocytes/macrophages in the cornea, spleen, peripheral blood, and draining lymph nodes was decreased by MSCs. Depletion of circulating CD11b+ monocytes by blocking antibodies replicated the effects of MSCs. Importantly, knockdown of tumor necrosis factor alpha (TNF-α)-stimulated gene/protein 6 (TSG-6) in MSCs abrogated the effects of MSCs in inhibiting corneal hemangiogenesis and lymphangiogenesis and monocyte/macrophage infiltration. Together, the results suggest that MSCs inhibit inflammatory neovascularization in the cornea by suppressing pro-angiogenic monocyte/macrophage recruitment in a TSG-6-dependent manner.

Effect of the retention ring-assisted continuous application of riboflavin in pulsed-light accelerated corneal collagen cross-linking on the progression of keratoconus.

BACKGROUND: To investigate the efficacy and safety of the retention ring-assisted continuous application of 0.1% riboflavin in pulsed-light accelerated corneal collagen cross-linking on the progression of keratoconus. METHODS: The medical records of 20 eyes of 18 patients with progressive keratoconus who received collagen cross-linking at Seoul National University Hospital were retrospectively reviewed. Isotonic 0.1% riboflavin was continuously applied for 10 min using an 8.0-mm retention ring before the irradiation and accelerated cross-linking was applied with 30-mW pulsed-ultraviolet light at a wavelength 365 nm for eight minutes (1 s on/1 s off; 30 mW/cm2, cumulative dose of 7 .2J/cm2) without further intermittent application of riboflavin. Visual acuity, refractive error, topographic index, corneal thickness, and endothelial cell density were evaluated before the operation and at 1, 3, 6, and 12 months. RESULTS: The best corrected visual acuity in logMAR improved from preoperative 0.43 to 0.17 in 12 months (p = 0.050). Maximum keratometry decreased from 51.8 D to 50.4 D at 6 months (p = 0.015) and 50.1 D at 12 months (p = 0.0003). Astigmatism decreased from preoperative 5.5 D to 4.1 D at 12 months (p < 0.0001). Thinnest corneal thickness decreased at three and 6 months but recovered in 12 months (p > 0.05). Endothelial cell density decreased at postoperative 1 month (p = 0.02) but gradually recovered in 12 months (p > 0.05). CONCLUSIONS: Retention ring-assisted continuous application of riboflavin for 10 minutes in pulsed-light accelerated cross-linking is a comparably safe and effective treatment for halting the progression of keratoconus in 12 months when compared to outcomes of the standard Dresden protocol shown in previous reports.

Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

BACKGROUND: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). METHODS: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. RESULTS: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. CONCLUSIONS: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. TRIAL REGISTRATION: KCT0002180 , retrospectively registered on 23 December 2016.