Genetics and Age-Related Eye Disease Study Formulation Interaction in Neovascular Age-Related Macular Degeneration.

Purpose: This work aims to determine whether previously defined genotype risk groups interact with Age-Related Eye Disease Study formulation (AREDS-F) use in progression to neovascular age-related macular degeneration (nvAMD). Methods: We conducted a case-only study of 265 nvAMD patients. Patients were anonymously genotyped at the complement factor H and age-related maculopathy susceptibility 2 loci and segregated into genotype groups (GTGs) defined by specific combinations of risk alleles. Physicians, who were blind to patients' GTGs, obtained patients' AREDS-F use history. The facility performing genetic analysis was blind to the AREDS-F use history. We used logistic analysis to estimate the interaction coefficient between AREDS-F use and GTG 2 vs GTG 3 in a general-population model. Results: The odds ratio of numbers of patients reporting prior AREDS-F use to nonuse for GTG 2 vs GTG 3 was 4.18 (P = .001). Logistic regression, correcting for nongenetic risk factors, gave an estimate of the ß for interaction of AREDS-F with genotype of 1.57 (P = .001). This estimates a corrected odds ratio associated with the effect of interaction of 4.81 between those in GTG 2 compared with those in GTG 3. Conclusions: Our data indicate an interaction between GTGs and AREDS-F use that is consistent in size and direction with previously published reports, which had found that using AREDS-F supplements significantly increases the risk of nvAMD for some users and significantly protects other users.

The Use of a Venous Catheter as a Stent for Treatment of Acquired Punctal and Canalicular Stenosis.

PURPOSE: The aim of this study was to describe a simple technique to insert a venous catheter as a stent for the treatment of acquired punctal and canalicular stenosis. METHODS: We performed this technique using a central venous catheter as a stent for the treatment of acquired punctal and canalicular stenosis. RESULTS: The results show the easy availability of the material used for the intervention, its easy execution, and the low costs of materials. The goal of this technique is to have a lacrimal dot dilated and canalicular duct easy to irrigate. CONCLUSION: The use of a venous catheter as a stent for treatment of acquired punctal and canalicular stenosis seems to be simple, safe, repeatable, and noninvasive.

The Use of a Double Suture and Conjunctival Cuts in the Lateral Tarsal Strip: A New Approach to Involutional Ectropion.

PURPOSE: To describe the use of a double suture and conjunctival cuts in the lateral tarsal strip (LTS) and to evaluate postsurgical outcome in patients with severe involutional ectropion. METHODS: A prospective randomized study was conducted on 16 eyelids of 8 patients with symptomatic severe involutional ectropion. The 8 patients were between 62 and 79 years. They were distributed into 2 groups consisting of 4 patients each. The control group was treated with a conventional lateral tarsal strip (C-LTS), the second group underwent a modified lateral tarsal strip (M-LTS). The mean follow-up was 18 months. Success was defined as relief in lid laxity. The recurrence rate was also evaluated. RESULTS: Patients treated with M-LTS showed lower horizontal laxity (3.5 ±â€Š0.2) than patients treated with C-LTS (5.7 ±â€Š0.2). During the 18-month follow-up, a statistically significant difference was found between the 2 groups with P value <0.05. CONCLUSIONS: The use of a double suture and conjunctival cuts in the lateral tarsal strip proposed by Meduri showed a reduction of postsurgical ectropion's grade and postsurgical recurrences. This technique could be used for the treatment of patients with a severe ectropion.

Cataract surgery on post radial keratotomy patients.

This study aims to evaluate and to compare three different approaches of cataract surgery to patients with previous radial keratotomy (RK), and to analyze the mechanical properties of the cornea after cataract surgery. Three groups of patients, each one including 8 eyes of patients with 16 RK incisions. The first group includes eyes with the first cataract incision superiorly, the second group in the temporal area, the third group in temporal area and a precautionary stabilizing suture across the RK incision adjacent to the main tunnel. In the first group intraoperative dehiscence occurred in three eyes (37.5%): it required immediate application of a suture. In the second group dehiscence occurred intraoperatively in two radial scars (20%): it required immediate application of a suture. In the third group, no intraoperative dehiscences were observed. The stabilizing suture of the RK incision works safer, with a lower risk of dehiscences and less post-operative astigmatism.

Trypan blue as a surgical adjunct in pediatric cataract surgery.

PURPOSE: To study the effect of trypan blue on lens capsule elasticity and ease of completing a continuous curvilinear capsulorhexis (CCC) in a sheep lens model and to subsequently observe the effects of trypan blue in the surgical setting of 3 pediatric patients. SETTING: State University of New York, Downstate Medical Center, Brooklyn, New York, USA. DESIGN: Prospective case series. METHODS: Twenty-four lenses were excised from fresh sheep globes. Twelve lenses were immersed in trypan blue for 2.5 minutes, and 12 lenses were immersed in a balanced salt solution for 2.5 minutes. Ease of completion of CCC was graded, and intralenticular pressure was quantified. A pediatric cataract surgeon used trypan blue to stain the lens capsules of 3 children during cataract surgery. The surgeon noted the effects of trypan blue on capsule elasticity and on the ease of completion of the CCC. RESULTS: Lenses immersed in trypan blue had a mean score of 2.58 in ease of completion of capsulorhexis compared with the control group (1.5) (P = .031). Capsulorhexis was successfully completed in 91.7% of trypan blue cases compared with 58.3% of controls. Immersion in trypan blue decreased the intralenticular pressure by a mean of 4.5 mm Hg (P = .025). Successful capsulorhexis was completed in the 3 pediatric cases. CONCLUSION: Trypan blue improved the success rate of CCC completion in the sheep lens by decreasing lens capsule elasticity. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Human Platelet Lysate as a Replacement for Fetal Bovine Serum in Limbal Stem Cell Therapy.

PURPOSE: To evaluate the use of human platelet lysate (HPL) as an alternative supplement for limbal explant culture. METHODS: Culture media were prepared using either 10% pooled HPL (PHPL), single donor HPL, or fetal bovine serum (FBS). Limbal tissues, obtained from the Minnesota Lions Eye Bank, were cultured in each medium on plastic plates or on denuded amniotic membrane (AM). Immunofluorescence staining was performed for ABCG2, tumor protein p63α, and cytokeratin 3 (K3). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to evaluate the expression of ABCG2 and p63. Limbal explants grown in each medium were labeled with bromodeoxyuridine (BrdU) to assess the proliferative capacity in each medium. Concentration of growth factors including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß), and platelet derived growth factor (PDGF) in HPL and PHPL was compared to that in human serum (HS). RESULTS: Immunofluorescence staining on AM showed prominent expression of ABCG2, p63α but sparse expression of K3 in HPL and PHPL supplemented medium. Real time-PCR showed 1.7 fold higher expression of ABCG2 in PHPL supplemented medium (p = 0.03), and similar expression of p63 in HPL and PHPL supplemented medium compared to FBS medium. The proliferation assay showed that LSCs retained their proliferative potential in HPL supplemented medium. Higher concentration of growth factors were found in HPL, compared to HS. CONCLUSIONS: Human platelet lysate has higher concentration of grown factors and is effective in maintaining growth and stem cell phenotype of corneal limbal explant cultures.

Iritis, glaucoma and corneal decompensation associated with BrightOcular cosmetic iris implant.

PURPOSE: NewColorIris cosmetic iris implants have a record of high ocular morbidity and are no longer in use. Newer generation of iris implants, BrightOcular, have patented posterior grooves in order to decrease iris touch and facilitate aqueous flow around the implant. However, little is known about their safety despite their implantations in 10 countries. METHODS: Collaborative case series of patients who had bilateral implantation of cosmetic iris implants solely for cosmetic reasons. RESULTS: 12 cases were collected being distributed as Caucasian (10) and Asian (2), women (11) and man (1) and with a mean age of 32 years. Ocular manifestations were present in 11 subjects and included anterior uveitis (10 of 12; 83.3%), glaucoma (7 of 12; 58.3%) and corneal decompensation (6 of 12; 50%). Visual acuity was normal in seven, decreased in five with two having visual recovery following explantation of the implant. Glaucoma could not be controlled medically in two patients. CONCLUSIONS: Cosmetic iris implants carry the risk of ocular damage when implanted in the anterior chamber of normal phakic eyes.

Rare Anterior Segment Retinoblastoma Masquerading as Corneal Endotheliitis.

We present a unique case involving a 6-year-old female with a unilateral corneal endotheliitis-like finding, who was ultimately found to have a form of anterior diffuse infiltrating retinoblastoma with no evidence of retinal involvement. The patient's presumed endotheliitis was initially treated with topical dexamethasone and oral acyclovir without improvement. She then underwent multiple fine-needle aspirations of anterior chamber fluid, which were negative for abnormal findings of viral polymerase chain reaction, viral cultures, and flow cytometry. Months after initial presentation, an anterior chamber angle mass developed and a biopsy identified retinoblastoma cells. The patient underwent plaque radiotherapy of the cornea and systemic chemotherapy. The patient regained good vision and is tumor-free at 13 months. Anterior inflammation is a rare form of masquerade syndrome associated with retinoblastoma; however, it tends to be associated with diffuse posterior segment retinoblastoma when it does occur. Diffuse anterior retinoblastoma is a rare form of retinoblastoma with no apparent focus in the retina. Ultimately, our patient developed an anterior chamber angle lesion, which was biopsied and proven to be retinoblastoma. Unusual corneal endotheliitis-like findings in children that are not responsive to conventional treatment should raise the clinician's suspicion of malignancy, even when no retinal lesion is detected.

Boston Keratoprosthesis: Outcomes and Complications: A Report by the American Academy of Ophthalmology.

OBJECTIVE: To review the published literature on safety and outcomes of the Boston type I keratoprosthesis (BI-KPro) for the surgical treatment of corneal opacification not amenable to human cadaveric corneal transplantation. METHODS: Searches of peer-reviewed literature were conducted in PubMed and the Cochrane Library in December 2012, July 2013, and January 2014 without date restrictions. The searches were limited to studies published in English and yielded 587 citations. The abstracts of these articles were reviewed, 48 articles were selected for possible clinical relevance, and 22 were determined to be relevant for the assessment objectives. Nine studies were rated as level II evidence and 13 studies were rated as level III evidence. Excluded were level III evidence, case reports, review articles, letters, editorials, and case series with fewer than 25 eyes. RESULTS: In 9 articles, a best-corrected Snellen visual acuity (BCSVA) of 20/200 or better occurred in 45% to 89% of eyes. Five articles described a BCSVA of 20/50 or better in 43% to 69% of eyes, and 4 articles found a BCSVA of 20/40 or better in 11% to 39% of eyes. Retention rates of the BI-KPro ranged from 65% to 100%. Reasons for loss of vision after BI-KPro implantation most commonly included corneal melts resulting from exposure keratopathy, endophthalmitis, and infectious keratitis or corneal ulceration. The 2 most common complications after surgery were retroprosthetic membrane formation (range, 1.0%-65.0%; mean ± standard deviation [SD], 30.0±19.0%) and elevated intraocular pressure (range, 2.4%-64.0%; mean ± SD, 27.5±18.1%). The 2 most common posterior segment complications were endophthalmitis (range, 0%-12.5%; mean ± SD, 4.6±4.6%) and vitritis (range, 0%-14.5%; mean ± SD, 5.6±4.7%). CONCLUSIONS: The reviewed articles on BI-KPro use suggest that the device improves vision in cases of severe corneal opacification that were not amenable to corneal transplantation using human cadaveric keratoplasty techniques. A number of severe anterior and posterior segment complications can develop as follow-up continues, making ongoing close observation paramount for patients undergoing this surgery. These complications include infection, device extrusion, and permanent vision loss.

The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents.

p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. We characterized the activity of AMG 232 and its effect on p53 signaling in several preclinical tumor models. AMG 232 binds the MDM2 protein with picomolar affinity and robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation. AMG 232 treatment inhibited the in vivo growth of several tumor xenografts and led to complete and durable regression of MDM2-amplified SJSA-1 tumors via growth arrest and induction of apoptosis. Therapeutic combination studies of AMG 232 with chemotherapies that induce DNA damage and p53 activity resulted in significantly superior antitumor efficacy and regression, and markedly increased activation of p53 signaling in tumors. These preclinical data support the further evaluation of AMG 232 in clinical trials as both a monotherapy and in combination with standard-of-care cytotoxics.

A mutation in Ampd2 is associated with nephrotic syndrome and hypercholesterolemia in mice.

BACKGROUND: Previously, we identified three loci affecting HDL-cholesterol levels in a screen for ENU-induced mutations in mice and discovered two mutated genes. We sought to identify the third mutated gene and further characterize the mouse phenotype. METHODS: We engaged, DNA sequencing, gene expression profiling, western blotting, lipoprotein characterization, metabolomics assessment, histology and electron microscopy in mouse tissues. RESULTS: We identify the third gene as Ampd2, a liver isoform of AMP Deaminase (Ampd), a central component of energy and purine metabolism pathways. The causative mutation was a guanine-to-thymine transversion resulting in an A341S conversion in Ampd2. Ampd2 homozygous mutant mice exhibit a labile hypercholesterolemia phenotype, peaking around 9 weeks of age (251 mg/dL vs. wildtype control at 138 mg/dL), and was evidenced by marked increases in HDL, VLDL and LDL. In an attempt to determine the molecular connection between Ampd2 dysfunction and hypercholesterolemia, we analyzed hepatic gene expression and found the downregulation of Ldlr, Hmgcs and Insig1 and upregulation of Cyp7A1 genes. Metabolomic analysis confirmed an increase in hepatic AMP levels and a decrease in allantoin levels consistent with Ampd2 deficiency, and increases in campesterol and ß-sitosterol. Additionally, nephrotic syndrome was observed in the mutant mice, through proteinuria, kidney histology and effacement and blebbing of podocyte foot processes by electron microscopy. CONCLUSION: In summary we describe the discovery of a novel genetic mouse model of combined transient nephrotic syndrome and hypercholesterolemia, resembling the human disorder.

Delayed presentation of retained nuclear fragment following phacoemulsification cataract extraction.

UNLABELLED: An 87-year-old woman presented 11 months after routine phacoemulsification cataract extraction and posterior chamber intraocular lens implantation in her left eye complaining of the abrupt onset of redness and decreased vision in that eye. Examination revealed a mild anterior chamber reaction and significant corneal edema. The eye was minimally responsive to topical steroid therapy, and initial serial slitlamp examinations with gonioscopy were unrevealing. After multiple head-positioning maneuvers were performed, a retained nuclear fragment was uncovered. The nuclear fragment was aspirated and liquefied by the phacoemulsification device in the anterior chamber. A retained nuclear fragment with an intact posterior capsule is a recognized cause of inflammation in the immediate postoperative presentation. Delayed presentation of symptoms is rare and presumably secondary to sequestration of the fragment behind the iris. We present a case and a review of the literature regarding sequestered retained nuclear fragments following what is initially thought to be uneventful cataract extraction. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Integrins protect cardiomyocytes from ischemia/reperfusion injury.

Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7ß1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of ß1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7ß1D exposed to I/R had a substantial reduction in infarct size compared with that of α5ß1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7ß1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that ß1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7ß1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.