Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.

To assess whether Tie2-mediated vascular stabilization ameliorates neovascular age-related macular degeneration (AMD), we investigated the impact of adeno-associated virus-mediated gene therapy with cartilage oligomeric matrix protein angiopoietin-1 (AAV2.COMP-Ang1) on choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) in a mouse model of the disease. We treated mice with subretinal injections of AAV2.COMP-Ang1 or control (AAV2.AcGFP, AAV2.LacZ, and phosphate-buffered saline). Subretinal AAV2 localization and plasmid protein expression was verified in the retinal pigment epithelium (RPE)/choroid of mice treated with all AAV2 constructs. Laser-assisted simulation of neovascular AMD was performed and followed by quantification of HIF, VEGF, and CNV in each experimental group. We found that AAV2.COMP-Ang1 was associated with a significant reduction in VEGF levels (29-33%, p < 0.01) and CNV volume (60-70%, p < 0.01), without a concomitant decrease in HIF1-α, compared to all controls. We concluded that a) AAV2 is a viable vector for delivering COMP-Ang1 to subretinal tissues, b) subretinal COMP-Ang1 holds promise as a prospective treatment for neovascular AMD, and c) although VEGF suppression in the RPE/choroid may be one mechanism by which AAV2.COMP-Ang1 reduces CNV, this therapeutic effect may be hypoxia-independent. Taken together, these findings suggest that AAV2.COMP-Ang1 has potential to serve as an alternative or complementary option to anti-VEGF agents for the long-term amelioration of neovascular AMD.

Femoral Artery Closure Devices vs Manual Compression During Cardiac Catheterization and Percutaneous Coronary Intervention.

Background: Femoral arterial access remains widely used despite recent increase in radial access for cardiac catheterization and percutaneous coronary intervention (PCI). Various femoral artery closure devices have been developed and are commonly used to shorten vascular closure times, with variable rates of vascular complications observed in clinical trials. We sought to examine the rates of contemporary outcomes during diagnostic catheterization and PCI with the most common femoral artery closure devices. Methods: We identified patients who had undergone either diagnostic catheterization alone (n = 14,401) or PCI (n = 11,712) through femoral artery access in the Indiana University Health Multicenter Cardiac Cath registry. We compared outcomes according to closure type: manual compression, Angio-Seal, Perclose, or Mynx. Access complications and bleeding outcomes were measured according to National Cardiovascular Data â€‹Registry standard definitions. Results: The use of any vascular closure device as compared to manual femoral arterial access hold was associated with a significant reduction in vascular access complications and bleeding events in patients who underwent PCI. No significant difference in access-site complications was observed for diagnostic catheterization alone. Among closure devices, Perclose and Angio-Seal had a lower rate of hematoma than Mynx. Conclusions: The use of femoral artery access closure devices is associated with a reduction in vascular access complication rates as compared to manual femoral artery compression in patients who undergo PCI.

Keratoplasty Outcomes in Patients With Uveitis.

PURPOSE: To examine the corneal transplant failure rates and associations with uveitic eye disease. METHODS: The retrospective chart review identified 70 eyes from 42 patients with uveitis that underwent 40 primary transplants and 30 repeat transplants at 2 major academic centers over a 9-year period. The graft failure rate was calculated. Variables hypothesized to be associated with graft failure were analyzed as covariates using a Cox proportional hazards analysis clustered by the patients to determine their association with failure rates. RESULTS: Of the 70 grafts, the mean duration of follow-up for patients was 40.6 months (range 4-90 months) and the median survival time was 24.1 months (interquartile range of 9-290 months). Twenty-two patients (52%) had graft failure. There was a higher rate of graft failure in patients with infectious uveitis as compared to those with noninfectious uveitis (hazard ratio 2.46, P = 0.031). Patients with successful grafts had their inflammation controlled for a longer period of time before transplantation as compared to those with failed grafts (38.6 vs. 13.6 months, P = 0.004). Worse preoperative visual acuities were significantly associated with graft failure (P < 0.001). CONCLUSIONS: There is limited knowledge of corneal transplant outcomes in uveitic patients in the current literature. In our study, over half of the grafts failed. Infectious uveitis (especially viral) was a strong predictor of graft failure. A shorter period of inflammation control before transplantation, previously failed grafts, and worse preoperative visual acuity were also associated with graft failure.

Adaptive optics ophthalmoscopy, multifocal ERG and OCTA in unique case of suspected torpedo maculopathy presenting with vitelliform lesion.

PURPOSE: To report the case of a ten-year old girl with torpedo maculopathy with a complete vitelliform lesion and describe associated optical coherence tomography (OCT), OCT angiography (OCTA), multifocal electroretinogram (ERG) and adaptive optics ophthalmoscopy (AOO) imaging of the lesion. OBSERVATIONS: An asymptomatic ten-year old girl with visual acuity of 20/15 OU was referred for evaluation of possible Best's disease of her left eye. The unilaterality, location, and shape of the lesion was consistent with torpedo maculopathy. OCT and autofluorescence (AF) revealed that the entire lesion was composed of subretinal hyperreflective material that was hyperautofluorescent, consistent with vitelliform material. Within the boundary of the lesion, OCTA showed reduced choriocapillaris density while adjacent to the lesion, the choriocapillaris density was slightly increased. Microperimetry demonstrated normal sensitivity in both eyes, electrooculograms (EOG) were normal and multifocal ERG showed symmetrical mildly supernormal amplitudes. Additionally, AOO demonstrated that nasal to the lesion there were clusters of hyper-reflective areas, and immediately adjacent to the lesion cones were poorly resolved. However, there was a return to more normal photoreceptor architecture outside of the lesion. CONCLUSIONS AND IMPORTANCE: Torpedo maculopathy lesions typically present with outer retinal attenuation and retinal pigmented epithelium (RPE) atrophy. Vitelliform material was recently observed for the first time in association with Torpedo maculopathy in a case report that described small vitelliform material at the periphery of the lesion. We report the second case of torpedo maculopathy associated with a vitelliform lesion and the first description of a torpedo lesion composed fully of presumed vitelliform material. We also describe findings of OCTA, multifocal ERG and AOO imaging in torpedo maculopathy with vitelliform lesion.

The temporal stability and predictive validity of pupils' causal attributions for difficult classroom behaviour.

BACKGROUND: Recent studies have investigated the causal attributions for difficult pupil behaviour made by teachers, pupils, and parents but none have investigated the temporal stability or predictive validity of these attributions. AIMS: This study examines the causal attributions made for difficult classroom behaviour by students on two occasions 30 months apart. The longitudinal stability of these attributions is considered as is the predictive validity of the first set of attributions in relation to teachers' later judgments about individual students' behaviour. SAMPLE: Two hundred and seventeen secondary school age pupils (114 males, 103 females) provided data on the two occasions. Teachers also rated each student's behaviour at the two times. METHOD: A questionnaire listing 63 possible causes of classroom misbehaviour was delivered to pupils firstly when they were in Year 7 (aged 11-12) and then again, 30 months later. Responses were analysed through exploratory factor analysis (EFA). Additionally, teachers were asked to rate the standard of behaviour of each of the students on the two occasions. RESULTS: EFA of the Years 7 and 10 data indicated that pupils' attributions yielded broadly similar five-factor models with the perceived relative importance of these factors remaining the same. Analysis also revealed a predictive relationship between pupils' attributions regarding the factor named culture of misbehaviour in Year 7, and teachers' judgments of their standard of behaviour in Year 10. CONCLUSION: The present study suggests that young adolescents' causal attributions for difficult classroom behaviour remain stable over time and are predictive of teachers' later judgments about their behaviour.

Case Series of Stickler Syndrome Presenting With Acute Angle Closure.

PURPOSE: Stickler syndrome is associated with open-angle glaucoma, but no reports exist of adults presenting with acute angle closure. Here, we report the clinical associations and short-term outcomes in 2 patients with Stickler syndrome who presented with acute angle closure at a single tertiary referral center. OBSERVATIONS: A 36-year-old female with Stickler syndrome presented with acute onset of red and painful left eye with cloudy vision. Initial intraocular pressure (IOP) was measured to be 54 mm Hg. Gonioscopy revealed no angle structures or peripheral anterior synechiae in the left eye. Two laser peripheral iridotomies were created 5 days apart without adequate IOP lowering. Left eye cataract extraction with intraocular lens implantation and Ahmed glaucoma drainage device implantation were performed with resolution of ocular hypertension.A 35-year-old male with Stickler syndrome presented with intermittent right eye pain and blurry vision. IOP was 42 mm Hg and gonioscopy revealed 270 degrees of angle closure in the right eye. The patient underwent laser peripheral iridotomy in the right eye with resolution of ocular hypertension by the next day. CONCLUSIONS: Recognizing angle closure as a potential feature of Stickler syndrome can help providers adequately screen and manage patients with Stickler syndrome presenting with acutely elevated IOP.

Chronic kidney disease and dipstick proteinuria are risk factors for stent thrombosis in patients with myocardial infarction.

BACKGROUND: Kidney failure (stage 5 chronic kidney disease [CKD]) is an independent risk factor for stent thrombosis (ST). Moderate (stage 3-4) CKD and proteinuria are both associated with adverse cardiovascular events, including worse outcomes after myocardial infarction (MI). Whether moderate CKD and proteinuria increase the risk of ST after MI is not known. This study evaluated the risk of ST associated with moderate CKD and dipstick proteinuria. METHODS: We retrospectively analyzed clinical and laboratory data from 956 non-stage 5 CKD patients who were admitted with MI and received intracoronary stenting. Clinical follow-up was collected at 1 year for definite or probable ST, as well as for all-cause mortality, nonfatal MI or death, and target vessel revascularization or coronary artery bypass graft surgery. RESULTS: After adjustment for multiple clinical and biochemical covariates, patients with both estimated glomerular filtration rate (GFR) of 15 to 59 mL min(-1) 1.73 m(-2) and > or =30 mg/dL dipstick proteinuria had increased cumulative incidence of ST (hazard rate [HR] 3.69, 95% CI 1.54-8.89), all-cause mortality (HR 2.68, 95% CI 1.34-5.37), and nonfatal MI or death (HR 3.20, 95% CI 1.77-5.81) at 1 year. In addition, estimated GFR of 15 to 59 mL min(-1) 1.73 m(-2) was a significant independent predictor of ST (HR 2.61, 95% CI 1.33-5.10). Dipstick proteinuria > or =30 mg/dL was associated with a trend toward increased risk for all outcomes. CONCLUSIONS: In an acute MI population, moderate CKD was identified as a novel prognostic marker for ST. In addition, patients with both decreased GFR and proteinuria had higher incidences of all-cause mortality and nonfatal MI or death than patients with either condition alone.

Treatment of Coats' disease: an analysis of pooled results.

AIM: To elucidate the association of treatment modality to vitreoretinal fibrosis and traction retinal detachment (TRD) in Coats' disease. METHODS: A PubMed search for Coats' disease with included studies describing eyes with clinical features and treatment course of Coats' disease. Binary logistic regression with fibrosis at presentation and treatment type as independent variables was performed to determine predictors of TRD historically (since 1921) and in the anti-vascular endothelial growth factor (VEGF) era (since 2007). Odds ratios (OR) with 95% confidence intervals (CI) reported. RESULTS: Of 175 articles described 1183 eyes. Vitreoretinal fibrosis increased from presentation (5.4%) to follow-up (15.5%) and TRD increased from 0.44% to 3.9% at follow up. Laser was protective against vitreoretinal fibrosis (OR 0.6, 95%CI 0.4-0.9) but TRD was borderline (OR 0.6, 95%CI 0.3-1.1). Cryotherapy showed a higher association with TRD (OR 1.9, 95%CI 1.0-3.7) than with vitreoretinal fibrosis (OR 0.8, 95%CI 0.5-1.2). Similarly, intravitreal anti-VEGF alone was not associated with fibrosis (OR 1.1, 95%CI 0.6-1.8) nor TRD (OR 1.1, 95%CI 0.5-2.6) but the combination of laser and anti-VEGF therapy was protective [Fibrosis: 0.1 (0.03, 0.35); TRD: 0.05 (0.01, 0.23)] compared to anti-VEGF plus cryotherapy (P<0.001). Disease stage ≤2B or ≥3A was not associated with TRD. CONCLUSION: Vitreoretinal fibrosis and TRD increase after treatment in Coats' disease. The combination of anti-VEGF agents and cryotherapy may lead to higher risk for TRD. Presence of pre-treatment fibrosis is the highest risk factor for post-treatment worsening of vitreoretinal fibrosis and TRD.

Measuring and treating serum lipids in patients in a chest pain observation unit.

We evaluated opportunities to initiate statin therapy in 574 consecutive subjects admitted to a chest pain observation unit (CPOU). Ten-year Framingham risk scores were retrospectively calculated for all patients according to the National Cholesterol Education Program and Adult Treatment Panel III 2001 recommendations. Subjects were then stratified according to (1) recommendations for initiation of a lipid-lowering medication and (2) whether they received lipid-lowering drug therapy at discharge. Of 574 subjects, we excluded 50 with previously established coronary heart disease or who were already taking a statin medication on presentation, 23 with missing data, and 80 who did not have a low-density lipoprotein (LDL) measurement at admission. Of the remaining 421 subjects, the mean age was 47 years, 40% were men, 57% were white, 31% had hypertension, 27% were current smokers, and 6% had diabetes. Ten-year risk calculation classified 47% (n=199) at low risk (<2 risk factors), 32% (n=134) at moderate risk (>or=2 risk factors and <10% risk), 11% (n=48) at moderate-high risk (10% to 20% risk), and 10% (n=40) at high risk (>20% risk). Of the entire cohort, 23% of subjects (n=96) had hypercholesterolemia, of which 52% (n=50) met indications for initiation of lipid-lowering medication. Only 6% of patients with an indication for treatment (n=3) were prescribed a lipid-lowering medication on discharge, leaving 94% (n=47) untreated for their hypercholesterolemia. In conclusion, patients admitted to a CPOU have a high prevalence of hypercholesterolemia, and therefore, an increased long-term risk for cardiovascular events. In addition to their primary role, CPOUs should focus on primary prevention and reduction of long-term risk.

A Case of Coats Disease and Concurrent Anisometropic Amblyopia.

PURPOSE: The aim of this report was to demonstrate a case of Coats disease in a patient with concurrent anisometropic amblyopia. OBSERVATIONS: A 10-year-old boy was diagnosed with Coats disease during routine ophthalmic examination. Visual acuity was 20/20 OD and 20/50 OS with cycloplegic refraction of +1.25 (OD) and +3.25 (OS). Examination under anesthesia showed macular exudates in the left eye that encroached near the fovea superotemporally. Despite the poor visual acuity and macular exudates, the foveal architecture of both eyes appeared normal on spectral domain optical coherence tomography. Because of the differing refractive error between the two eyes in the presence of foveal-sparing exudates, anisometropic amblyopia was suspected. After initial laser therapy, the patient was started on a daily patching regimen of the right eye. The patient's vision steadily improved to 20/25 OS with a final cycloplegic refraction of +1.00 (OD), +3.00 (OS) at 2 years. This report demonstrates the importance of assessing for other common and treatable causes of vision loss in the setting of Coats disease. CONCLUSIONS AND IMPORTANCE: This case demonstrates the importance of detecting and correcting for concurrent amblyopia in pediatric retina conditions that may, on fundus examination alone, appear to have a retinal cause for reduced visual acuity.

Comparison of a torsional and a standard tip with a monitored forced infusion phacoemulsification system.

PURPOSE: To compare the relative efficiency and chatter of the 30-degree 0.9 mm Kelman tip (standard tip) and Ozil Intrepid Balanced tip (torsional tip) with identical optimum settings. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Porcine nuclei were fixed in formalin and cut into 2.0 mm cubes. Lens cubes were phacoemulsified with standard and torsional tips at 60% and 100% torsional amplitude with 0%, 25%, 50%, 75%, and 100% longitudinal power with monitored forced infusion. Experiments were performed at a constant vacuum, aspiration rate, and intraocular pressure. RESULTS: Linear regression showed increased efficiency with up to 75% longitudinal power at 60% torsional amplitude for both tips (P = .046 standard; P = .0093 torsional). Longitudinal did not significantly increase efficiency at 100% torsional power for either tip. Torsional tips were on average 29% more efficient than standard tips throughout the range tested (P < .0001), and 100% torsional power was on average 45% more efficient than 60% torsional power (P = .0028). Chatter was minimal except at 100% longitudinal power, which was greater than at 75% longitudinal power (P < .0001). At 100% longitudinal power, torsional tips had more chatter than standard tips (at 60% torsional, P < .0001; at 100% torsional, P = .0022). CONCLUSIONS: Increasing up to 75% longitudinal power increased the efficiency at 60% torsional for standard and torsional tips. Torsional tips were more efficient than standard tips. Chatter was generally minimal. Torsional tips showed more chatter than standard tips at 100% longitudinal power. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Risk factors and biomarkers of age-related macular degeneration.

A biomarker can be a substance or structure measured in body parts, fluids or products that can affect or predict disease incidence. As age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, much research and effort has been invested in the identification of different biomarkers to predict disease incidence, identify at risk individuals, elucidate causative pathophysiological etiologies, guide screening, monitoring and treatment parameters, and predict disease outcomes. To date, a host of genetic, environmental, proteomic, and cellular targets have been identified as both risk factors and potential biomarkers for AMD. Despite this, their use has been confined to research settings and has not yet crossed into the clinical arena. A greater understanding of these factors and their use as potential biomarkers for AMD can guide future research and clinical practice. This article will discuss known risk factors and novel, potential biomarkers of AMD in addition to their application in both academic and clinical settings.

Intraocular pressure study using monitored forced-infusion system phacoemulsification technology.

PURPOSE: To optimize phacoemulsification efficiency by varying the intraocular pressure (IOP) using the Centurion Vision System, a monitored forced-infusion system. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Laboratory investigation. METHODS: Porcine lenses were soaked in formalin and divided into 2.0 mm cubes; 0.9 mm balanced tips were used. Intraocular pressure levels were tested from 30 to 110 mm Hg at 10 mm Hg intervals. Vacuum was set at 500 mm Hg, aspiration at 35 mL/min, and torsional power at 60%. Efficiency (time to lens removal) and chatter (number of lens fragment repulsions from the tip) were measured. RESULTS: There was a linear relationship between efficiency and IOP. Increasing IOP led to an increase in efficiency (ie, to a decrease in time necessary to remove the lens fragment) (R(2) = .5769, P = .0176). Chatter correlated with IOP in the range of 30 to 50 mm Hg (R(2) = .4506, P = .0448) and was minimal at higher IOPs. CONCLUSIONS: Increasing IOP in the monitored forced-infusion system improved efficiency. Chatter was also decreased or eliminated with increasing IOP. Additional studies will be required to understand the reasons for these findings. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Ocular dysmotility after intra-arterial chemotherapy for retinoblastoma.

We report the case of a 15-month-old boy with retinoblastoma who developed exotropia secondary to a right medial rectus infarct after intra-arterial chemotherapy. He had unilateral sporadic group C tumor (International Classification of Retinoblastoma) and was treated with intra-arterial melphalan. One week after the first session of intra-ophthalmic arterial melphalan chemotherapy, he was noted to have orbital congestion, exotropia, and right adduction limitation. Magnetic resonance imaging was suggestive of a right medial rectus infarct. The tumor showed a good response to intra-arterial chemotherapy but the exotropia persisted.

Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth.

Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.