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Cheung CS, VanderVeen DK. Intraocular Lens Techniques in Pediatric Eyes with Insufficient Capsular Support: Complications and Outcomes. Semin Ophthalmol 2019;:1-10.Abstract
Intraocular lens (IOL) implantation in pediatric eyes with insufficient capsular support is challenging and there are multiple IOL options. These include placement of an IOL within the capsular bag with a capsular tension ring, a scleral-fixated posterior-chamber IOL (PCIOL) with or without capsular tension segment or ring, an intra-scleral fixated IOL, an iris-sutured PCIOL, or an anterior chamber iris-fixated IOL. We reviewed 48 articles and 1 published abstract describing the surgical techniques, complications and visual outcomes of different IOL options in the management of aphakic pediatric eyes with insufficient capsular support. The present review found that the visual acuity outcomes of various IOLs are comparable. Furthermore, each .
Shu DY, Hutcheon AEK, Zieske JD, Guo X. Epidermal Growth Factor Stimulates Transforming Growth Factor-Beta Receptor Type II Expression In Corneal Epithelial Cells. Sci Rep 2019;9(1):8079.Abstract
We previously demonstrated that inhibition of epidermal growth factor receptor (EGFR) slowed corneal epithelial migration. Here we examine the effect of EGF on transforming growth factor-beta receptor II (TGF-βRII) in a corneal wound-healing model and primary human corneal epithelial cells (pHCE). Corneal debridement wounds were made and allowed to heal ± Tyrphostin AG1478 (EGFR inhibitor), and assayed for EGFR activation and EGFR and TGF-βRII localization. Primary HCE were treated with EGF ± U0126 (MEK inhibitor) and assayed for TGF-βRII expression. EGFR activation was maximal 15 minutes after wounding and localized in the migrating epithelial cells. TGF-βRII localization was also observed in the migrating epithelium and was reduced when EGFR was blocked. When pHCE were treated with EGF for 6 hours, the cells produced enhanced levels of TGF-βRII, which was blocked by U0126. Downstream signaling pathways of MEK (p38 and ERK1/2) were then examined, and TGF-β1 and EGF were found to have differential effects on the phosphorylation of p38 and ERK1/2, with TGF-β1 upregulating p-p38 but not pERK1/2 and EGF upregulating pERK1/2 but not p-p38. Taken together, these data indicate that EGF stimulates TGF-βRII through ERK1/2 and EGFR signaling, suggesting interplay between EGF- and TGF-β-signaling pathways during corneal wound repair.
LeBlanc ME, Saez-Torres KL, Cano I, Hu Z, Saint-Geniez M, Ng Y-S, D'Amore PA. Glycocalyx regulation of vascular endothelial growth factor receptor 2 activity. FASEB J 2019;33(8):9362-9373.Abstract
We have previously shown that knockdown of endomucin (EMCN), an integral membrane glycocalyx glycoprotein, prevents VEGF-induced proliferation, migration, and tube formation and angiogenesis . In the endothelium, VEGF mediates most of its angiogenic effects through VEGF receptor 2 (VEGFR2). To understand the role of EMCN, we examined the effect of EMCN depletion on VEGFR2 endocytosis and activation. Results showed that although VEGF stimulation promoted VEGFR2 internalization in control endothelial cells (ECs), loss of EMCN prevented VEGFR2 endocytosis. Cell surface analysis revealed a decrease in VEGFR2 following VEGF stimulation in control but not siRNA directed against EMCN-transfected ECs. EMCN depletion resulted in heightened phosphorylation following VEGF stimulation with an increase in total VEGFR2 protein. These results indicate that EMCN modulates VEGFR2 endocytosis and activity and point to EMCN as a potential therapeutic target.-LeBlanc, M. E., Saez-Torres, K. L., Cano, I., Hu, Z., Saint-Geniez, M., Ng, Y.-S., D'Amore, P. A. Glycocalyx regulation of vascular endothelial growth factor receptor 2 activity.
Fayed M, Chen TC. Pediatric Intraocular Pressure Measurements: Tonometers, Central Corneal Thickness, and Anesthesia. Surv Ophthalmol 2019;Abstract
Measuring intraocular pressure (IOP) is the cornerstone of a comprehensive glaucoma exam. In babies or small children, however, IOP measurements are problematic, cannot often be done at the slit lamp, and are sometimes require general anesthesia. Therefore, it is essential for an ophthalmologist who examines a pediatric patient to be aware of the different tonometers used in children, as well as the effects of central corneal thickness (CCT) and anesthesia on IOP measurements. Goldmann applanation tonometry is the gold standard for IOP assessment. Most alternative tonometers tend to give higher IOP readings compared to the Goldmann applanation tonometer, and readings between different tonometers are often not interchangeable. Like Goldmann tonometry, many of these alternative tonometers are affected by CCT, with thicker corneas having artifactually high IOP readings and thinner corneas having artifactually lower IOP readings. Although various machines can be used to compensate for corneal factors (e.g. the dynamic contour tonometer and ocular response analyzer), it is important to be aware that certain ocular diseases can be associated with abnormal CCT values and that their IOP readings need to be interpreted accordingly. Because induction and anesthetics can affect IOP, office IOPs taken in awake patients are always the most accurate.
Aronow ME, Wiley HE, Gaudric A, Krivosic V, Gorin MB, Shields CL, Shields JA, Jonasch EW, Singh AD, Chew EY. VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects. Retina 2019;39(12):2243-2253.Abstract
PURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.
Szczotka-Flynn LB, Maguire MG, Ying G-S, Lin MC, Bunya VY, Dana R, Asbell PA, and Group DEAM (DREAM) SR. Impact of Dry Eye on Visual Acuity and Contrast Sensitivity: Dry Eye Assessment and Management Study. Optom Vis Sci 2019;96(6):387-396.Abstract
SIGNIFICANCE: Identification of the association of specific signs of dry eye disease with specific visual function deficits may allow for more targeted approaches to treatment. PURPOSE: The purpose of this study was to explore the association of dry eye signs and symptoms with visual acuity (VA) and contrast sensitivity in the Dry Eye Assessment and Management study. METHODS: Baseline data from participants in the Dry Eye Assessment and Management study were used in this secondary cross-sectional analysis. Standardized procedures were used to obtain results on the Ocular Surface Disease Index (OSDI), high-contrast logMAR VA, contrast sensitivity, tear film debris, tear breakup time (TBUT), corneal fluorescein staining, meibomian gland evaluation, conjunctival lissamine green staining, and Schirmer test scores. Generalized linear models that included age, refractive error status, and cataract status were used to assess the association between VA and contrast sensitivity with OSDI score and each dry eye sign. The Hochberg procedure was used to account for multiple comparisons. RESULTS: Among 487 participants (974 eyes), worse VA was associated with worse mean score on the OSDI vision subscale (39.4 for VA 20/32 or worse vs. 32.4 for VA 20/16 or better; adjusted linear trend, P = .02); scores were not associated with contrast sensitivity. Severe meibomian gland plugging and abnormal secretions were associated with worse mean log contrast sensitivity (1.48 for severe vs. 1.54 for not plugged [P = .04] and 1.49 for obstructed vs. 1.57 for clear [P = .002], respectively). Longer TBUT was associated with better mean log contrast sensitivity (1.57 for TBUT >5 seconds and 1.51 for TBUT ≤2 seconds, P < .0001). CONCLUSIONS: Worse VA rather than worse contrast sensitivity drives vision-related symptoms in dry eye. Greater tear film instability was associated with worse contrast sensitivity.
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai L-H. Single-cell transcriptomic analysis of Alzheimer's disease. Nature 2019;570(7761):332-337.Abstract
Alzheimer's disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer's disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer's disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease.
Wang JC, Miller JB. For Mass Eye and Ear Special Issue: Optical Coherence Tomography Angiography: Review of Current Technical Aspects and Applications in Chorioretinal Disease. Semin Ophthalmol 2019;:1-7.Abstract
Optical coherence tomography angiography (OCT-A) has enabled fast, non-invasive, high-resolution visualization of vasculature within the eye. In the past few years, it has become increasingly utilized for a range of disorders including age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, and uveitis among others. This article reviews technical aspects of OCT-A, its applications in chorioretinal disease, and known limitations of the technology.
Rong SS, Lee BY, Kuk AK, Yu XT, Li SS, Li J, Guo Y, Yin Y, Osterbur DL, Yam JCS, Cheung CY, Chen LJ, Wong TY, Ng DS-C. Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis. Br J Ophthalmol 2019;103(12):1777-1783.Abstract
AIM: To determine the association between dementia and age-related macular degeneration (AMD) using meta-analysis. METHODS: We searched in the MEDLINE, EMBASE, Web of Knowledge, PsycInfo and Cochrane database of systematic reviews for studies published from March 1959 to March 2018. We included cross-sectional, case-control and cohort studies that evaluated the association of dementia/Alzheimer's disease (AD) with AMD (as outcome) and the association of AMD with dementia/AD (as outcome). Studies that compared cognitive functions between AMD and controls were also included. The summary outcomes, namely odds ratio (OR), relative risk, mean differences and corresponding 95% CIs, were estimated using random effects models. We performed sensitivity analysis based on study quality and individual study effect to control for potential biases. RESULTS: Among 2159 citation records, we identified 21 studies consisting of 7 876 499 study subjects for meta-analysis. Patients with dementia (p≤0.017, OR≥1.24, I≤9%) or AD (p=0.001, OR=2.22, I=50%) were at risk for AMD, particularly for late AMD (p<0.001, OR=1.37, I=0). AMD was also significantly associated with increased risk of AD/cognitive impairment (p=0.037, OR=2.42, I=38%). Moreover, patients with AMD had poorer cognitive functions when compared with controls, including Mini-Mental State Examination (p<0.001, I≤79%) and Trail Making Test A (p<0.001, I=0). Sensitivity analysis and Egger's test indicated our results were less likely biased. CONCLUSIONS: A significant association between dementia/AD and AMD calls for greater clinical awareness. The cost-effectiveness of routine screening for the other condition in patients with primary diagnosis of dementia/AD or AMD requires further study.
Silva RNE, Chiou CA, Wang M, Wang H, Shoji MK, Chou JC, D'Souza EE, Greenstein SH, Brauner SC, Alves MR, Pasquale LR, Shen LQ. Microvasculature of the Optic Nerve Head and Peripapillary Region in Patients With Primary Open-Angle Glaucoma. J Glaucoma 2019;28(4):281-288.Abstract
PURPOSE: To assess optic nerve head (ONH) and peripapillary microvasculature in primary open-angle glaucoma (POAG) of mild to moderate severity using swept-source optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: In a cross-sectional study, swept-source OCTA images were analyzed for 1 eye from each of 30 POAG patients with glaucomatous Humphrey visual field loss and 16 controls. The anatomic boundary of ONH was manually delineated based on Bruch's membrane opening and large vessels were removed from en face angiography images to measure vessel density (VD) and the integrated OCTA by ratio analysis signal (IOS), suggestive of flow, in the ONH and peripapillary region. POAG subgroup analysis was performed based on a history of disc hemorrhage (DH) matched by visual field mean deviation (MD). RESULTS: POAG (mean MD±SD, -3.3±3.0 dB) and control groups had similar demographic characteristics and intraocular pressure on the day of imaging. Groups did not differ in superficial ONH VD or flow indicated by IOS (P≥0.28). POAG eyes showed significantly lower VD (39.4%±4.0%) and flow (38.8%±5.6%) in deep ONH, peripapillary VD (37.9%±2.9%) and flow (43.6%±4.0%) compared with control eyes (44.1%±5.1%, 44.7%±6.9%, 40.7%±1.7%, 47.8%±2.5%, respectively; P≤0.007 for all). In the subgroup analysis, POAG eyes with (n=14) and without DH (n=16) had similar measured OCTA parameters (P>0.99 for all). CONCLUSIONS: The image processing methodology based on the anatomic boundary of ONH demonstrated compromised microvasculature in the deep ONH and peripapillary region in eyes with mild to moderate POAG, regardless of the history of DH.
Jaffe GJ, Foster SC, Pavesio CE, Paggiarino DA, Riedel GE. Effect of an Injectable Fluocinolone Acetonide Insert on Recurrence Rates in Chronic Noninfectious Uveitis Affecting the Posterior Segment: Twelve-Month Results. Ophthalmology 2019;126(4):601-610.Abstract
PURPOSE: To assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic noninfectious posterior uveitis. DESIGN: Multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial. PARTICIPANTS: One hundred twenty-nine participants with recurrent noninfectious posterior uveitis were assigned randomly to FA insert (n = 87) or sham injection (n = 42). The more severely affected eye in participants with bilateral disease was designated as the study eye. METHODS: The insert (FA, 0.18 mg) was injected into the vitreous cavity; sham injection mimicked the insert delivery procedure. Ophthalmic examinations, OCT, and ocular tolerability and discomfort assessments were conducted; study visits were on days 7 and 28 and months 2, 3, 6, 9, and 12. Uveitis recurrence was treated as needed. The 6-month recurrence rate was the primary outcome measure. RESULTS: The 6-month (28% and 91%) and 12-month (38% and 98%) uveitis recurrence rates were significantly lower (P < 0.001) with FA insert vs. sham, respectively. Fewer recurrences per study eye (mean, 0.7 vs. 2.5), lower incidence of 15-letter or more decrease in best-corrected visual acuity (14% vs. 31%), and reduced systemic (19% vs. 40%) and local (7% vs. 62%) uveitis adjunctive treatments were observed with FA insert vs. sham, respectively. The FA insert group showed higher rates of cataract. Intraocular pressure-lowering treatment use was similar between groups. No deaths, treatment-related study discontinuations, or unanticipated safety signals were observed through 12 months. CONCLUSIONS: Chronic noninfectious posterior uveitis was managed successfully in this study population; FA insert eyes experienced fewer uveitis recurrence episodes, required fewer adjunctive treatments, and demonstrated less visual acuity loss compared with sham eyes. The FA insert treatment group showed higher rates of cataract; delivery by injection was not associated with an increase in ocular adverse events or any other safety measures not typically associated with local steroid use, suggesting the procedure is appropriate for an office setting.
Di Zazzo A, Micera A, Coassin M, Varacalli G, Foulsham W, De Piano M, Bonini S. InflammAging at Ocular Surface: Clinical and Biomolecular Analyses in Healthy Volunteers. Invest Ophthalmol Vis Sci 2019;60(5):1769-1775.Abstract
Purpose: To assess the ocular surface in volunteers who consider themselves as healthy, in order to evaluate how para-inflammatory mechanisms fail with age, and thus investigate the phenomenon of "InflammAging." Methods: In this observational prospective cohort study, volunteers were categorized into three groups according to age: young (19-40 years), middle-aged (41-60 years), and older adults (61-93 years). Clinical assessments included tear breakup time (T-BUT) and Schirmer test type I. Dry eye symptoms were evaluated by the Ocular Surface Disease Index (OSDI) questionnaire. Conjunctival mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), MUC5AC, and IL-8 were measured by real-time PCR and immunofluorescence. Results: A total of 82 volunteers (38 males and 44 females) were enrolled. T-BUT decreased significantly with increasing age (young: 11.13 ± 0.18 seconds; middle-aged: 10.83 ± 0.56 seconds; older: 9.00 ± 1.00 seconds, P < 0.05). Schirmer test values decreased significantly with age (young: 20.6 ± 1.0 mm; middle-aged: 19.2 ± 1.2 mm; older: 16.0 ± 1.1 mm, P < 0.05). OSDI scores increased with age in both groups, but they were substantially higher in women. Conjunctival expression of inflammatory markers ICAM-1, IL-8, and MUC5AC increased with age. Conclusions: Clinical signs, symptoms, and biomarkers of chronic inflammation increased with age in a cohort of volunteers who considered themselves healthy, indicating an age-related progressive impairment of ocular surface system function.

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