Inhibition of Rho-associated protein kinase activity enhances oxidative phosphorylation to support corneal endothelial cell migration.

Corneal endothelial cell (CEC) dysfunction causes corneal edema and severe visual impairment that require transplantation to restore vision. To address the unmet need of organ shortage, descemetorhexis without endothelial keratoplasty has been specifically employed to treat early stage Fuchs endothelial corneal dystrophy, which is pathophysiologically related to oxidative stress and exhibits centrally located corneal guttae. After stripping off central Descemet's membrane, rho-associated protein kinase (ROCK) inhibitor has been found to facilitate CEC migration, an energy-demanding task, thereby achieving wound closure. However, the correlation between ROCK inhibition and the change in bioenergetic status of CECs remained to be elucidated. Through transcriptomic profiling, we found that the inhibition of ROCK activity by the selective inhibitor, ripasudil or Y27632, promoted enrichment of oxidative phosphorylation (OXPHOS) gene set in bovine CECs (BCECs). Functional analysis revealed that ripasudil, a clinically approved anti-glaucoma agent, enhanced mitochondrial respiration, increased spare respiratory capacity, and induced overexpression of electron transport chain components through upregulation of AMP-activated protein kinase (AMPK) pathway. Accelerated BCEC migration and in vitro wound healing by ripasudil were diminished by OXPHOS and AMPK inhibition, but not by glycolysis inhibition. Correspondingly, lamellipodial protrusion and actin assembly that were augmented by ripasudil became reduced with additional OXPHOS or AMPK inhibition. These results indicate that ROCK inhibition induces metabolic reprogramming toward OXPHOS to support migration of CECs.

Development and validation of an intuitive biomechanics-based method for intraocular pressure measurement: a modal analysis approach.

BACKGROUND: Current intraocular pressure (IOP) measurements based on non-contact tonometry are derived from statistics-driven equations and lack biomechanical significance, which often leads to under-estimation in post-refractive surgery cornea. This study aims to introduce and validate modal analysis-derived intraocular pressure (mIOP) as a novel method generated through Legendre-based modal decomposition of the anterior corneal contour; it provides an accurate and intuitive IOP measurement from an energy-based perspective. METHODS: This retrospective study included 680 patients. Healthy participants were divided into reference (n = 385) and validation (n = 142) datasets, and the others underwent either femtosecond-assisted laser in situ keratomileusis (FS-LASIK, n = 58) or transepithelial photorefractive keratectomy (TPRK, n = 55). Corneal curvature of the right eyes was extracted from raw serial cross-sectional images of the cornea generated by Corvis ST, a noncontact tonometer with a high-speed Scheimpflug-camera. Legendre expansion was then applied to the corneal curvature to obtain the modal profiles (i.e., temporal changes of the coefficient for each basis polynomial [modes]). Using the reference dataset, feature selection on the modal profiles generated a final mIOP model consisting of a single parameter: total area under curve (frames 1-140) divided by the area under curve of the rising phase (frames 24-40) in the fourth mode, i.e. the M4 ratio. Validation was performed in both the healthy validation and postoperative datasets. IOP-Corvis, pachymetry-corrected IOP, biomechanically corrected IOP, and mIOP values were compared. For the FS-LASIK and TPRK groups, pairwise postoperative IOP changes were analyzed through repeated measures analysis of variance, and agreement was examined through Bland-Altman analysis. Using a finite element analysis based three-dimensional model of the human cornea, we further compared the M4 ratio with the true intraocular pressure within the physiological range. RESULTS: The M4 ratio-based mIOP demonstrated weak to negligible association with age, radius of corneal curvature, and central corneal thickness (CCT) in all validation analyses, and performed comparably with biomechanically corrected IOP (bIOP) in the refractive surgery groups. Both remained nearly constant postoperatively and were not influenced by CCT changes. Additionally, M4 ratio accurately represented true intraocular pressure in the in silico model. CONCLUSIONS: mIOP is a reliable IOP measurement in healthy and postrefractive surgery populations. This energy-based, ratio-derived approach effectively filters out pathological, rotational, misaligned movements and serves as an interpatient self-calibration index. Modal analysis of corneal deformation dynamics provides novel insights into regional corneal responses against pressure loading.

Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy.

BACKGROUND: We investigated whether antiplatelet/anticoagulant (APAC) therapy can protect patients with type 2 diabetes mellitus (T2DM) from the development or progression of diabetic retinopathy (DR). METHODS: This is a retrospective cohort study using Longitudinal Health Insurance Database in Taiwan. A total of 73,964 type 2 diabetic patients older than 20 years old were included. Hazard ration (HR) of non-proliferative DR (NPDR), proliferative DR (PDR), and diabetic macular edema (DME) were analyzed with APAC usage as a time-dependent covariate. Age, sex, comorbidities, and medicines were further adjusted in a multi-variable model. Contributions of respective APAC was investigated with sensitivity analysis. RESULTS: Compared with nonusers, APAC users had a lower cumulative incidence of NPDR (P < 0.001), overall incidence of NPDR (10.7 per 1000 person-years), and risk of developing NPDR (adjusted HR = 0.78, 95% CI = 0.73-0.83). However, no significant differences were observed between APAC users and nonusers in the risks of PDR or DME. Hypertension, diabetic nephropathy and diabetic neuropathy were risk factors for NDPR development, while heart disease, cardiovascular disease, peripheral arterial occlusive disease, and statin usage were covariates decreasing NPDR development. Aspirin and Dipyridamole showed significant protection against NPDR development. Clopidogrel, Ticlopidine, and warfarin showed enhanced protection in combination with aspirin usage. CONCLUSIONS: APAC medications have a protective effect against NPDR development. Diabetic patients benefit from single use of aspirin or dipyridamole on prevention of NPDR.

Influence of parental behavior on myopigenic behaviors and risk of myopia: analysis of nationwide survey data in children aged 3 to 18 years.

BACKGROUND: Preventive parental behavior may play an important role in the outcomes of children's myopia. We investigated associations between parental behavior and children's myopia status and daily activities using data from the most recent myopia survey in Taiwan. METHODS: In total, 3845 children aged 3 to 18 years who completely responded to the questionnaire were included (total score ranging from 0 to 75). A score of ≥ 50 was considered to indicate beneficial parental behavior. Time allocation data for near-work activities, using electronic devices, and outdoor activities were collected using a separate self-reported questionnaire. Associations between beneficial parental behavior and children's myopia status and activity patterns were analyzed and stratified by school level. RESULTS: Beneficial parental behavior was positively associated with children's myopia in the overall samples [adj. odds ratio (OR): 1.31, 95% confidence interval (CI): 1.08-1.59, p = 0.006)] and at the elementary school level (adj. OR: 1.43, 95% CI: 1.11-1.83, p = 0.005). However, a negative association with high myopia was observed in the overall samples (adj. OR: 0.71, 95% CI: 0.50-0.99, p = 0.049) and high school level (adj. OR: 0.62, 95% CI: 0.41-0.92, p = 0.02). Beneficial parental behavior was associated with less time spent on near work (≥ 180 min/day) and electronic device use (≥ 60 min/day), but not with outdoor activities. CONCLUSION: In Taiwan, children's myopia is associated with higher rate of parents' beneficial behaviors, which suggests that regular vision surveillance is necessary to promote better parental behavior toward children's eye care. Certain parental practices may influence children's behavior pattern and reduce the risk of children's high myopia development in the long run.

Refractive outcomes of femtosecond laser-assisted cataract surgery with arcuate keratotomy and standard phacoemulsification with toric intraocular lens implantation.

PURPOSE: Femtosecond laser arcuate keratotomy (FS-AK) and toric intraocular lens (IOL) implantation are effective for the correction of eyes with corneal astigmatism. In this study, the postoperative refractive outcomes of patients receiving femtosecond laser-assisted cataract surgery (FLACS) with FS-AK and patients receiving standard phacoemulsification with toric IOL implantation were evaluated. METHODS: This retrospective study reviewed the postoperative outcomes of patients undergoing FLACS with FS-AK (the FS-AK group) and patients undergoing standard phacoemulsification with toric IOL implantation (the toric IOL group). The main outcome measures were uncorrected and corrected visual acuities, keratometric and refractive astigmatism, and vector analysis. RESULTS: The FS-AK group included 41 eyes with preoperative keratometric astigmatism of - 1.64 ± 0.42 diopters (D), and the toric IOL group included 53 eyes with preoperative keratometric astigmatism of - 2.29 ± 0.91 D (P < 0.001). Postoperative refractive astigmatism was comparable between the two groups. Compared with the FS-AK group, postoperative uncorrected visual acuity was significantly better (P = 0.005) and corrected visual acuity was marginally better in the toric IOL group (P = 0.051). The absolute angles of error were 9.95° ± 9.57° and 5.08° ± 4.94° (P = 0.02) in the FS-AK and the toric IOL groups, respectively. CONCLUSION: Both FLACS with FS-AK and standard phacoemulsification with toric IOL implantation are safe and effective methods for astigmatism correction during cataract surgery. Standard phacoemulsification with toric IOL implantation achieves better visual acuity than FLACS with FS-AK at the 6-month follow-up.

Evolution of the Prevalence of Myopia among Taiwanese Schoolchildren: A Review of Survey Data from 1983 through 2017.

PURPOSE: The aim of this study was to evaluate the changes in the prevalence of myopia in Taiwanese schoolchildren over the past few decades and to analyze the risk factors for myopia. DESIGN: Analysis of 8 consecutive population-based myopia surveys conducted from 1983 through 2017. PARTICIPANTS: An average of 8917 (5019-11 656) schoolchildren 3 to 18 years of age were selected using stratified systematic cluster sampling or by probability proportional to size sampling. METHODS: All participants underwent complete ophthalmic evaluations. Three drops of 0.5% tropicamide were used to obtain the cycloplegic refractive status of each participant. Questionnaires were used to acquire participant data from the 1995, 2005, 2010, and 2016 surveys. MAIN OUTCOME MEASURES: Prevalence of myopia (spherical equivalence of ≤-0.25 diopter [D]) and high myopia (≤-6.0 D) was assessed. Multivariate analyses of risk factors were conducted. RESULTS: The prevalence of myopia among all age groups increased steadily. From 1983 through 2017, the weighted prevalence increased from 5.37% (95% confidence interval [CI], 3.50%-7.23%) to 25.41% (95% CI, 21.27%-29.55%) for 7-year-olds (P = 0.001 for trend) and from 30.66% (95% CI, 26.89%-34.43%) to 76.67% (95% CI, 72.94%-80.40%) for 12-year-olds (P = 0.001 for trend). The prevalence of high myopia also increased from 1.39% (95% CI, 0.43%-2.35%) to 4.26% (95% CI, 3.35%-5.17%) for 12-year-olds (P = 0.008 for trend) and from 4.37% (95% CI, 2.91%-5.82%) to 15.36% (95% CI, 13.78%-16.94%) for 15-year-olds (P = 0.039 for trend). In both the 2005 and 2016 survey samples, children who spent less than 180 minutes daily on near-work activities showed significantly lower risks for myopia developing (<60 minutes: odds ratio [OR], 0.48 and 0.56; 60-180 minutes: OR, 0.69 and 0.67). In the 2016 survey, spending more than 60 minutes daily on electronic devices was associated significantly with both myopia and high myopia (OR, 2.43 and 2.31). CONCLUSIONS: The prevalence of myopia among schoolchildren increased rapidly from 1983 through 2017 in Taiwan. The major risk factors are older age and time spent on near-work activities. Use of electronic devices increased the amount of time spent on near-work and may increase the risk of developing myopia.

Exploring a peptidomimetic approach of N-cadherin in modulating fibroblast growth factor receptor signaling for corneal endothelial regeneration.

Endothelial rejection and a critical shortage of corneal transplants present an unmet medical need in corneal regeneration research area. Although basic fibroblast growth factor (bFGF) is a potent mitogenic factor for corneal ex vivo expansion, it is also a morphogen eliciting unfavorable endothelial-mesenchymal transition (EnMT) of corneal endothelial cells. A pharmacological reagent that retains the beneficial proliferative effect while lacking the EnMT effect of bFGF would be of great potential in corneal regeneration. In present study, we demonstrated that bFGF not only activated the canonical fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase pathway, but also further upregulated matrix metalloproteinase activity to cleave N-cadherin into N-terminus and C-terminus fragments, which activated the classical FGFR1 tyrosine kinase pathway and a cryptic ß-catenin pathway to affect corneal proliferation and EnMT, respectively. We generated the synthetic peptides resembling a critical motif in the ectodomain of N-cadherin and found these peptides enhanced downstream proliferative signaling of FGFR1 but without seemingly EnMT effect. The potential of these peptides can be demonstrated on both ex vivo cell culture and in vivo rat cryo-injury model. Our study indicated this peptidomimetic approach of N-cadherin can stimulate corneal regeneration and offer a promising therapeutic option to treat corneal endothelial dysfunction.

Heat-shock-induced tyrosinase gene ablation with CRISPR in zebrafish.

Tyrosinase (TYR) converts L-tyrosine into 3,4-dihydroxyphenylalanine (L-DOPA) and L-DOPA into L-dopaquinone, which can produce melanin pigment. The abrogation of the functional activity of TYR can result in albino skin and eye diseases because of a deficiency in melanin pigment production. In this study, we developed and characterized an inducible knockout TYR platform comprising the heat-inducible heat-shock-promoter-70-driving CRISPR/Cas9 system and a zU6-promoter-driving tyr single guide RNA (sgRNA) system to investigate the temporal expression of TYR genes. To overcome the difficulty of identifying zebrafish germline integrations and facilitate the observation of Cas9 expression, heart-specific cmlc2:enhanced green fluorescent protein (EGFP; used to confirm tyr sgRNA expression) and two selectable markers (P2A-mCherry and internal ribosomal entry site-EGFP) were applied in our system. Heat shock treatment administered to Cas9 transgenic embryos induced mCherry or EGFP fluorescence expression throughout the embryos' bodies, and Cas9 protein was detected 1 h after heat shock treatment. Mutations were created by direct injection and line crossing, which led to mosaic and complete depigmentation phenotypes in approximately 50% and 100% of the embryos, respectively. Using our system, conditional TYR knockout in zebrafish was achieved efficiently and simply.

Genome-Wide Association Study in Asians Identifies Novel Loci for High Myopia and Highlights a Nervous System Role in Its Pathogenesis.

PURPOSE: To identify novel susceptibility loci for high myopia. DESIGN: Genome-wide association study (GWAS) followed by replication and meta-analysis. PARTICIPANTS: A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls). METHODS: We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses. MAIN OUTCOME MEASURES: We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study. RESULTS: We identified 9 loci with genome-wide significance (P < 5.0 × 10-8). Three loci were previously reported myopia-related loci (ZC3H11B on 1q41, GJD2 on 15q14, and RASGRF1 on 15q25.1), and the other 6 were novel (HIVEP3 on 1p34.2, NFASC/CNTN2 on 1q32.1, CNTN4/CNTN6 on 3p26.3, FRMD4B on 3p14.1, LINC02418 on 12q24.33, and AKAP13 on 15q25.3). The GO analysis revealed a significant role of the nervous system related to synaptic signaling, neuronal development, and Ras/Rho signaling in the pathogenesis of high myopia. CONCLUSIONS: The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level.

Clinical features and outcomes of Acanthamoeba keratitis in a tertiary hospital over 20- year period.

PURPOSE: To analyze the outcomes of Acanthamoeba keratitis (AK) in terms of different clinical presentations in a tertiary hospital in Taiwan over a 20- year period. METHODS: This is a retrospective case series. Patients with AK diagnosed at the National Taiwan University Hospital between January 1996 and December 2015 were identified. A diagnosis of AK was made on the basis of positive Acanthamoeba smear/cultures or pathological identification of Acanthamoeba cysts on keratoplasty specimens. Patient demographics, clinical presentations, treatment courses, and final visual outcomes were collected and analyzed. Visual acuity, postoperative complications and graft survivals were measured as outcomes. RESULTS: Of the 62 patients with AK in our study, 64.5% were medically treated while 35.5% underwent surgical treatment. In those with ring infiltrate, 52.4% patients could be successfully treated with medications. In eyes receiving penetrating keratoplasty, postoperative complications were more common in therapeutic penetrating keratoplasty (TPK) than those in optical penetrating keratoplasty (OPK) group (82.4% versus 40%, p = 0.04). The graft size was larger in TPK than that in OPK group (8.56 versus 7.83 mm, p = 0.002). Furthermore, post-operative glaucoma, which was the major complication, was found to be associated with larger graft size (p = 0.02) and dilated pupil/iris atrophy (p = 0.01). CONCLUSION: Even in advanced cases with ring infiltrate, eradication of infection with anti-amoebic drugs is possible. In those requiring keratoplasty, the surgical timing should be made meticulously considering graft size and signs of dilated pupil/iris atrophy in terms of post-operative glaucoma.

Therapeutic penetrating keratoplasty for microbial keratitis in Taiwan from 2001 to 2014.

PURPOSE: To study the surgical outcome of therapeutic penetrating keratoplasty (TPK) for medically uncontrolled microbial keratitis at a tertiary hospital in Taiwan over a 14-year period. METHODS: This is a retrospective case series study. Patients who underwent TPK at National Taiwan University Hospital in 2001-2014 were included. Patients were divided into 3 diagnostic groups: bacterial keratitis, fungal keratitis, and acanthamoeba keratitis. Each of the following criteria was evaluated: graft clarity at 1 month and 1 year postoperatively, cure of the disease, and anatomical success rate. RESULTS: A total of 107 TPKs were included. TPK eradicated the infection in 57/62 (91.9%) of bacterial keratitis, 33/41 (80.5%) of fungal keratitis, and 9/10 (90.0%) of acanthamoeba keratitis. 22/57 grafts (38.6%) of bacterial keratitis, 22/38 grafts (57.9%) of fungal keratitis, and 5/10 grafts (50.0%) of acanthamoeba keratitis remained clear at 1 year postoperatively. The 1-year graft survival rate did not significantly differ among these 3 groups. The leading causes of graft failure were late endothelial decompensation and graft reinfection. A higher percentage of graft clarity was achieved in grafts <8.5 mm in diameter than in larger grafts (55.4% vs. 31.4%, P = 0.027). Of the 14 patients with endophthalmitis at the time of TPK, the infection was successfully treated in 13 patients except 1 patient required evisceration. CONCLUSION: TPK is valuable in the management of medically uncontrolled microbial keratitis, although the 1-year graft survival rate is unsatisfactory. TPK combined with intravitreal antibiotics and vitrectomy is also a beneficial treatment strategy for patients with endophthalmitis secondary to microbial keratitis.

Dermatologic tacrolimus ointment on the eyelids for steroid-refractory vernal keratoconjunctivitis.

PURPOSE: The study aims to evaluate the therapeutic effects of dermatologic tacrolimus ointment on eyelids to treat refractory vernal keratoconjunctivitis (VKC). METHOD: This institutional study examined the effects of steroid treatment for 10 patients diagnosed with severe VKC refractory to steroid treatment. Patients received 0.1% dermatologic topical tacrolimus treatment on their eyelids once or twice daily for concomitant atopic dermatitis. The therapeutic outcomes were evaluated according to change in severity of clinical findings recorded with serial external ocular photography and change in requirement for steroid treatment. RESULTS: Clinical signs and symptoms improved substantially after tacrolimus treatment. Significant reduction in size of papillae, decrease of discharge, improvement in hyperemia, and shield ulcer healing with re-epithelization were observed in all patients. Six out of 10 (60%) patients did not receive steroid treatment. Long-term maintenance of tacrolimus was required to prevent episodic exacerbation. Patients' only treatment-related complaints were of mild burning sensations during medication application to eyelids, and this sensation disappeared a few days after treatment. CONCLUSIONS: Application of 0.1% dermatologic tacrolimus ointment to eyelids is effective and safe in the treatment of refractory VKC in patients with concomitant atopic dermatitis. This treatment may serve as a substitute for or decrease the requirement of steroid treatment.

Epibulbar complex choristoma with simultaneous involvement of eyelid: a case report.

BACKGROUND: Epibulbar complex choristoma, a rare congenital epibulbar tumor, has many diverse forms. Reviewing the literature, it can present clinically as either a circumferential or isolated epibulbar mass, limbal tumor, lateral canthal mass, aggregate of ectopic cilia in the upper eyelid, eyelid mass mimicking chalazion, or lacrimal caruncle mass. The management depends on the extent of involvement, the risk of amblyopia, and cosmetic concerns. Here, we report an atypical presentation of epibulbar complex choristoma with simultaneous eyelid involvement. CASE PRESENTATION: A 1-month-old full-term boy was brought to our clinic with congenital epibulbar mass of the right eye with simultaneous eyelid involvement. Dilated fundus examination was unremarkable. Survey for linear nevus sebaceous Jadassohn was negative. Due to concerns of possible amblyopia and cosmetics, lamellar keratectomy, sclerotomy, and conjunctivoplasty were performed to remove the epibulbar lesion. The eyelid defect was reconstructed with 6-0 Vicryl sutures. Histopathological examination reported complex choristoma. Upon three-year follow-up, low astigmatism and favorable cosmetics results were achieved. CONCLUSIONS: Congenital complex choristoma can present clinically as an epibulbar mass with eyelid involvement. The management depends on the extent of involvement, the risk of amblyopia, and cosmetic concerns. The method of eyelid reconstruction should be tailored according to the residual eyelid defect.

Clinicopathologic correlation of ocular surface squamous neoplasia from a university hospital in North Taiwan 1994 to 2014.

BACKGROUND/PURPOSE: To describe the clinical and histologic characteristics of ocular surface squamous neoplasia (OSSN) and evaluate factors significant in recurrence at a university hospital in North Taiwan. METHODS: Patient charts, clinical features, and pathology records were retrospectively reviewed in patients with pathology-proved OSSN from January, 1994 to December, 2014. Clinicopathologic correlation was analyzed. RESULTS: Thirty-six patients were recruited. Mean age was 63.4 ± 13.0 (ranging from 23 to 87) years old. OSSN was predominant in men (21/36). Clinical appearances included papilliform in 17 eyes, gelatinous in 11 eyes, leukoplakic in 3 eyes, and 5 eyes in corneal intraepithelial neoplasia (CIN). Of 31 conjunctival OSSN, there were 4 in CIN I, 11 in CIN II, 13 in CIN III, and 3 in squamous cell carcinoma. Superior location was associated with higher-grade OSSN. Although statistical analysis was not significant, papilliform and multifocal lesions showed a trend of high-grade OSSN. The stages of tumor were 4, 5, 26, and 1 eye(s) in T1 to T4, respectively. Recurrence of disease occurred in 9 cases (25%) with mean recurrence time of 20.6 (range: 4 to 65) months. Multifocal lesion has a higher tendency for recurrence. CONCLUSION: Superior location was associated with high-grade OSSN, and papilliform OSSN might have a tendency of severe and invasive lesions. Multifocal lesions might be associated with higher-grade OSSN and higher recurrence rates.

Mini-Scleral Lenses for Correction of Refractive Errors After Radial Keratotomy.

OBJECTIVE: To evaluate the factors affecting clinical outcomes of correcting cumulative refractive errors or irregular astigmatism after radial keratotomy (RK) using mini-scleral lenses. METHODS: We retrospectively analyzed 36 eyes receiving mini-scleral lenses after RK from July 2011 to June 2016. Analyses included age, refractive errors, best spectacle-corrected visual acuity (BSCVA), best contact lens-corrected visual acuity (BCLCVA), topographic indices, RK treatment zone diameter (TZD), power difference (PrD) within the RK treatment zone, and decentration distance (DD) of the RK treatment zone center. An increase of three lines or more of Snellen visual acuity was considered a successful fitting. RESULTS: Of the eyes fitted with mini-scleral lenses, the BCLCVA (logarithm of the minimum angle of resolution [logMAR] 0.19±0.22) was significantly better than the BSCVA (logMAR 0.47±0.30). Twenty-three patients (64%) had a successful fitting. There was no statistically significant difference between successful and unsuccessful fittings with regard to age, prefitting refractive error, BSCVA, corneal astigmatism, simulated steep/flat K values, surface regularity index, TZD, or PrD. However, successful fittings had better centration of treatment zones with an average DD of 0.54±0.44 mm compared with a DD of 0.92±0.53 mm in the unsuccessfully fitted eyes. In addition, our case series showed that there was a negative impact on fitting outcomes in the presence of small central clear zones resulting from central incisions or scars. CONCLUSIONS: Although decentration of the RK treatment zone and small central clear zones were related to less optimal fitting results, mini-scleral lenses are a feasible option to correct cumulative refractive errors and irregular astigmatism in post-RK patients.

Analysis of SmartPlug Insertion-Related Complications.

PURPOSE: To evaluate the complications and the treatment results of SmartPlug-related complications. METHODS: Retrospective review of all patients from a single medical hospital who received SmartPlug (Medennium, Inc., Irvine, CA) insertions from October 2007 to February 2014. All patients who developed SmartPlug-related canaliculitis and pyogenic granuloma were analyzed. Lacrimal irrigation with antibiotics was performed in most patients. RESULTS: Six hundred thirty-one eyes received SmartPlug insertion and 18 eyes developed SmartPlug-related complications (14 canaliculitis and 4 pyogenic granuloma). The mean time interval from insertion to development of the complications is 3.0 (0.5-6.9) years. Sixteen eyes received lacrimal irrigation with antibiotics, and all the eyes showed improvement without recurrence. The other two eyes had recurrence of granuloma pyogenica only after surgical excision. CONCLUSIONS: SmartPlug-related complications, including canaliculitis and granuloma pyogenica, required long-term follow-up. Most of the complications can be cured by lacrimal irrigation of antibiotics.

Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity.

Conjunctival goblet cells primarily synthesize mucins to lubricate the ocular surface, which is essential for normal vision. Notch signaling has been known to associate with goblet cell differentiation in intestinal and respiratory tracts, but its function in ocular surface has yet to be fully characterized. Herein, we demonstrate that conditional inhibition of canonical Notch signaling by expressing dominant negative mastermind-like 1 (dnMaml1) in ocular surface epithelia resulted in complete suppression of goblet cell differentiation during and subsequent to development. When compared with the ocular surface of wild-type mice (OS(Wt)), expression of dnMaml1 at the ocular surface (OS(dnMaml1)) caused conjunctival epithelial hyperplasia, aberrant desquamation, failure of Mucin 5ac (Muc5ac) synthesis, subconjunctival inflammation and epidermal metaplasia in cornea. In addition, conditional deletion of Notch1 from the ocular surface epithelia partially recapitulated OS(dnMaml1) phenotypes. We have demonstrated that N1-ICD (Notch1 intracellular domain) transactivated the mouse Krüppel-like factor 4 (Klf) promoter and that Klf4 directly bound to and significantly potentiated the Muc5ac promoter. By contrast, OS(dnMaml1) dampened Klf4 and Klf5 expression, and diminished Muc5ac synthesis. Collectively, these findings indicated that Maml-mediated Notch signaling plays a pivotal role in the initiation and maintenance of goblet cell differentiation for normal ocular surface morphogenesis and homeostasis through regulation of Klf4 and Klf5.

Inhibition of matrix metalloproteinase activity reverses corneal endothelial-mesenchymal transition.

Ex vivo culture or regeneration of corneal endothelial cells often is subjected to gradual endothelial-mesenchymal transition and loss of function. Here, we found that during ex vivo culture, bovine corneal endothelial cells underwent endothelial-mesenchymal transition and had an up-regulated expression and activity of matrix metalloproteinases. Inhibition of matrix metalloproteinase activity in confluent bovine corneal endothelial cells decreased the level of endothelial-mesenchymal transition regulators: snail and slug. The phosphorylation and degradation of the key Wnt signaling pathway modulator active ß-catenin also were accelerated with the broad-spectrum matrix metalloproteinase inhibitor Marimastat, which may result from decreased N-cadherin shedding and increased intact N-cadherin molecules on the cell membrane. Intracameral injection of Marimastat also suppressed basic fibroblast growth factor-induced endothelial-mesenchymal transition in a rat corneal endothelium cryo-injury model and significantly diminished the corneal edema. Our study indicated that inhibition of matrix metalloproteinase activity can reverse endothelial-mesenchymal transition and preserve the function of corneal endothelial cells both during ex vivo culture and in vivo. This may offer a potential therapeutic target in regenerative medicine for the treatment of corneal endothelial dysfunctions.