Publications by authors named "Bernard F Godley"

21 Publications

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How Academic Medical Centers Can Navigate the Pandemic and its Aftermath: Solutions for Three Major Issues.

Acad Med 2021 May 11. Epub 2021 May 11.

B.F. Godley is Adjunct Professor, Ophthalmology and Visual Sciences, University of Texas, Medical Branch. T.J. Lawley is William P. Timmie Professor of Dermatology and Former Dean at Emory School of Medicine. A. Rubenstein is Professor in the Department of Medicine and the Division of Endocrinology and Former Dean and Executive Vice President at the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania. P.A. Pizzo is the David and Susan Heckerman Professor of Pediatrics and of Microbiology and Immunology at Stanford and Former Dean, School of Medicine and Founding Director of the Stanford Distinguished Careers Institute, Stanford University; ORCID: https://orcid.org/0000-0002-1000-6516.

The COVID-19 crisis has seriously affected academic medical centers (AMCs) on multiple levels. Combined with many trends that were already under way pre-pandemic, the current situation has generated significant disruption and underscored the need for change within and across AMCs. In this article, the authors explore some of the major issues and propose actionable solutions in 3 areas of concentration. First, the impact on medical students is considered, particularly the tradeoffs associated with online learning and the need to place greater pedagogical emphasis on virtual care delivery and other skills that will be increasingly in demand. Solutions described include greater utilization of technology, building more public health knowledge into the curriculum, and partnering with a wide range of academic disciplines. Second, leadership recruiting, vital to long-term success for AMCs, has been complicated by the crisis. Pressures discussed include adapting to the dynamics of competitive physician labor markets as well as attracting candidates with the skill sets to meet the requirements of a shifting AMC leadership landscape. Solutions proposed in this domain include making search processes more focused and streamlined, prioritizing creativity and flexibility as core management capabilities to be sought, and enhancing efforts with assistance from outside advisors. Finally, attention is devoted to the severe financial impact wrought by the pandemic, creating challenges whose resolution is central to planning future AMC directions. Specific challenges include recovery of lost clinical revenue and cash flow, determining how to deal with research funding, and the precarious economic balancing act engendered by the need to continue distance education. A full embrace of telehealth, collaborative policy-making among the many AMC constituencies, and committing fully to being in the vanguard of the transition to value-based care form the solution set offered.
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http://dx.doi.org/10.1097/ACM.0000000000004155DOI Listing
May 2021

Ophthalmological Evaluation of Integrated Resistance and Aerobic Training During 70-Day Bed Rest.

Aerosp Med Hum Perform 2017 Jul;88(7):633-640

Introduction: We evaluated ophthalmic changes in healthy individuals who underwent integrated resistance and aerobic training (iRAT) during 70-d 6° head-down tilt (HDT) bed rest (BR).

Methods: Participants were selected using NASA standard screening procedures. Standardized NASA BR conditions were implemented. Subjects were randomly assigned to the iRAT protocol or no exercise during HDTBR. Weekly ophthalmic examinations were performed in the sitting (pre/post-BR only) and HDT (BR only) positions. Mixed-effects linear models compared pre- and post-HDTBR intraocular pressure (IOP), Spectralis OCT circumpapillary retinal nerve fiber layer (cpRNFL) thickness, and peripapillary retinal thickness observations between groups.

Results: Six controls and nine exercisers completed the study. There was an overall effect of BR on our outcomes. Except Goldmann IOP (mean pre/post difference in controls and exercisers: -0.47 mmHg vs. +1.14 mmHg), the magnitude of changes from baseline was not significantly different between groups. There was a +1.38 mmHg and a +1.63 mmHg iCare IOP increase during BR in controls and exercisers, respectively. Spectralis OCT detected a +1.33 μm average cpRNFL thickness increase in both groups, and a +9.77 μm and a +6.65 μm peripapillary retinal thickening post-BR in controls and exercisers, respectively. Modified Amsler grid, red dot test, confrontational visual field, color vision, and stereoscopic fundus photography were unremarkable.

Conclusions: HDTBR for 70 d induced peripapillary retinal thickening and cpRNFL thickening without visible signs of optic disc edema. The magnitude of such changes was not different between controls and exercisers. A slight IOP increase during BR subsided post-BR. Further study should evaluate whether different physical exercise paradigms may prevent/mitigate the risk of space-related visual impairment.Taibbi G, Cromwell RL, Zanello SB, Yarbough PO, Ploutz-Snyder RJ, Godley BF, Vizzeri G. Ophthalmological evaluation of integrated resistance and aerobic training during 70-day bed rest. Aerosp Med Hum Perform. 2017; 88(7):633-640.
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http://dx.doi.org/10.3357/AMHP.4768.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568005PMC
July 2017

Ocular Outcomes Comparison Between 14- and 70-Day Head-Down-Tilt Bed Rest.

Invest Ophthalmol Vis Sci 2016 Feb;57(2):495-501

Department of Ophthalmology and Visual Sciences The University of Texas Medical Branch at Galveston, Galveston, Texas, United States.

Purpose: To compare ocular outcomes in healthy subjects undergoing 14- and/or 70-day head-down-tilt (HDT) bed rest (BR).

Methods: Participants were selected by using NASA standard screening procedures. Standardized NASA BR conditions were implemented. Subjects maintained a 6° HDT position for 14 and/or 70 consecutive days. Weekly ophthalmologic examinations were performed in the sitting (pre/post-BR only) and HDT positions. Mixed-effects linear models compared pre- and post-HDT BR observations between 14- and 70-day HDT BR in best-corrected visual acuity, spherical equivalent, intraocular pressure (IOP), Spectralis OCT retinal nerve fiber layer thickness, peripapillary and macular retinal thicknesses.

Results: Sixteen and six subjects completed the 14- and 70-day HDT BR studies, respectively. The magnitude of HDT BR-induced changes was not significantly different between the two studies for all outcomes, except the superior (mean pre/post difference of 14- vs. 70-day HDT BR: +4.69 μm versus +11.50 μm), nasal (+4.63 μm versus +11.46 μm), and inferior (+4.34 μm versus +10.08 μm) peripapillary retinal thickness. A +1.42 mm Hg and a +1.79 mm Hg iCare IOP increase from baseline occurred during 14- and 70-day HDT BR, respectively. Modified Amsler grid, red dot test, confrontational visual field, color vision, and stereoscopic fundus photography were unremarkable.

Conclusions: Seventy-day HDT BR induced greater peripapillary retinal thickening than 14-day HDT BR, suggesting that time may affect the amount of optic disc swelling. Spectralis OCT detected retinal nerve fiber layer thickening post BR, without clinical signs of optic disc edema. A small IOP increase during BR subsided post HDT BR. Such changes may have resulted from BR-induced cephalad fluids shift. The HDT BR duration may be critical for replicating microgravity-related ophthalmologic changes observed in astronauts on ≥6-month spaceflights.
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http://dx.doi.org/10.1167/iovs.15-18530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758300PMC
February 2016

Utilization of Portable Radios to Improve Ophthalmology Clinic Efficiency in an Academic Setting.

J Med Syst 2016 Mar 22;40(3):64. Epub 2015 Dec 22.

Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.

Improvement in clinic efficiency in the ambulatory setting is often looked at as an area for development of lean management strategies to deliver a higher quality of healthcare while reducing errors, costs, and delays. To examine the benefits of improving team communication and its impact on clinic flow and efficiency, we describe a time-motion study performed in an academic outpatient Ophthalmology clinic and its objective and subjective results. Compared to clinic encounters without the use of the portable radios, objective data demonstrated an overall significant decreases in mean workup time (15.18 vs. 13.10), room wait (13.10 vs. 10.47), and decreased the total time needed with an MD per encounter (9.45 vs. 6.63). Subjectively, significant improvements were seen in careprovider scores for patient flow (60.78 vs. 84.29), getting assistance (61.89 vs. 88.57), moving patient charts (54.44 vs. 85.71), teamwork (69.56 vs. 91.0), communications (62.33 vs. 90.43), providing quality patient care (76.22 vs. 89.57), and receiving input on the ability to see walk-in patients (80.11 vs. 90.43). For academic purposes, an improvement in engagement in patient care and learning opportunities was noted by the clinic resident-in-training during the pilot study. Portable radios in our pilot study were preferred over the previous method of communication and demonstrates significant improvements in certain areas of clinical efficiency, subjective perception of teamwork and communications, and academic learning.
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http://dx.doi.org/10.1007/s10916-015-0417-xDOI Listing
March 2016

Photokinetic Drug Delivery: Light-Enhanced Permeation in an In Vitro Eye Model.

J Ocul Pharmacol Ther 2015 Dec 27;31(10):650-7. Epub 2015 Aug 27.

3 Electron Microscopy Laboratory, University of Texas Medical Branch , Galveston, Texas.

Purpose: To investigate light-enhanced molecular movement as a potential technology for drug delivery. To do this, we developed an in vitro eye model while representing similar concentration gradient conditions and compositions found in the eye.

Methods: The eye model unit was fabricated by inserting a cross-linked type I collagen membrane in a spectrophotometer cuvette with 1% hyaluronic acid as the drug recipient medium. Photokinetic delivery was studied by illuminating 1 mg/mL methotrexate (MTX) placed in the drug donor compartment on top of the membrane, with noncoherent 450 nm light at 8.2 mW from an LED source pulsed at 25 cycles per second, placed in contact with the solution. A modified UV-visual spectrophotometer was employed to rapidly determine the concentration of MTX, at progressive 1 mm distances away from the membrane, within the viscous recipient medium of the model eye after 1 h.

Results: A defined, progressive concentration gradient was observed within the nonagitated drug recipient media, diminishing with greater distances from the membrane. Transport of MTX through the membrane was significantly enhanced (ranging from 2 to 3 times, P < 0.05 to P ≤ 0.001) by photokinetic methods compared with control conditions by determining drug concentrations at 4 defined distances from the membrane. According to scanning electron microscopy images, no structural damage or shunts were created on the surface of the cross-linked gelatin membrane.

Conclusion: The application of pulsed noncoherent visible light significantly enhances the permeation of MTX through a cross-linked collagen membrane and hyaluronic acid recipient medium without causing structural damage to the membrane.
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http://dx.doi.org/10.1089/jop.2015.0005DOI Listing
December 2015

Ocular outcomes evaluation in a 14-day head-down bed rest study.

Aviat Space Environ Med 2014 Oct;85(10):983-92

Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX, USA.

Introduction: We evaluated ocular outcomes in a 14-d head-down tilt (HDT) bed rest (BR) study designed to simulate the effects of microgravity on the human body.

Methods: Healthy subjects were selected using NASA standard screening procedures. Standardized NASA BR conditions were implemented (e.g., strict sleep-wake cycle, standardized diet, 24-hour-a-day BR, continuous video monitoring). Subjects maintained a 6° HDT position for 14 consecutive days. Weekly ophthalmological examinations were performed in the sitting (pre/post-BR) and HDT (in-bed phase) positions. Equivalency tests with optimal-alpha techniques evaluated pre/post-BR differences in best-corrected visual acuity (BCVA), spherical equivalent, intraocular pressure (IOP), Spectral-domain OCT retinal nerve fiber layer thickness (RNFLT), optic disc and macular parameters.

Results: 16 subjects (12 men and 4 women) were enrolled. Nearly all ocular outcomes were within our predefined clinically relevant thresholds following HDTBR, except near BCVA (pre/post-BR mean difference: -0.06 logMAR), spherical equivalent (-0.30 D), Tonopen XL IOP (+3.03 mmHg) and Spectralis OCT average (+1.14 μm), temporal-inferior (+1.58 μm) and nasal-inferior RNFLT (+3.48 μm). Modified Amsler grid, red dot test, confrontational visual field, and color vision were within normal limits throughout. No changes were detected on stereoscopic color fundus photography.

Discussion: A few functional and structural changes were detected after 14-d HDTBR, notably an improved BCVA possibly due to learning effect and RNFL thickening without signs of optic disc edema. In general, 6° HDTBR determined a small nonprogressive IOP elevation, which returned to baseline levels post-BR. Further studies with different BR duration and/or tilt angle are warranted to investigate microgravity-induced ophthalmological changes.
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http://dx.doi.org/10.3357/ASEM.4055.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240225PMC
October 2014

Optic disc pit maculopathy recurring in the absence of vitreous gel.

JAMA Ophthalmol 2014 Nov;132(11):1375-6

Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston.

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http://dx.doi.org/10.1001/jamaophthalmol.2014.2054DOI Listing
November 2014

Nicotine accelerates diabetes-induced retinal changes.

Curr Eye Res 2015 Apr 9;40(4):368-77. Epub 2014 Jun 9.

Center for Biomedical Engineering .

Purpose: To investigate the effects of nicotine on retinal alterations in early-stage diabetes in an established rodent model.

Materials And Methods: Sprague-Dawley rats were examined using a combination of confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography to determine changes in retinal structure in response to nicotine exposure, diabetes and the combined effects of nicotine and diabetes. Diabetes was induced by a single injection of 65 mg/kg streptozotocin and nicotine injections were administered subcutaneously daily. Retinal thickness in the superior, inferior, nasal and temporal quadrants were determined based on the spectral domain optical coherence tomography (SD-OCT) volume scans (20° × 20°) centered on the optic disc. Segmentation of discrete retinal layers was performed on a subset of SD-OCT cross-sections to further examine changes in each treatment group. Survival of neurons within the ganglion cell layer (GCL) was assessed by confocal morphometric imaging.

Results: The control group did not experience any significant change throughout the study. The nicotine treatment group experienced an average decrease in total retinal thickness (TRT) of 9.4 µm with the majority of the loss localized within the outer nuclear layer (ONL) as determined by segmentation analysis (p < 0.05). The diabetic group exhibited a trend toward decreased TRT while segmentation analysis of the diabetic retinopathy (DR) group revealed significant thinning within the ONL (p < 0.05). The combination of nicotine and diabetes revealed a significant increase of 8.9 µm in the TRT (p < 0.05) accompanied by a decrease in the number of GCL neurons.

Conclusions: We demonstrated significant temporal changes in retinal morphology in response to nicotine exposure, diabetes and with the combined effects of nicotine and diabetes. These findings may have implications in determining treatment strategies for diabetic patients using products containing nicotine, such as cigarettes, smokeless tobacco, electronic cigarettes or smoking cessation products.
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http://dx.doi.org/10.3109/02713683.2014.924147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451833PMC
April 2015

TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization.

Invest Ophthalmol Vis Sci 2014 Feb 10;55(2):801-13. Epub 2014 Feb 10.

Department of Ophthalmology and Visual Sciences, the University of Texas Medical Branch, Galveston, Texas.

Purpose: Retinal neovascularization (NV) is a major cause of vision loss in ischemia-induced retinopathy. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor inducible-14 (Fn14), have been implicated in angiogenesis, but their role in retinal diseases is unknown. The goal of this study was to investigate the role of TWEAK/Fn14 pathway in retinal NV.

Methods: Studies were performed in a mouse model of oxygen-induced retinopathy (OIR) and in primary human retinal microvascular endothelial cells (HRMECs). Hyperoxia treatment was initiated on postnatal day (P)14. Immunohistochemistry and quantitative PCR (qPCR) were used to assess retinal vascular changes in relation to expression of Fn14 and TWEAK.

Results: Fibroblast growth factor-inducible 14 mRNA was prominently increased from P13 to P17 in OIR retinas, whereas TWEAK level was slightly decreased. These alterations were normalized by hyperoxia treatment and were more striking in isolated retinal vessels. There was a discernible shift in the immunoreactivity of Fn14 and TWEAK from the neuronal layers in the healthy retina to the neovascular tufts in that of OIR. Blockade of TWEAK/Fn14 significantly prevented retinal NV while slightly accelerated revascularization. In contrast, activation of Fn14 positively regulated survival pathways in the B-cell lymphoma-2 (Bcl2) family and robustly enhanced HRMEC survival. Furthermore, gene analysis revealed the regulatory region of Fn14 gene contains several conserved hypoxia inducible factor (HIF)-1α binding sites. Overexpression of HIF-1α prominently induced Fn14 expression in HRMECs.

Conclusions: We found that the TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible-14 (Fn14) pathway is involved in the development of pathologic retinal neovascularization. Hypoxia inducible factor-1α is likely implicated in the upregulation of Fn14.
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http://dx.doi.org/10.1167/iovs.13-12812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920863PMC
February 2014

Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression.

Arthritis Rheum 2013 Nov;65(11):2835-46

State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, and Chinese Academy of Sciences, Beijing, China.

Objective: The protease HTRA-1 is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA-1 expression are currently unknown. This study was undertaken to determine the regulatory role of Toll-like receptors (TLRs) on HTRA-1 expression in mice with collagen-induced arthritis (CIA) and in synovial cells from RA patients.

Methods: HTRA-1 messenger RNA and protein production in mouse fibroblasts, mouse macrophages, and freshly isolated RA patient synovial cells treated with TLR ligands were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Arthritis incidence and severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA-1 in lipopolysaccharide (LPS)-increased arthritis incidence and severity in mice was determined using anti-HTRA-1 monoclonal antibody. The signal pathways involved in HTRA-1 expression were accessed by specific inhibitors, RNA interference, dual-luciferase reporter, and chromatin immunoprecipitation methods.

Results: LPS and tenascin-C, but not the other TLR ligands tested, strongly induced HTRA-1 expression. LPS significantly increased HTRA-1 expression in the joint tissue as well as arthritis incidence and severity in mice with CIA. Blocking HTRA-1 by antibody significantly decreased LPS-promoted CIA severity. Inhibiting NF-κB significantly decreased LPS-induced HTRA-1 expression in mouse and human cells. Dual-luciferase reporter assay and ChIP analysis showed that p65 directly binds to HTRA-1 promoter (amino acid 347).

Conclusion: Our findings indicate that TLR-4 activation increases HTRA-1 expression through the NF-κB pathway in fibroblasts and macrophages. HTRA-1 expression is involved in the enhancing effects of LPS on CIA. This study offers new insights into the regulation of HTRA-1 expression via LPS/TLR-4 and the role of HTRA-1 in RA pathogenesis.
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http://dx.doi.org/10.1002/art.38124DOI Listing
November 2013

Effects of 30-day head-down bed rest on ocular structures and visual function in a healthy subject.

Aviat Space Environ Med 2013 Feb;84(2):148-54

Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX 77555-1106, USA.

Introduction: We report ocular changes occurring in a healthy human subject enrolled in a bed rest (BR) study designed to replicate the effects of a low-gravity environment.

Case Report: A 25-yr-old Caucasian man spent 30 consecutive days in a 6 degrees head-down tilt (HDT) position at the NASA Flight Analogs Research Unit. Comprehensive ophthalmologic exams, optic disc stereo-photography, standard automated perimetry (SAP), and optic disc Spectralis OCT scans were performed at baseline, immediately post-BR (BR+0), and 6 mo post-BR.

Main Outcome Measures: changes in best-corrected visual acuity, intraocular pressure (IOP), cycloplegic refraction, SAP, and Spectralis OCT measures. At BR+0 KIOP was 11 and 10 mmHg in the right (OD) and left eye (OS), respectively (a bilateral 4-mmHg decrease compared to baseline); SAP documented a possible bilateral symmetrical inferior scotoma; Spectralis OCT showed an average 19.4 microm (+5.2%) increase in peripapillary retinal thickness, and an average 0.03 mm3 (+5.0%) increase in peripapillary retinal volume bilaterally. However, there were no clinically detectable signs of optic disc edema. At 6 mo post-BR, IOP was 13 and 14 mmHg in OD and OS, respectively, and the scotoma had resolved. Spectralis OCT measurements matched the ones recorded at baseline.

Discussion: In this subject, a reduction in IOP associated with subtle structural and functional changes compared to baseline were documented after prolonged head-down BR. These changes may be related to cephalad fluid shifts in response to tilt. Further studies should clarify whether decreased translaminar pressure (i.e., the difference between IOP and intracranial pressure) may be responsible for these findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742446PMC
http://dx.doi.org/10.3357/asem.3520.2013DOI Listing
February 2013

The effect of microgravity on ocular structures and visual function: a review.

Surv Ophthalmol 2013 Mar-Apr;58(2):155-63. Epub 2013 Jan 29.

Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX 77555-1106, USA.

Ocular structural and functional changes, including optic disk edema and reduction of near visual acuity, have been recently described in some astronauts returning from long-duration space travels. It is hypothesized that ocular changes related to spaceflight may occur, in predisposed individuals, as a result of cephalad shift of body fluids, possibly leading to elevated intracranial pressure (ICP). Results from head-down bed-rest studies (used to simulate the effects of microgravity) and from parabolic flight experiments (used to produce transient periods of microgravity) indicate that ocular blood flow and intraocular pressure (IOP) may undergo changes in a low-gravity environment. Recent studies suggest that changes in translaminar pressure (i.e., IOP minus ICP) may be implicated in the pathophysiology of optic disk neuropathies. Because postural changes exert an effect on both IOP and ICP, the head-down bed-rest analog may also be used as a platform to characterize the relationship between IOP and ICP, and their reciprocal influence in the pathophysiology of conditions such as optic disk edema or glaucoma.
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http://dx.doi.org/10.1016/j.survophthal.2012.04.002DOI Listing
June 2013

Delayed suprachoroidal hemorrhage after cataract surgery.

Retin Cases Brief Rep 2012 ;6(4):390-2

Department of Ophthalmology and Visual Sciences, University of Texas-Medical Branch, Galveston, Texas.

Purpose: To describe the clinical course of 61-year-old man who developed a delayed suprachoroidal hemorrhage 4 days after cataract surgery.

Method: This is an observational case report. The patient's clinical course is reviewed, and his clinical findings are correlated to B-scan ultrasonography and posterior funduscopic photography. We describe a successful surgical intervention with external sclerotomy and partial drainage of the suprachoroidal hemorrhage.

Results: Initial medical management of delayed suprachoroidal hemorrhage failed to improve the patient's pain, vision, and clinical findings. Two weeks later, an external sclerotomy with partial drainage of the suprachoroidal blood resulted in an expedited pain relief, with complete resolution of the suprachoroidal hemorrhage and restoration of baseline visual acuity.

Conclusion: Delayed suprachoroidal hemorrhage is a well-recognized but rare postoperative complication of cataract surgery. This case highlights the benefits of a timely surgical intervention after conservative management. We propose that a conservative external surgical approach with partial drainage of a suprachoroidal hemorrhage and closure by secondary intention was sufficient to tip the balance of intraocular hemodynamics and led to full recuperation.
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http://dx.doi.org/10.1097/ICB.0b013e3182437da2DOI Listing
November 2014

Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration.

Invest Ophthalmol Vis Sci 2011 Jun 1;52(6):3521-9. Epub 2011 Jun 1.

Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas 77555-1106, USA.

Purpose: Mitochondrial DNA (mtDNA) damage may be associated with age-related diseases, such as age-related macular degeneration (AMD). The present study was designed to test whether the frequency of mtDNA damage, heteroplasmic mtDNA mutations, and repair capacity correlate with progression of AMD.

Methods: Macular and peripheral RPE cells were isolated and cultured from human donor eyes with and without AMD. The stages of AMD were graded according to the Minnesota Grading System. Confluent primary RPE cells were used to test the frequency of endogenous mtDNA damage by quantitative PCR. Mutation detection kits were used to detect heteroplasmic mtDNA mutation. To test the mtDNA repair capacity, cultured RPE cells were allowed to recover for 3 and 6 hours after exposure to H(2)O(2), and repair was assessed by quantitative PCR. The levels of human OGG1 protein, which is associated with mtDNA repair, were analyzed by Western blot.

Results: This study showed that mtDNA damage increased with aging and that more lesions occurred in RPE cells from the macular region than the periphery. Furthermore, mtDNA repair capacity decreased with aging, with less mtDNA repair capacity in the macular region compared with the periphery in samples from aged subjects. Most interestingly, the mtDNA damage was positively correlated with the grading level of AMD, whereas repair capacity was negatively correlated. In addition, more mitochondrial heteroplasmic mutations were detected in eyes with AMD.

Conclusions: These data show macula-specific increases in mtDNA damage, heteroplasmic mutations, and diminished repair that are associated with aging and AMD severity.
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http://dx.doi.org/10.1167/iovs.10-6163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109040PMC
June 2011

Mitochondrial DNA damage and its potential role in retinal degeneration.

Prog Retin Eye Res 2008 Nov 23;27(6):596-607. Epub 2008 Sep 23.

Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, USA.

Mitochondria are central to retinal cell function and survival. There is increasing evidence to support an association between mitochondrial dysfunction and a number of retinal pathologies including age-related macular degeneration (AMD), diabetic retinopathy and glaucoma. The past decade has highlighted mitochondrial genomic instability as an important factor in mitochondrial impairment culminating in age-related changes and age-related pathology. This represents a combination of the susceptibility of mitochondrial DNA (mtDNA) to oxidative damage and a limited base excision repair pathway. This random cumulative mtDNA damage leads to cellular heteroplasmy and, if the damage affects a sufficient proportion of mitochondria within a given cell, results in loss of cell function and greater susceptibility to stress. mtDNA damage is increased in the neural retina and RPE with ageing and appears to be greatest in AMD. It thus appears that the mitochondrial genome is a weak link in the antioxidant defenses of retinal cells and that deficits in mitochondrial DNA (mtDNA) repair pathways are important contributors to the pathogenesis of retinal degeneration. Specifically targeting mitochondria with pharmacological agents able to protect against oxidative stress or promote repair of mtDNA damage may offer potential alternatives for the treatment of retinal degenerations such as AMD.
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http://dx.doi.org/10.1016/j.preteyeres.2008.09.001DOI Listing
November 2008

Blue light induces mitochondrial DNA damage and free radical production in epithelial cells.

J Biol Chem 2005 Jun 29;280(22):21061-6. Epub 2005 Mar 29.

Retina Foundation of the Southwest, Dallas, Texas 75231, USA.

Exposure of biological chromophores to ultraviolet radiation can lead to photochemical damage. However, the role of visible light, particularly in the blue region of the spectrum, has been largely ignored. To test the hypothesis that blue light is toxic to non-pigmented epithelial cells, confluent cultures of human primary retinal epithelial cells were exposed to visible light (390-550 nm at 2.8 milliwatts/cm2) for up to 6 h. A small loss of mitochondrial respiratory activity was observed at 6 h compared with dark-maintained cells, and this loss became greater with increasing time. To investigate the mechanism of cell loss, the damage to mitochondrial and nuclear genes was assessed using the quantitative PCR. Light exposure significantly damaged mitochondrial DNA at 3 h (0.7 lesion/10 kb DNA) compared with dark-maintained controls. However, by 6 h of light exposure, the number of lesions was decreased in the surviving cells, indicating DNA repair. Isolated mitochondria exposed to light generated singlet oxygen, superoxide anion, and the hydroxyl radical. Antioxidants confirmed the superoxide anion to be the primary species responsible for the mitochondrial DNA lesions. The effect of lipofuscin, a photoinducible intracellular generator of reactive oxygen intermediates, was investigated for comparison. Exposure of lipofuscin-containing cells to visible light caused an increase in both mitochondrial and nuclear DNA lesions compared with non-pigmented cells. We conclude that visible light can cause cell dysfunction through the action of reactive oxygen species on DNA and that this may contribute to cellular aging, age-related pathologies, and tumorigenesis.
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http://dx.doi.org/10.1074/jbc.M502194200DOI Listing
June 2005

Enhanced expression of glutathione-S-transferase A1-1 protects against oxidative stress in human retinal pigment epithelial cells.

Exp Eye Res 2005 Jan;80(1):113-9

Retina Foundation of the Southwest, 9900 N. Central Expressway, Suite 400, Dallas, TX 75231, USA.

Glutathione-S-transferases (GSTs) play an important role in protection mechanisms against oxidative stress. We sought to determine whether over-expression of human GSTA1-1 in RPE cells is able to attenuate H(2)O(2)-induced oxidative stress. SV40-transformed human fetal RPE cells were stably transfected with pRC/hGSTA1-1 vector which carries a full-length of human GSTA1-1 cDNA. The control RPE cells were either non-transfected or transfected with control vector pRC. Expression of hGSTA1-1 protein in these cells was confirmed by Western blot and immunocytochemical analyses. The protective effects of hGSTA1-1 on cell viability and mitochondrial DNA (mtDNA) damage caused by H(2)O(2) were examined with MTT assay and quantitative PCR (QPCR), respectively. The hGSTA1-1 transfected RPE cells exhibited a similar morphology and growth rate as control RPE cells. Immunocytochemical analysis showed robust expression hGSTA1-1 in hGSTA1-1 transfected cells versus background staining in control cells. Western blotting of protein extracts from cells transfected with hGSTA1-1 revealed a 26 kDa protein band which corresponds to the size of recombinant mature hGSTA1-1. The active GST present in the hGSTA1-1 transfected cells was approximately three times higher than in control cells. The MTT assay showed a significantly greater viability of hGSTA1-1 cells in response to H(2)O(2) (100 and 200 microm) compared to control cells (p<0.05). QPCR indicated that mtDNA damage was significantly decreased in hGSTA1-1 cells than in control cells (p<0.05). Human GSTA1-1 transfection protect against RPE cell death and mtDNA damage caused by H(2)O(2), suggesting an important role of GST in protection against oxidative stress in RPE cells.
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http://dx.doi.org/10.1016/j.exer.2004.08.017DOI Listing
January 2005

Melatonin protects human retinal pigment epithelial (RPE) cells against oxidative stress.

Exp Eye Res 2004 Jun;78(6):1069-75

Retina Foundation of Sothwest, Dallas, TX 75231, USA.

Oxidative stress is involved in the pathogenesis of age-related macular degeneration (AMD). Administration of conventional antioxidants has been shown to slow the progression of AMD and vision loss. Melatonin, an endogenous neurohormone produced by the pineal gland and retina, has been reported to be a potent antioxidant and free radical scavenger. In this study we tested whether melatonin can protect retinal pigment epithelial (RPE) cells against hydrogen peroxide (H(2)O(2))-induced cell death. Since mitochondrial DNA (mtDNA) is preferentially susceptible to oxidative damage, we tested whether melatonin can reduce H(2)O(2)-induced mtDNA lesions. A human RPE cell line (ARPE-19) was cultured and exposed to H(2)O(2) (100 and 200 microm) for 1 hr to induce cell death. Prior to H(2)O(2) treatment, cells were treated with various concentrations (0.1-200 microm) of melatonin for 2, 24 or 72 hr. Control cells received either melatonin or ethanol alone. Cell viability, as determined by MTT assay, showed no significant (P>0.05) protection against H(2)O(2) toxicity in cells receiving 2- and 24-hr pretreatment of melatonin at either concentration. However, when melatonin was administered diurnally for 3 consecutive days, this prolonged treatment markedly reduced H(2)O(2)-induced cell death (P>0.05) MtDNA damage, as assessed with quantitative PCR, was significantly decreased (P<0.05) in RPE cells pretreated with melatonin as compared to those without melatonin treatment. These results suggest that melatonin may play a role in protecting RPE cells from oxidative stress.
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http://dx.doi.org/10.1016/j.exer.2004.02.003DOI Listing
June 2004

Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration.

Exp Eye Res 2003 Apr;76(4):397-403

Retina Foundation of the Southwest, Anderson Vision Research Center, 9900 N. Central Expressway, Suite 400, Dallas, TX 75231, USA.

Oxidative stress is believed to contribute to the pathogenesis of many diseases, including age-related macular degeneration (AMD). Although the vision loss of AMD results from photoreceptor damage in the central retina, the initial pathogenesis involves degeneration of RPE cells. Evidence from a variety of studies suggests that RPE cells are susceptible to oxidative damage. Mitochondrial DNA (mtDNA) is particularly prone to oxidative damage compared to nuclear DNA (nDNA). Using the quantitative PCR assay, a powerful tool to measure oxidative DNA damage and repair, we have shown that human RPE cells treated with H(2)O(2) or rod outer segments resulted in preferential damage to mtDNA, but not nDNA; and damaged mtDNA is not efficiently repaired, leading to compromised mitochondrial redox function as indicated by the MTT assay. Thus, the susceptibility of mtDNA to oxidative damage in human RPE cells, together with the age-related decrease of cellular anti-oxidant system, provides the rationale for a mitochondria-based model of AMD.
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http://dx.doi.org/10.1016/s0014-4835(03)00023-xDOI Listing
April 2003

Factors affecting visual outcomes after small-incision phacoemulsification in diabetic patients.

J Cataract Refract Surg 2002 Aug;28(8):1364-71

Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA.

Purpose: To examine the factors affecting visual outcome after phacoemulsification and evaluate the use of preoperative visual potential in assessing the visual prognosis in diabetic patients.

Setting: Department of Ophthalmology, University of Texas Medical Branch, Galveston, Texas, USA.

Methods: In a retrospective chart review of 1345 consecutive patients who had uneventful small-incision phacoemulsification, operated eyes from 106 diabetic and 55 nondiabetic control patients were selected. Data on demographics, level of retinopathy, perioperative glycosylated hemoglobin (HbA(Ic)), surgical duration, preoperative best corrected visual acuity (BCVA), and visual potential were collected.

Results: The age, sex, preoperative BCVA, and visual potential in the diabetic and control eyes were comparable. Throughout the postoperative period, BCVA was worse of the diabetic group. At 1 year, BCVA was 20/40 in 82.1% of the diabetic group and 94.7% of the control group (P =.01). The most important factors affecting postoperative BCVA included coexisting diabetes and preoperative level of retinopathy. No correlation was found between perioperative and postoperative BCVA. Diabetic patients were less likely than control patients to achieve a BCVA better than or equal to the preoperative visual potential at 4 years (hazard ratio 0.6; 95% confidence interval, 0.4-0.9; P =.011). Patients with nonproliferative diabetic retinopathy were nearly 5 times less likely (P =.023) and patients with proliferative diabetic retinopathy 30 times less likely (P <.0001) to achieve a postoperative BCVA of 20/40 than diabetic patients without retinopathy.

Conclusions: Although uneventful small-incision phacoemulsification improved visual acuity in diabetic patients, this group had an overall worse visual outcome than nondiabetic patients. The most important predictors of visual outcome were coexisting diabetes and the extent of preoperative retinopathy. Methods used to assess preoperative visual potential provided a reasonable estimate of postoperative BCVA in diabetic patients. Given the inverse association between the level of retinopathy and visual outcome, it may be better to perform cataract extraction in diabetic patients during earlier stages of retinopathy.
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http://dx.doi.org/10.1016/s0886-3350(02)01319-6DOI Listing
August 2002

Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H(2)O(2).

Exp Eye Res 2002 Jun;74(6):663-9

Retina Foundation of the Southwest, Dallas, TX 75321, USA.

The integrity of the retinal pigment epithelium, especially that of the macula is essential for the preservation of vision into old age. The chronic exposure to sunlight and peroxidized lipids from phagocytized photoreceptor outer segments imposes a high level of oxidative stress on the retinal tissues, which increases with age as antioxidant protection declines and therefore could accelerate apoptosis. Bcl-2 known to facilitate mitochondrial DNA repair and cellular survival in other tissues was overexpressed in a single clone of human retinal pigment epithelium cells after stable transfection with humanbcl-2 in rhoSFV-neoexpression factor. Near confluent cells (2nd-4th generation permanently bcl-2 transfected) were protected from mitochondrial dysfunction after exposure to H(2)O(2) up to 150 microM. With 200 microM H(2)O(2), function in transfected cells declined by only 25% control activity as determined by MTT reduction assays, compared to wild type and vector only transfected cells expressing normal bcl-2 levels. Similarly the bcl-2 -transfected cells were more resistant to mitochondrial DNA damage after H(2)O(2) treatment than the other groups and suffered 50% less damage after exposure to 200 microM H(2)O(2), as assayed by quantitative polymerase chain reaction assays. These data suggest that bcl-2 overexpression protects human RPE cells from mitochondrial respiratory dysfuction, mitochondrial DNA damage and promotes cellular survival in response to oxidative stress induced by H(2)O(2).
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http://dx.doi.org/10.1006/exer.2001.1146DOI Listing
June 2002