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Elhusseiny AM, Jamerson EC, Menshawey R, Tam EK, El Sayed YM. Collector Channels: Role and Evaluation in Schlemm's Canal Surgery. Curr Eye Res 2020;45(10):1181-1187.Abstract
OBJECTIVES: 1) To elucidate the role of collector channels in the aqueous humor outflow pathway 2) To suggest anatomic and functional methods of imaging collector channels in-vitro and in-vivo and 3) To discuss the role of such imaging modalities in the surgical management of glaucoma. METHODS: A thorough literature search was conducted on databases for studies published in English regarding the available methods to determine the role of collecting channels in normal and glaucomatous patients and to assess their patency. RESULTS: Intraocular pressure (IOP) exists as a balance between aqueous humor production and aqueous humor outflow. Collector channels are an essential anatomical constituent of the distal portion of the conventional aqueous humor outflow pathway. There are different surgical options for glaucoma management and with the recent advances in Schlemm's canal-based surgeries, collector channel's patency became a key factor in determining the optimum management for the glaucomatous eye. The advent of anatomic imaging methods has improved the ability to visualize collector channel morphology in-vitro, including swept-source optical coherence tomography (SS-OCT), spectral domain optical coherence tomography (SD-OCT), micro-computed tomography (micro CT), new immunohistochemistry techniques and scanning electron microscopy. The recent advent of real-time assessment of collector channel patency (including evaluation of episcleral venous outflow, observation of episcleral venous fluid wave, and tracer studies utilizing fluorescein, indocyanine green, and trypan blue) has been validated by the aforementioned anatomic imaging modalities. CONCLUSIONS: New modalities of in-vitro and in-vivo studies of collector channels provide promise to aid in the assessment of collector channel patency and individualization of surgical management for glaucoma patients.
Collett G, Elhusseiny AM, Scelfo C, Whitman MC, VanderVeen DK. Ocular injury via epinephrine auto-injector. J AAPOS 2020;Abstract
Intraocular injury by epinephrine auto-injector has been rarely reported. Toxic risk to the intraocular structures is suspected, but the evidence is inconclusive. We present the case of a 2-year-old girl who sustained an injury to her right eye by inadvertent epinephrine injection. Cataract surgery was performed to treat an increasingly opaque lens, and an intraocular lens was implanted. The visual outcome was good, with no retinal damage.
Gise R, Elhusseiny AM, Scelfo C, Mantagos IS. Mycoplasma Pneumoniae-Induced Rash and Mucositis: A Longitudinal Perspective and Proposed Management Criteria. Am J Ophthalmol 2020;219:351-356.Abstract
PURPOSE: To evaluate the natural history and ophthalmologic morbidity of Mycoplasma pneumoniae-induced rash and mucositis (MIRM) and propose a treatment algorithm. DESIGN: Retrospective, interventional case series. METHODS: Retrospective chart review of all MIRM patients examined by the department of ophthalmology at a tertiary children's hospital. Diagnosis was established clinically concomitant with either positive Mycoplasma pneumoniae IgM or PCR testing from January 1, 2010, until December 31, 2019. The main outcome measures were best-corrected visual acuity, long-term ocular sequelae, and duration and type of ophthalmic intervention. RESULTS: There were 15 patients (10 male and 5 female) aged 10.9 ± 4.2 years who had primary episodes of MIRM; of those, 4 had multiple episodes. All patients required topical steroid treatment, 3 required amniotic membrane transplantation, and 1 patient underwent placement of a sutureless biologic corneal badage device. There were no patients who suffered visual loss, but 1 was left with mild symblephara near the lateral canthus in each eye and 2 others had scarring of the eyelid margins and blepharitis. CONCLUSIONS: The ocular morbidity is significantly less in MIRM than in other closely related syndromes such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. However, these patients still require close observation and a low threshold for intervention to avoid permanent ophthalmic sequelae and possible blindness.
Agarwal A, Agrawal R, Raje D, Testi I, Mahajan S, Gunasekeran DV, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. Twenty-four Month Outcomes in the Collaborative Ocular Tuberculosis Study (COTS)-1: Defining the "Cure" in Ocular Tuberculosis. Ocul Immunol Inflamm 2020;:1-9.Abstract
PURPOSE: To report the clinical findings, anatomical features, and treatment outcomes in subjects with ocular tuberculosis (OTB) at 24 months in the Collaborative Ocular Tuberculosis Study (COTS)-1. METHODS: Of the 945 subjects included in COTS-1, those who completed a 24-month follow-up after completion of treatment were included. The main outcome measure was a number of patients with treatment failure (TF). RESULTS: 228 subjects (120 males; mean age of 42.82 ± 14.73 years) were included. Most common phenotype of uveitis was posterior ( = 81; 35.53%), and panuveitis ( = 76; 33.33%). Fifty-two patients (22.81%) had TF. On univariable analysis, odds of high TF was observed with bilaterality (OR: 3.46, = .003), vitreous haze (OR: 2.14, = .018), and use of immunosuppressive therapies (OR: 5.45, = .003). However, only bilaterality was significant in the multiple regression model (OR: 2.84; = .02). CONCLUSIONS: Majority of subjects (>75%) achieved cure in the COTS-1 at 24-month follow-up. The concept of "cure" may be a valuable clinical endpoint in trials for OTB.
Hu Z, Cano I, Saez-Torres KL, LeBlanc ME, Saint-Geniez M, Ng Y-S, Argüeso P, D'Amore PA. Elements of the Endomucin Extracellular Domain Essential for VEGF-Induced VEGFR2 Activity. Cells 2020;9(6)Abstract
Endomucin (EMCN) is the type I transmembrane glycoprotein, mucin-like component of the endothelial cell glycocalyx. We have previously shown that EMCN is necessary for vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2) internalization and downstream signaling. To explore the structural components of EMCN that are necessary for its function and the molecular mechanism of EMCN in VEGF-induced endothelial functions, we generated a series of mouse EMCN truncation mutants and examined their ability to rescue VEGF-induced endothelial functions in human primary endothelial cells (EC) in which endogenous EMCN had been knocked down using siRNA. Expression of the mouse full-length EMCN (FL EMCN) and the extracellular domain truncation mutants ∆21-81 EMCN and ∆21-121 EMCN, but not the shortest mutant ∆21-161 EMCN, successfully rescued the VEGF-induced EC migration, tube formation, and proliferation. ∆21-161 EMCN failed to interact with VEGFR2 and did not facilitate VEGFR2 internalization. Deletion of COSMC (C1GalT1C1) revealed that the abundant mucin-type -glycans were not required for its VEGFR2-related functions. Mutation of the two -glycosylation sites on ∆21-121 EMCN abolished its interaction with VEGFR2 and its function in VEGFR2 internalization. These results reveal ∆21-121 EMCN as the minimal extracellular domain sufficient for VEGFR2-mediated endothelial function and demonstrate an important role for -glycosylation in VEGFR2 interaction, internalization, and angiogenic activity.
Shu DY, Butcher E, Saint-Geniez M. EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration. Int J Mol Sci 2020;21(12)Abstract
Epithelial-mesenchymal transition (EMT) and endothelial-mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.
Chen JJ, Flanagan EP, Bhatti TM, Jitprapaikulsan J, Dubey D, Lopez Chiriboga ASS, Fryer JP, Weinshenker BG, McKeon A, Tillema J-M, Lennon VA, Lucchinetti CF, Kunchok A, McClelland CM, Lee MS, Bennett JL, Pelak VS, Van Stavern G, Adesina O-OO, Eggenberger ER, Acierno MD, Wingerchuk DM, Lam BL, Moss H, Beres S, Gilbert AL, Shah V, Armstrong G, Heidary G, Cestari DM, Stiebel-Kalish H, Pittock SJ. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology 2020;95(2):e111-e120.Abstract
OBJECTIVE: Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments. METHODS: We determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy. RESULTS: Seventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3-61 years; 33% <18 years), and 59% were female. The median annualized relapse rate (ARR) before treatment was 1.6. On maintenance immunotherapy, the proportion of patients with relapse was as follows: mycophenolate mofetil 74% (14 of 19; ARR 0.67), rituximab 61% (22 of 36; ARR 0.59), azathioprine 59% (13 of 22; ARR 0.2), and IV immunoglobulin (IVIG) 20% (2 of 10; ARR 0). The overall median ARR on these 4 treatments was 0.3. All 9 patients treated with multiple sclerosis (MS) disease-modifying agents had a breakthrough relapse on treatment (ARR 1.5). CONCLUSION: This large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.
Erickson S, Sullivan AG, Barabino S, Begovic E, Benitez-Del-Castillo JM, Bonini S, Borges JS, Brzheskiy V, Bulat N, Cerim A, Craig P, Cușnir V, Cușnir V, Cușnir V, Doan S, Dülger E, Farrant S, Geerling G, Goldblum D, Golubev S, Gomes JAP, González-Méijome JM, Grupcheva CN, Gündüz UÖmür, Horwath-Winter J, Källmark F, Karanadze N, Karcic HH, Karcic S, Kontadakis G, Messmer EM, Mrugacz M, Murphy C, O'Leary OE, Procopciuc V, Pult H, Raus P, Şahin A, Setälä N, Stanila A, Stanila DM, Utheim TP, Vehof J, Versura P, Villani E, Willcox MDP, Wolffsohn JS, Zagórski Z, Zoega GMár, Sullivan DA, Sullivan DA, Gomes JAP, Versura P, Willcox MDP. TFOS European ambassador meeting: Unmet needs and future scientific and clinical solutions for ocular surface diseases. Ocul Surf 2020;Abstract
The mission of the Tear Film & Ocular Surface Society (TFOS) is to advance the research, literacy, and educational aspects of the scientific field of the tear film and ocular surface. Fundamental to fulfilling this mission is the TFOS Global Ambassador program. TFOS Ambassadors are dynamic and proactive experts, who help promote TFOS initiatives, such as presenting the conclusions and recommendations of the recent TFOS DEWS II™, throughout the world. They also identify unmet needs, and propose future clinical and scientific solutions, for management of ocular surface diseases in their countries. This meeting report addresses such needs and solutions for 25 European countries, as detailed in the TFOS European Ambassador meeting in Rome, Italy, in September 2019.
Yang M, Bair JA, Hodges RR, Serhan CN, Dartt DA. Resolvin E1 Reduces Leukotriene B4-Induced Intracellular Calcium Increase and Mucin Secretion in Rat Conjunctival Goblet Cells. Am J Pathol 2020;190(9):1823-1832.Abstract
Leukotriene B4 (LTB4) is a major proinflammatory mediator important in host defense, whereas resolvins (Rvs) are produced during the resolution phase of inflammation. The authors determined the actions of both RvE1 and RvD1 on LTB4-induced responses of goblet cells cultured from rat conjunctiva. The responses measured were an increase in the intracellular [Ca] ([Ca]) and high-molecular-weight glycoprotein secretion. Treatment with RvE1 or RvD1 for 30 minutes significantly blocked the LTB4-induced [Ca] increase. The actions of RvE1 on LTB4-induced [Ca] increase were reversed by siRNA for the RvE1 receptor, and the actions of RvD1 were reversed by an RvD1 receptor inhibitor. The RvE1 and RvD1 block of LTB4-stimulated increase in [Ca] was also reversed by an inhibitory peptide to β-adrenergic receptor kinase. LTB4 and block of the LTB4-stimulated increase in [Ca] by RvE1 and RvD1 were partially mediated by the depletion of intracellular Ca stores. RvE1, but not RvD1, counterregulated the LTB4-induced high-molecular-weight glycoprotein secretion. Thus, both RvE1 and RvD1 receptors directly inhibit LTB4 by phosphorylating the LTB4 receptor using β adrenergic receptor kinase. RvE1 receptor counterregulates the LTB4-induced increase in [Ca] and secretion, whereas RvD1 receptor only counterregulates LTB4-induced [Ca] increase.
Hamad AE, Moinuddin O, Blair MP, Schechet SA, Shapiro MJ, Quiram PA, Mammo DA, Berrocal AM, Prakhunhungsit S, Cernichiaro-Espinosa LA, Mukai S, Yonekawa Y, Ung C, Holz ER, Harper AC, Young RC, Besirli CG, Nagiel A, Lee TC, Gupta MP, Walsh MK, Khawly JA, Campbell PJ, Kychenthal A, Nudleman ED, Robinson JE, Hartnett ME, Calvo CM, Chang EY. Late-Onset Retinal Findings and Complications in Untreated Retinopathy of Prematurity. Ophthalmol Retina 2020;4(6):602-612.Abstract
PURPOSE: To investigate late retinal findings and complications of eyes with a history of retinopathy of prematurity (ROP) that did not meet treatment criteria and did not receive treatment during infancy. DESIGN: Retrospective, nonconsecutive, noncomparative, multicenter case series. PARTICIPANTS: Three hundred sixty-three eyes of 186 patients. METHODS: Data were requested from multiple providers on premature patients with a history of ROP and no treatment during infancy who demonstrated late retinal findings or complications and included age, gender, gestational age and weight, zone and stage at infancy, visual acuity, current retina vascularization status, vitreous character, presence of peripheral retinal findings such as lattice retinal tears and detachments (RDs), retinoschisis, and fluorescein findings. MAIN OUTCOME MEASURES: Rate of RDs and factors conferring a higher risk of RDs. RESULTS: The average age was 34.5 years (range, 7-76 years), average gestational age was 26.6 weeks (range, 23-34 weeks), and average birth weight was 875 g (range, 425-1590 g). Findings included lattice in 196 eyes (54.0%), atrophic holes in 126 eyes (34.7%), retinal tears in 111 eyes (30.6%), RDs in 140 eyes (38.6 %), tractional retinoschisis in 44 eyes (11.9%), and visible vitreous condensation ridge-like interface in 112 eyes (30.5%). Fluorescein angiography (FA) was performed in 113 eyes, of which 59 eyes (52.2%) showed leakage and 16 eyes (14.2%) showed neovascularization. Incomplete vascularization posterior to zone 3 was common (71.6% of eyes). Retinal detachments were more likely in patients with a gestational age of 29 weeks or less (P < 0.05) and in eyes with furthest vascularization to posterior zone 2 eyes compared with zone 3 eyes (P = 0.009). CONCLUSIONS: Eyes with ROP not meeting the treatment threshold during infancy showed various late retinal findings and complications, of which RDs were the most concerning. Complications were seen in all age groups, including patients born after the Early Treatment for Retinopathy of Prematurity Study. Contributing factors to RDs included atrophic holes within peripheral avascular retina, visible vitreous condensation ridge-like interface with residual traction, and premature vitreous syneresis. We recommend regular examinations and consideration of ultra-widefield FA examinations. Prospective studies are needed to explore the frequency of complications and benefit of prophylactic treatment and if eyes treated with anti-vascular endothelial growth factor therapy are at risk of similar findings and complications.
Bispo PJM, Ung L, Chodosh J, Gilmore MS. Hospital-Associated Multidrug-Resistant MRSA Lineages Are Trophic to the Ocular Surface and Cause Severe Microbial Keratitis. Front Public Health 2020;8:204.Abstract
Methicillin-resistant (MRSA) is a common cause of severe and difficult to treat ocular infection. In this study, the population structure of 68 ocular MRSA isolates collected at Massachusetts Eye and Ear between January 2014 and June 2016 was assessed. By using a combination of multilocus sequence typing (MLST) analysis, SCC typing and detection of the panton-valentine leukocidin (PVL) gene, we found that the population structure of ocular MRSA is composed of lineages with community and hospital origins. As determined by eBURST analysis of MLST data, the ocular MRSA population consisted of 14 different sequence types (STs) that grouped within two predominant clonal complexes: CC8 (47.0%) and CC5 (41.2%). Most CC8 strains were ST8, harbored type IV SCC and were positive for the PVL-toxin (93.7%). The CC5 group was divided between strains carrying SCC type II (71.4%) and SCC type IV (28.6%). Remaining isolates grouped in 6 different clonal complexes with 3 isolates in CC6 and the other clonal complexes being represented by a single isolate. Interestingly, major MRSA CC5 and CC8 lineages were isolated from discrete ocular niches. Orbital and preseptal abscess/cellulitis were predominantly caused by CC8-SCC IV PVL-positive strains. In contrast, infections of the cornea, conjunctiva and lacrimal system were associated with the MDR CC5 lineage, particularly as causes of severe infectious keratitis. This niche specialization of MRSA is consistent with a model where CC8-SCC IV PVL-positive strains are better adapted to cause infections of the keratinized and soft adnexal eye tissues, whereas MDR CC5 appear to have greater ability in overcoming innate defense mechanisms of the wet epithelium of the ocular surface.
Xue Y, Razafsky D, Hodzic D, Kefalov VJ. Mislocalization of cone nuclei impairs cone function in mice. FASEB J 2020;Abstract
The nuclei of cone photoreceptors are located on the apical side of the outer nuclear layer (ONL) in vertebrate retinas. However, the functional role of this evolutionarily conserved localization of cone nuclei is unknown. We previously showed that Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) are essential for the apical migration of cone nuclei during development. Here, we developed an efficient genetic strategy to disrupt cone LINC complexes in mice. Experiments with animals from both sexes revealed that disrupting cone LINC complexes resulted in mislocalization of cone nuclei to the basal side of ONL in mouse retina. This, in turn, disrupted cone pedicle morphology, and appeared to reduce the efficiency of synaptic transmission from cones to bipolar cells. Although we did not observe other developmental or phototransduction defects in cones with mislocalized nuclei, their dark adaptation was impaired, consistent with a deficiency in chromophore recycling. These findings demonstrate that the apical localization of cone nuclei in the ONL is required for the timely dark adaptation and efficient synaptic transmission in cone photoreceptors.
Xiao W, Kreiman G. XDream: Finding preferred stimuli for visual neurons using generative networks and gradient-free optimization. PLoS Comput Biol 2020;16(6):e1007973.Abstract
A longstanding question in sensory neuroscience is what types of stimuli drive neurons to fire. The characterization of effective stimuli has traditionally been based on a combination of intuition, insights from previous studies, and luck. A new method termed XDream (EXtending DeepDream with real-time evolution for activation maximization) combined a generative neural network and a genetic algorithm in a closed loop to create strong stimuli for neurons in the macaque visual cortex. Here we extensively and systematically evaluate the performance of XDream. We use ConvNet units as in silico models of neurons, enabling experiments that would be prohibitive with biological neurons. We evaluated how the method compares to brute-force search, and how well the method generalizes to different neurons and processing stages. We also explored design and parameter choices. XDream can efficiently find preferred features for visual units without any prior knowledge about them. XDream extrapolates to different layers, architectures, and developmental regimes, performing better than brute-force search, and often better than exhaustive sampling of >1 million images. Furthermore, XDream is robust to choices of multiple image generators, optimization algorithms, and hyperparameters, suggesting that its performance is locally near-optimal. Lastly, we found no significant advantage to problem-specific parameter tuning. These results establish expectations and provide practical recommendations for using XDream to investigate neural coding in biological preparations. Overall, XDream is an efficient, general, and robust algorithm for uncovering neuronal tuning preferences using a vast and diverse stimulus space. XDream is implemented in Python, released under the MIT License, and works on Linux, Windows, and MacOS.

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