Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) resulting from diminished aqueous humor (AH) drainage through the trabecular pathway. Developing effective therapies for increased IOP in glaucoma patients requires identification and characterization of molecular mechanisms that regulate IOP and AH outflow. This study describes the identification and role of autotaxin (ATX), a secretory protein and a major source for extracellular lysophosphatidic acid (LPA), in regulation of IOP in a rabbit model. Quantitative proteomics analysis identified ATX as an abundant protein in both human AH derived from non-glaucoma subjects and in AH from different animal species. The lysophospholipase D (LysoPLD) activity of ATX was found to be significantly elevated (by ∼1.8 fold; n = 20) in AH derived from human primary open angle glaucoma patients as compared to AH derived from age-matched cataract control patients. Immunoblotting analysis of conditioned media derived from primary cultures of human trabecular meshwork (HTM) cells has confirmed secretion of ATX and the ability of cyclic mechanical stretch of TM cells to increase the levels of secreted ATX. Topical application of a small molecular chemical inhibitor of ATX (S32826), which inhibited AH LysoPLD activity in vitro (by >90%), led to a dose-dependent and significant decrease of IOP in Dutch-Belted rabbits. Single intracameral injection of S32826 (∼2 µM) led to significant reduction of IOP in rabbits, with the ocular hypotensive response lasting for more than 48 hrs. Suppression of ATX expression in HTM cells using small-interfering RNA (siRNA) caused a decrease in actin stress fibers and myosin light chain phosphorylation. Collectively, these observations indicate that the ATX-LPA axis represents a potential therapeutic target for lowering IOP in glaucoma patients.
Purpose We have recently developed a high-resolution microscope-integrated spectral domain optical coherence tomography (MIOCT) device designed to enable OCT acquisition simultaneous with surgical maneuvers. The purpose of this report is to describe translation of this device from preclinical testing into human intraoperative imaging. Methods Prior to human imaging, surgical conditions were fully simulated for extensive preclinical MIOCT evaluation in a custom model eye system. MIOCT images were then acquired in normal human volunteers and during vitreoretinal surgery in patients who consented to participate in a prospective Institutional Review Board-approved study. MIOCT images were obtained before and at pauses in surgical maneuvers and were compared based on pre-determined diagnostic criteria to images obtained with a high-resolution research handheld spectral domain OCT system (HHOCT, Bioptigen Inc., Research Triangle Park, NC) at the same time point. Cohorts of five consecutive patients were imaged. Successful endpoints were pre-defined, including ≥80% correlation in identification of pathology between MIOCT and HHOCT in ≥80% of patients. Results MIOCT was favorably evaluated by study surgeons and scrub nurses, all of whom responded that they would consider participating in human intraoperative imaging trials. The preclinical evaluation identified significant improvements that were made prior to MIOCT use during human surgery. The MIOCT transition into clinical human research was smooth. MIOCT imaging in normal human volunteers demonstrated high-resolution comparable to tabletop scanners. In the operating room, after an initial learning curve, surgeons successfully acquired human macular MIOCT images before and after surgical maneuvers. MIOCT imaging confirmed preoperative diagnoses, such as full-thickness macular hole and vitreomacular traction, and demonstrated post-surgical changes in retinal morphology. Two cohorts of five patients were imaged. In the second cohort, the predefined endpoints were exceeded with ≥80% correlation between MMOCT and HHOCT imaging in 100% of patients. Conclusion This report describes high-resolution MIOCT imaging using our prototype device in human eyes during vitreoretinal surgery, with successful achievement of pre-defined endpoints for imaging. Further refinements and investigations will be directed towards fully integrating MIOCT with vitreoretinal and other ocular surgery to image surgical maneuvers in real time.
Purpose: To compare the outcomes of an intraoperative aberrometer (ORA) to the Barrett Universal II (Barrett II) and Hill-RBF 2.0 (Hill-RBF) intraocular lens (IOL) power calculation formulas. Setting: Duke University Eye Center, Durham, North Carolina, USA. Design: Retrospective study. Methods: Patients without history of refractive corneal surgery who had an uneventful cataract surgery from April 2016 to June 2018 were enrolled. Refractive prediction error was calculated with the Barrett II formula, the Hill-RBF formula, and the ORA intraoperative aberrometer (OIA) and was stratified by axial length, IOL type, and the percentage of eyes within a diopteric range of target refraction. Results: Nine-hundred forty-nine eyes were included. The mean and median absolute predictive errors were 0.29 diopters (D) and 0.23 D (Barrett II), 0.31 D and 0.24 D (Hill-RBF), and 0.31 D and 0.25 D (intraoperative aberrometry), respectively (P > .05). Axial length stratification did not influence statistical difference in the IOL prediction methods. Barrett II outperformed the OIA toric multifocal (P = .011) group. Postoperative refraction was within 0.50 D of target in 84% (Barrett II), 83% (Hill-RBF), and 82% (OIA) of eyes (P > .05). Conclusions: Comparing the OIA to the Barrett II and Hill-RBF calculators, there was minimal clinical difference in the toric multifocal group. Regarding postoperative predicted spherical equivalent, for patients without a history of refractive surgery and good potential visual acuity, refractive outcome was not improved by utilizing the OIA.
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