Purpose-To compare optic disc and retinal nerve fiber layer (RNFL) imaging methods to discriminate eyes with early glaucoma from normal eyes.Design-Retrospective, cross-sectional study. Methods-Setting:Tertiary care academic glaucoma center. Ninety-two eyes of 92 subjects (46 with early perimetric open-angle glaucoma and 46 controls) were studied. Diagnostic performance of optical coherence tomography (StratusOCT), scanning laser polarimetry (GDx-VCC), confocal laser ophthalmoscopy (Heidelberg Retinal Tomograph III), and qualitative assessment of stereoscopic optic disc photographs were compared. Outcome measures were areas under receiver operator characteristic curves (AUC) and sensitivities at fixed specificities. Classification and Regression Trees (CART) analysis was used to evaluate combinations of quantitative parameters.Results-The average (±SD) visual field mean deviation for glaucomatous eyes was −4.0±2.5 dB. Parameters with largest AUCs (±SE) were: average RNFL thickness for StratusOCT (0.96±0.02), nerve fiber indicator for GDx-VCC (0.92±0.03), FSM discriminant function for HRT III (0.91±0.03), and 0.97±0.02 for disc photograph evaluation. At 95% specificity, sensitivity of disc photograph evaluation (90%) was greater than GDx-VCC (p=0.05) and HRT III (p=0.002), but not significantly different than that of StratusOCT (p>0.05). Combination of StratusOCT average RNFL thickness and HRT III cup/disc area with CART produced a sensitivity of 91% and specificity of 96% Conclusions-StratusOCT, GDx-VCC, and HRT III performed as well as, but not better than, qualitative evaluation of optic disc stereophotographs for detection of early perimetric glaucoma. The combination of StratusOCT average RNFL thickness and HRT III cup/disc area ratio provided a high diagnostic precision.

Ubiquitin-dependent proteolysis of cyclins plays a critical role in cell cycle progression and tumorigenesis. We examined the expression of ubiquitin-conjugating enzyme E2C (UBE2C) during progression from Barrett's metaplasia to esophageal adenocarcinoma (EA) and the effects of targeting this enzyme on EA-derived cell lines. Using oligonucleotide microarrays UBE2C expression was elevated in 73% (11 of 15) of EAs relative to Barrett's metaplasia. Tissue microarray showed elevated UBE2C in 70% (7 of 10) of dysplastic samples and in 87% (58 of 67) of tumors relative to metaplastic samples. Transfection of dominant-negative UBE2C into Seg-1 cells decreased proliferation (P = .04) and increased mitotic arrest compared to vector controls (63.5% vs 6.8%; P < .001). Transfection of UBE2C small interfering RNA also caused inhibiton of cell proliferation and distortion of the cell cycle, with maximal increase of G(2) cells (155% of mock cells) at 72 hours and of S-phase cells (308% of mock cells) at 24 hours. Treatment of Seg-1 cells with the proteasome inhibitor MG-262 (1 nM-1 microM) showed decreased proliferation (P = .02). EA-derived cells expressing UBE2C are sensitive to treatment with MG-262 and to silencing of UBE2C, suggesting that patients with EAs overexpressing UBE2C may benefit from agents targeting this ubiquitin-conjugating enzyme.

The L-type amino acid transporter-1 (LAT-1) has been associated with tumor growth. Using cDNA microarrays, overexpression of LAT-1 was found in 87.5% (7/8) of esophageal adenocarcinomas relative to 12 Barrett's samples (33% metaplasia and 66% dysplasia) and was confirmed in 100% (28/28) of Barrett's adenocarcinomas by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed LAT-1 staining in 37.5% (24/64) of esophageal adenocarcinomas on tissue microarray. LAT-1 also transports the amino acid-related chemotherapeutic agent, melphalan. Two esophageal adenocarcinoma and one esophageal squamous cell line, expressing LAT-1 on Western blot analysis, were sensitive to therapeutic doses of melphalan (P <.001). Simultaneous treatment with the competitive inhibitor, BCH [2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid], decreased sensitivity to melphalan (P <.05). In addition, confluent esophageal squamous cultures were less sensitive to melphalan (P <.001) and had a decrease in LAT-1 protein expression. Tumors from two esophageal adenocarcinoma cell lines grown in nude mice retained LAT-1 mRNA expression. These results demonstrate that LAT-1 is highly expressed in a subset of esophageal adenocarcinomas and that Barrett's adenocarcinoma cell lines expressing LAT-1 are sensitive to melphalan. LAT-1 expression is also retained in cell lines grown in nude mice providing a model to evaluate melphalan as a chemotherapeutic agent against esophageal adenocarcinomas expressing LAT-1.

Laser-assisted in-situ keratomileusis (LASIK) is one of the most commonly performed refractive procedures with excellent visual outcomes. Dry eye syndrome is one of the most frequently seen complications after LASIK, with most patients developing at least some mild dry eye symptoms postoperatively. To achieve improved visual outcomes and greater patient satisfaction, it is essential to identify patients prone to dry eyes preoperatively, and initiate treatment early in the course. Enhanced understanding of the pathophysiology of post-LASIK dry eye will help advance our approach to its management.

Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.

Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.

How will you respond when a patient asks, “Doctor, what can I do to prevent myself from going blind from glaucoma like mom?”. There is optimism that genetic profiling will help target patients to individualized treatments based on validated disease risk alleles, validated pharmacogenetic markers and behavioral modification. Personalized medicine will become a reality through identification of disease and pharmacogenetic markers, followed by careful study of how to employ this information in order to improve treatment outcomes. With advances in genomic technologies, research has shifted from the simple monogenic disease model to a complex multigenic and environmental disease model to answer these questions. Our challenges lie in developing risk models that incorporate gene–gene interactions, gene copy-number variations, environmental interactions, treatment effects and clinical covariates.

PurposeChromosome 22q11.2 micro-duplication syndrome (MDS), is a rare autosomal dominant condition, with a highly variable phenotype that ranges from unremarkable and asymptomatic, to fatal due to cardiovascular defects. Hypertelorism, downslanting palpebral fissures, superior displacement of the eyebrows, and ptosis are the most commonly reported ocular manifestations. Here, we report a newborn with bilateral exposure, entropion, and corneal ulceration related to 22q11.2 MDS.ObservationA newborn girl presented with bilateral upper eyelid entropion, bilateral lower eyelid ectropion, and lagophthalmos. She subsequently developed bilateral corneal ulcers. Topical antibacterial drops, bandage contact lenses, medroxyprogesterone 1%, and fluorometholone 0.1%, together with partial tarsorrhaphy and correction of eyelid malposition, were used to treat the ulcers and address the underlying issues of exposure and entropion. Genetic testing revealed chromosome 22q11.2.MDS; further evaluation revealed systemic manifestations of this syndrome. The ocular surface healed well with gradual improvement of corneal opacification as well as bilateral partial tarsorrhaphy.Conclusion and importanceThis report is the first that describes a newborn with 22q11.2 MDS presenting with sight-threatening corneal ulceration. Entropion, ectropion, and lagophthalmos were identified and treated, allowing for healing of the corneal surface. Genetic testing revealed a syndrome not known to be associated with eyelid abnormalities and corneal ulceration, but with other important systemic and ocular implications. Bilateral partial tarsorrhaphy should not be excluded as a treatment option for infants who fail more conservative measures for the treatment of exposure.