Oklahoma City, OK, United States
Oklahoma City, OK, United States

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Head C.A.,Georgia Regents University | Swerdlow P.,Wayne State University | McDade W.A.,University of Chicago | Joshi R.M.,Dean McGee Eye Institute | And 3 more authors.
American Journal of Hematology | Year: 2010

Pain from vaso-occlusive crisis (VOC) is the major cause of hospitalization in patients with sickle cell disease (SCD). The beneficial therapeutic effects of inhaled nitric oxide (NO) on the pathophysiology of SCD have been reported. A double-blind, randomized, placebo-controlled clinical trial was conducted to determine whether NO breathing reduces acute VOC pain in adult patients and to study the safety of inhaled NO. Twenty-three patients experiencing acute VOC were enrolled. After randomization but before treatment, five were found to not meet final eligibility criteria. Nine patients were assigned to inhaled NO (80 ppm) and nine to placebo (21% O2). Primary outcome was the mean change in pain scores after 4 hr of inhalation, measured on a 10-cm visual analog scale (VAS). Both groups had similar baseline VAS pain scores but inhaled NO significantly reduced pain scores compared with placebo (P = 0.02) at the end of NO inhalation. Secondary outcome was parenteral morphine use at baseline, 4, and 6 hr. Parenteral morphine use was lower in the inhaled NO group, but the difference was not statistically significant. Safety assessments included systolic blood pressure measurements, pulse oximetry readings, concentration of delivered nitrogen dioxide, and concentration of methemoglobin (metHb). None of these NO toxicities was observed.


PubMed | Dean McGee Eye Institute, Northwestern University, Glaucoma Associates of Texas, Vold Vision and 2 more.
Type: Journal Article | Journal: BMC ophthalmology | Year: 2016

Antifibrotic agents are commonly utilized to enhance the success rates of trabeculectomy. Novel approaches to further improve success rates and reduce the risks of complications are needed. The purpose of this study was to compare intraocular pressure (IOP)-lowering efficacy and safety of trabeculectomy or combined phacoemulsification and trabeculectomy with mitomycin-C (MMC) vs. Collagen Matrix (CM).A prospective, multicenter, randomized controlled trial was performed. Ninety-five eyes of 94 patients with uncontrolled glaucoma despite medical therapy, without previous incisional glaucoma surgery underwent trabeculectomy (85 eyes) or combined phacoemulsification and trabeculectomy (10 eyes) and were randomized to MMC or CM. One eye of each subject was analyzed. Patients were followed for 24months. The criteria for complete success were IOP >5 and 21mmHg with at least a 20% reduction below medicated baseline without additional glaucoma surgery or medications. The main outcome measures were complete success rates at 24months with Kaplan-Meier analysis and incidence of adverse events.The baseline IOPs were 20.46.0mmHg and 21.26.1 (meanstandard deviation, p=0.49) on 3.21.1 and 3.11.0 medications (p=0.53) compared to 11.85.2 and 12.83.7 (p=0.36) on 0.50.8 and 0.61.0 medications (p=0.63) at 2years in the MMC and CM groups, respectively. Kaplan-Meier analysis demonstrated complete success rates were similar in both groups at 24months: 38.47.6% with MMC and 56.27.9% with CM (meanstandard error, p=0.112, log rank test); however, a significantly higher incidence of failure due to persistent hypotony was observed with MMC (p=0.002).Use of the CM implant at the time of trabeculectomy or combined phacoemulsification and trabeculectomy is associated with similar complete success rates compared to adjunctive MMC; however, the risk of persistent hypotony is higher with MMC.ClinicalTrials.gov registration number NCT01440751 . Registered 9/14/11.


Rajala A.,The University of Oklahoma Health Sciences Center | Rajala A.,Dean McGee Eye Institute | Wang Y.,The University of Oklahoma Health Sciences Center | Wang Y.,Dean McGee Eye Institute | And 2 more authors.
Oncotarget | Year: 2016

In humans, daylight vision is primarily mediated by cone photoreceptors. These cells die in age-related retinal degenerations. Prolonging the life of cones for even one decade would have an enormous beneficial effect on usable vision in an aging population. Photoreceptors are postmitotic, but shed 10% of their outer segments daily, and must synthesize the membrane and protein equivalent of a proliferating cell each day. Although activation of oncogenic tyrosine kinase and inhibition of tyrosine phosphatase signaling is known to be essential for tumor progression, the cellular regulation of this signaling in postmitotic photoreceptor cells has not been studied. In the present study, we report that a novel G-protein coupled receptor-mediated insulin receptor (IR) signaling pathway is regulated by non-receptor tyrosine kinase Src through the inhibition of protein tyrosine phosphatase IB (PTP1B). We demonstrated the functional significance of this pathway through conditional deletion of IR and PTP1B in cones, in addition to delaying the death of cones in a mouse model of cone degeneration by activating the Src. This is the first study demonstrating the molecular mechanism of a novel signaling pathway in photoreceptor cells, which provides a window of opportunity to save the dying cones in retinal degenerative diseases.


Allan E.J.,Dean McGee Eye Institute | Khaimi M.A.,Dean McGee Eye Institute | Jones J.M.,The University of Oklahoma Health Sciences Center | Ding K.,The University of Oklahoma Health Sciences Center | Skuta G.L.,Dean McGee Eye Institute
Ophthalmology | Year: 2015

Purpose To investigate the long-term surgical outcomes of the Baerveldt 250 mm2 versus Baerveldt 350 mm2 glaucoma drainage implants (GDIs) (Abbott Laboratories Inc., Abbott Park, IL) in the treatment of refractory glaucoma. Design Comparative case study. Participants A total of 89 consecutive eyes in 86 patients treated at Dean McGee Eye Institute between January 2006 and December 2008. Methods We retrospectively reviewed patient data from the following postoperative visits: 1 week, 1 month, 2 months, 3 months, 6 months, and every 3 months thereafter. Postoperative complications were also recorded. The mean follow-up time was 40 months (range, 2-78 months) for the Baerveldt 250 mm2 group and 31 months (range, 3-75 months) for the Baerveldt 350 mm2 group. Main Outcome Measures The primary outcome measure was surgical success. Secondary outcome measures included visual acuity (VA), intraocular pressure (IOP), and number of medications. Results There was no difference in surgical success (P = 0.98). No significant differences were observed in VA measured using the logarithm of the minimum angle of resolution (logMAR) scale, IOP, and number of medications at the last visit (P = 0.09, 0.23, and 0.82, respectively). Complication and failure rates were comparable (P = 0.82 and 0.64, respectively). Conclusions With a mean follow-up of 40 and 31 months, no differences in surgical success, VA, IOP, number of medications at the last visit, and complication/failure rates were noted between the Baerveldt 250 mm2 and 350 mm2 GDIs, respectively. The size of the GDI may not be associated with surgical outcomes. © 2015 American Academy of Ophthalmology.


Sluch I.M.,Dean McGee Eye Institute | Siatkowski R.L.,Dean McGee Eye Institute | Shah V.A.,Dean McGee Eye Institute
Cornea | Year: 2016

Purpose: To report a case of Mycobacterium chelonae scleral abscess after an intravitreal injection of ranibizumab. Methods: A 54-year-old female received an intravitreal ranibizumab injection for diabetic macular edema. Two weeks postinjection, a scleral abscess developed at the injection site. The patient was treated with incision and drainage of the abscess, subconjunctival injection of amikacin, topical clarithromycin and amikacin, and oral clarithromycin. Results: After 4 weeks of treatment, the inflammation and infection resolved, and the patient returned to best-corrected preinjection visual acuity. Conclusions: Injection-site scleral abscesses are very rare and serious complications of intravitreal injections. Once the abscess is drained, it is possible to identify the organism and treat the infection with appropriate combination antibiotic therapy. © 2016 Wolters Kluwer Health, Inc.


Agbaga M.-P.,The University of Oklahoma Health Sciences Center | Agbaga M.-P.,Dean McGee Eye Institute | Tam B.M.,University of British Columbia | Wong J.S.,University of British Columbia | And 4 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Autosomal dominant Stargardt macular dystrophy caused by mutations in the Elongation of Very Long Chain fatty acids (ELOVL4) gene results in macular degeneration, leading to early childhood blindness. Transgenic mice and pigs expressing mutant ELOVL4 develop progressive photoreceptor degeneration. The mechanism by which these mutations cause macular degeneration remains unclear, but have been hypothesized to involve the loss of an ER-retention dilysine motif located in the extreme C-terminus. Dominant negative mechanisms and reduction in retinal polyunsaturated fatty acids also have been suggested. To understand the molecular mechanisms involved in disease progression in vivo, we addressed the hypothesis that the disease-linked C-terminal truncation mutant of ELOVL4 exerts a dominant negative effect on wild-type (WT) ELOVL4, altering its subcellular localization and function, which subsequently induces retinal degeneration and loss of vision. Methods. We generated transgenic Xenopus laevis that overexpress HA-tagged murine ELOVL4 variants in rod photoreceptors. Results. Tagged or untagged WT ELOVL4 localized primarily to inner segments. However, the mutant protein lacking the dilysine motif was mislocalized to post-Golgi compartments and outer segment disks. Coexpression of mutant and WT ELOVL4 in rods did not result in mislocalization of the WT protein to outer segments or in the formation of aggregates. Fulllength HA-tagged ELOVL4 lacking the dilysine motif (K308R/K310R) necessary for targeting the WT ELOVL4 protein to the endoplasmic reticulum was similarly mislocalized to outer segments. Conclusions. We propose that expression and outer segment mislocalization of the diseaselinked 5-base-pair deletion mutant ELOVL4 protein alters photoreceptor structure and function,which subsequently results in retinal degeneration, and suggest three possible mechanisms by which mutant ELOVL4 may induce retinal degeneration in STGD3. © 2014 The Association for Research in Vision and Ophthalmology, Inc.


Zhang Q.,Emory University | Randleman J.B.,Emory University | Stulting R.D.,Emory University | Lee W.B.,Eye Consultants of Atlanta | And 4 more authors.
Archives of Ophthalmology | Year: 2010

Objective: To evaluate the clinical features of and histologic findings from failed Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: This retrospective observational case series evaluated 47 consecutive corneal specimens from 42 patients who underwent either penetrating keratoplasty or repeated DSAEK for failed DSAEK. Clinical information was obtained for the cases. Sections of the specimenswere examined using light microscopy. Immunohistochemical staining was performed for cytokeratins AE1/AE3 and for the myogenic marker smooth-muscle actin when indicated. Transmission electron microscopic examination was performed in some cases. Results: Graft survival ranged from 0.5 to 34 months. Histologic examination showed that 94% of the specimens (44 of 47) had endothelial cell loss. Residual host Descemet membrane (19%; 9 of 47), fibrocellular tissue (19%; 9 of 47), epithelial implantation (15%; 7 of 47), and fungal infection (4%; 2 of 47) were also identified. Immunohistochemical stains were positive for AE1/AE3 in the epithelial implantations and for smooth-muscle actin in cells in the fibrocellular proliferations. Conclusions: The principal cause of failed DSAEK is endothelial cell loss. Residual host Descemet membrane, fibrocellular tissue at the edge of the lenticule, and epithelial implantation are common histologic findings. Fungal infection may occur in the setting of DSAEK. ©2010 American Medical Association. All rights reserved.


Yu M.,The University of Oklahoma Health Sciences Center | Yu M.,University of Sichuan | Benham A.,The University of Oklahoma Health Sciences Center | Benham A.,Dean McGee Eye Institute | And 10 more authors.
Journal of Lipid Research | Year: 2012

We hypothesized that reduction/loss of very long chain PUFAs (VLC-PUFAs) due to mutations in the ELOngase of very long chain fatty acid-4 (ELOVL4) protein contributes to retinal degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3) and age-related macular degeneration; hence, increasing VLC-PUFA in the retina of these patients could provide some therapeutic benefits. Thus, we tested the efficiency of elongation of C20-C22 PUFA by the ELOVL4 protein to determine which substrates are the best precursors for biosynthesis of VLCPUFA. The ELOVL4 protein was expressed in pheochromocytoma cells, while green fluorescent protein-expressing and nontransduced cells served as controls. The cells were treated with 20:5n3, 22:6n3, and 20:4n6, either individually or in equal combinations. Both transduced and control cells internalized and elongated the supplemented FAs to C22-C26 precursors. Only ELOVL4-expressing cells synthesized C28-C38 VLC-PUFA from these precursors. In general, 20:5n3 was more efficiently elongated to VLC-PUFA in the ELOVL4-expressing cells, regardless of whether it was in combination with 22:6n3 or with 20:4n6. In each FA treatment group, C34 and C36 VLC-PUFAs were the predominant VLC-PUFAs in the ELOVL4-expressing cells. In summary, 20:5n3, followed by 20:4n6, seems to be the best precursor for boosting the synthesis of VLC-PUFA by ELOVL4 protein. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.


Bennett L.D.,The University of Oklahoma Health Sciences Center | Bennett L.D.,Dean McGee Eye Institute | Brush R.S.,The University of Oklahoma Health Sciences Center | Brush R.S.,Dean McGee Eye Institute | And 10 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Autosomal dominant Stargardt-like macular dystrophy (STGD3) is a juvenile-onset disease that is caused by mutations in Elovl4 (elongation of very long fatty acids-4). The Elovl4 catalyzes the first step in the conversion of C24 and longer fatty acids (FAs) to very long-chain FAs (VLC-FAs, ≥C26). Photoreceptors are particularly rich in VLC polyunsaturated FAs (VLC-PUFA). To explore the role of VLC-PUFAs in photoreceptors, we conditionally deleted Elovl4 in the mouse retina. Methods. Proteins were analyzed by Western blotting and lipids by gas chromatography (GC)-mass spectrometry, GC-flame ionization detection, and tandem mass spectrometry. Retina function was assessed by electroretinography (ERG), and structure was evaluated by bright field, immunofluorescence, and transmission electron microscopy. Results. Conditional deletion (KO) of retinal Elovl4 reduced RNA and protein levels by 91% and 96%, respectively. Total retina VLC-PUFAs were reduced by 88% compared to the wild type (WT) levels. Retinal VLC-PUFAs incorporated in phosphatidylcholine were less abundant at 12 months compared to 8-week-old levels. Amplitudes of the ERG a-wave were reduced by 22%, consistent with photoreceptor degeneration (11% loss of photoreceptors). Analysis of the rod a-wave responses gave no evidence of a role for VLC-PUFA in visual transduction. However, there were significant reductions in rod b-wave amplitudes (>30%) that could not be explained by loss of rod photoreceptors. There was no effect of VLC-PUFA reduction on cone ERG responses, and cone density was not different between the WT and KO mice at 12 months of age. Conclusions. The VLC-PUFAs are important for rod, but not cone, function and for rod photoreceptor longevity. © 2014 The Association for Research in Vision and Ophthalmology, Inc.


Bennett L.D.,The University of Oklahoma Health Sciences Center | Bennett L.D.,Dean McGee Eye Institute | Hopiavuori B.R.,Dean McGee Eye Institute | Hopiavuori B.R.,The University of Oklahoma Health Sciences Center | And 8 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Juvenile-onset autosomal dominant Stargardt-like macular dystrophy (STGD3) is caused by mutations in ELOVL4 (elongation of very long fatty acids-4), an elongase necessary for the biosynthesis of very long chain fatty acids (VLC-FAs ≥ C26). Photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which are necessary for long-term survival of rod photoreceptors. The purpose of these studies was to determine the effect of deletion of VLC-PUFAs on rod synaptic function in retinas of mice conditionally depleted (KO) of Elovl4. Methods. Retina function was assessed in wild-type (WT) and KO by electroretinography. Outer plexiform structure was evaluated by immunofluorescence and transmission electron microscopy. Single-cell recordings measured rod ion channel operation and rod bipolar glutamate signaling. Sucrose gradient centrifugation was used to isolate synaptosomes from bovine retina. Proteins and lipids were analyzed by Western blotting and tandem mass spectroscopy, respectively. Results. Inner retinal responses (b-wave, oscillatory potentials, and scotopic threshold responses) of the ERG were decreased in the KO mice compared to controls. However the rod ion channel operation and bipolar glutamate responses were comparable between groups. Biochemical analysis revealed that conventional and ribbon synapses have VLC-PUFAs. Ultrastructural analysis showed that the outer plexiform layer was disorganized and the diameter of vesicles in rod terminals was smaller in the KO mice. Conclusions. Very long chain PUFAs affect rod function by contributing to synaptic vesicle size, which may alter the dynamics of synaptic transmission, ultimately resulting in a loss of neuronal connectivity and death of rod photoreceptors. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

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