Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy.

Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related genetically complex disease characterized by increased oxidative DNA damage and progressive degeneration of corneal endothelial cells (HCEnCs). FECD has a greater incidence and advanced phenotype in women, suggesting a possible role of hormones in the sex-driven differences seen in the disease pathogenesis. In this study, catechol estrogen (4-OHE2), the byproduct of estrogen metabolism, induced genotoxic estrogen-DNA adducts formation, macromolecular DNA damage, and apoptotic cell death in HCEnCs; these findings were potentiated by menadione (MN)-mediated reactive oxygen species (ROS). Expression of NQO1, a key enzyme that neutralizes reactive estrogen metabolites, was downregulated in FECD, indicating HCEnC susceptibility to reactive estrogen metabolism in FECD. NQO1 deficiency in vitro exacerbated the estrogen-DNA adduct formation and loss of cell viability, which was rescued by the supplementation of N-acetylcysteine, a ROS scavenger. Notably, overexpression of NQO1 in HCEnCs treated with MN and 4-OHE2 quenched the ROS formation, thereby reducing the DNA damage and endothelial cell loss. This study signifies a pivotal role for NQO1 in mitigating the macromolecular oxidative DNA damage arising from the interplay between intracellular ROS and impaired endogenous estrogen metabolism in post-mitotic ocular tissue cells. A dysfunctional Nrf2-NQO1 axis in FECD renders HCEnCs susceptible to catechol estrogens and estrogen-DNA adducts formation. This novel study highlights the potential role of NQO1-mediated estrogen metabolite genotoxicity in explaining the higher incidence of FECD in females.

Deep anterior lamellar keratoplasty with femtosecond-laser zigzag incisions.

We describe a technique that uses IntraLase-created zigzag incisions for deep anterior lamellar keratoplasty. In this technique, the laser creates a precise incision that extends to within 70 microm of the recipient Descemet membrane. The deep incision minimizes air escape into the peripheral cornea during big-bubble formation. In cases that require hand dissection, the deep incision provides a reference for gauging the dissection depth. The angled incision edge facilitates final stromal excision with scissors. Compared with standard vertical incisions, the zigzag incision provides an interlocking wound configuration and facilitates matching the donor and recipient anterior surfaces.

Safety of incomplete incision patterns in femtosecond laser-assisted penetrating keratoplasty.

PURPOSE: To evaluate the wound integrity of incomplete contoured corneal incisions created with a femtosecond laser at a refractive surgery center followed by subsequent patient transfer to a separate surgical facility for penetrating keratoplasty (PKP). SETTING: Private tertiary referral center, Indianapolis, Indiana, USA. METHODS: This retrospective consecutive interventional case series comprised 46 eyes that had femtosecond laser PKP. Incomplete contoured incisions were created in the recipient cornea at a refractive surgery center. Patients were then transferred to an ambulatory surgical center for PKP. RESULTS: The indications for PKP included keratoconus, corneal scarring, bullous keratopathy, corneal dystrophy, and failed graft. Three incision contours were used: top hat (n=26), mushroom (n=13), and zigzag (n=7). The incomplete portion of the incision was 70.0 to 300.0 microm in length. Leaving 150.0 to 300.0 microm of the lamellar ring cut incomplete did not ensure wound stability, whereas leaving 70.0 to 75.0 microm of the anterior side cut or posterior side cut incomplete provided excellent wound stability. In all eyes, the partial-thickness incisions enabled safe transport of the patient to the operating room without wound rupture, even with subsequent placement of a retrobulbar injection and a Honan balloon. CONCLUSION: Incomplete femtosecond laser incision patterns that left some collagen lamellae intact maintained sufficient corneal strength to allow safe movement of the patient to a surgical facility for PKP.

Topical anesthesia for penetrating keratoplasty.

PURPOSE: To evaluate the use of topical anesthesia for penetrating keratoplasty (PKP) in situations where retrobulbar, peri/parabulbar, or general anesthesia are inadvisable or not readily available. METHODS: This was a retrospective analysis of a consecutive case series consisting of 8 eyes in 8 patients who had PKP with topical anesthesia between September 1995 and December 1997 in cases where retrobulbar, peri/parabulbar, or general anesthesia either could not be performed or presented too great a risk to the patient. Some cases were supplemented with small limbal injections, mild intravenous sedation (fentanyl), and/or intraocular anesthesia. In one case, intraocular 1% lidocaine was placed directly into the vitreous cavity to allow an open-sky vitrectomy. RESULTS: In all cases, PKP was completed without complications. All patients tolerated the procedure well and reported only mild discomfort. However, in 2 cases, an ACIOL was left in place because lens manipulation caused pain in the ciliary body and iris root areas. CONCLUSIONS: PKP can be performed successfully with topical anesthesia in cooperative patients who have perforated corneal ulcers, significant anticoagulation, or severe medical conditions, which make alternative forms of anesthesia more risky.