2020

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Yu M, Lee S-M, Lee HS, Amouzegar A, Nakao T, Chen Y, Dana R. Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting Antigen-Presenting Cell Maturation and T Helper 17 Cell Activation. Am J Pathol 2020;190(1):125-133.Abstract
Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion neurons are the major source of SP in DED. SP derived from trigeminal ganglion enhanced the expression of major histocompatibility complex class II maturation marker by bone marrow-derived dendritic cells, an effect that is abrogated by blockade of SP signaling using NK1R antagonist spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of major histocompatibility complex class II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.
Yu Z, Ma S, Wu M, Cui H, Wu R, Chen S, Xu C, Lu X, Feng S. Self-assembling hydrogel loaded with 5-FU PLGA microspheres as a novel vitreous substitute for proliferative vitreoretinopathy. J Biomed Mater Res A 2020;108(12):2435-2446.Abstract
The vitreous substitute for proliferative vitreoretinopathy (PVR) surgery remains an unmet clinical need in ophthalmology. In our study, we developed an in situ formed hydrogel by crosslinking polyvinyl alcohol (PVA) and chitosan as a potential vitreous substitute. 5-fluorouracil (5-FU) Poly (lactic-co-glycolic acid) (PLGA) microspheres were developed and loaded onto the PVA/chitosan hydrogels to treat PVR. In vitro, PVA/chitosan hydrogels at four concentrations were subjected to morphological, physical, rheological analyses, and cytotoxicity was evaluated together with the characterization of 5-FU PLGA microspheres. In vivo, pharmacologically induce PVR rabbits were performed a vitrectomy. In the PVA group, 3% PVA/chitosan hydrogel was injected into the vitreous cavity. In the PVA/MS group, 3% PVA/chitosan hydrogel and 5-FU PLGA microspheres were injected. In the Control group, phosphate-buffered saline was injected. Therapeutic efficacy was evaluated with postoperative examinations and histological analyses. This study demonstrated that the 3% PVA/chitosan hydrogel showed properties similar to those of the human vitreous and could be a novel in situ crosslinked vitreous substitute for PVR. Loading 5-FU PLGA microspheres onto this hydrogel may represent an effective strategy to improve the prognosis of PVR.
Yu G, Seto BK, Yamada K, Zeng K, Arroyo JG. Combined Pneumatic and Enzymatic Vitreolysis for Severe Cases of Vitreomacular Traction. Retin Cases Brief Rep 2020;Abstract
PURPOSE: To evaluate the efficacy of combined pneumatic and enzymatic vitreolysis for treatment of severe cases of vitreomacular traction (VMT). METHODS: We analyzed a retrospective, consecutive series of five patients diagnosed with severe VMT refractory to pneumatic vitreolysis (PV) who then received an additional ocriplasmin injection while their gas bubble from PV was still present between February 2015 to February 2019. VMT release was confirmed using spectral domain optical coherence tomography (OCT). RESULTS: Four out of 5 patients treated with combined pneumatic and enzymatic vitreolysis achieved VMT release by day 28, and all cases eventually achieved complete VMT release. In addition to having VMT refractory to PV, patient characteristics included broad adhesion diameter (>1500 μm, n=1), presence of epiretinal membrane (n=2), age > 65 years (n=4), and pseudophakia (n=1). Visual acuity (VA) improved by 3 or more lines at 6 months in both of the patients with initial vision worse than 20/50 on an ETDRS chart but not in those whose vision was already fairly good (i.e. VA > 20/60). None of the patients experienced the following complications after receiving this combined treatment: retinal tears or detachments, vitreous floaters, and ellipsoid zone changes. CONCLUSION: Sequential, combined pneumatic and enzymatic vitreolysis resulted in VMT release in all 5 cases (4 cases by 28 days) and may be a potentially useful alternative to surgical intervention for refractory VMT cases.
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Zampaglione E, Kinde B, Place EM, Navarro-Gomez D, Maher M, Jamshidi F, Nassiri S, Mazzone AJ, Finn C, Schlegel D, Comander J, Pierce EA, Bujakowska KM. Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. Genet Med 2020;22(6):1079-1087.Abstract
PURPOSE: Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy-number variations (CNVs), which have been shown as major contributors to unsolved IRD cases. METHODS: Five hundred IRD patients were analyzed with targeted next-generation sequencing (NGS). The NGS data were used to detect CNVs with ExomeDepth and gCNV and the results were compared with CNV detection with a single-nucleotide polymorphism (SNP) array. Likely causal CNV predictions were validated by quantitative polymerase chain reaction (qPCR). RESULTS: Likely disease-causing single-nucleotide variants (SNVs) and small indels were found in 55.6% of subjects. PVs in USH2A (11.6%), RPGR (4%), and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene. CONCLUSION: CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.
Zantut PRA, Veras MM, Yariwake VY, Takahashi WY, Saldiva PH, Young LH, Damico FM, Fajersztajn L. Effects of cannabis and its components on the retina: a systematic review. Cutan Ocul Toxicol 2020;39(1):1-9.Abstract
Cannabis is the most prevalent drug in the world and its consumption is growing. Cannabinoid receptors are present in the human central nervous system. Recent studies show evidence of the effects of cannabinoids on the retina, and synthesising the results of these studies may be relevant for ophthalmologists. Thus, this review adopts standardised, systematic review methodology to investigate the effects of exposure to cannabis and components on the retina. We searched five online databases for the combined terms for outcome ("retina") and exposure ("cannabis"). Eligibility of studies were conducted by two independent reviewers, and risk of bias was assessed. We retrieved 495 studies, screened 229 studies, assessed 52 studies for eligibility, and included 16 studies for qualitative analysis. The cannabinoids most frequently investigated were delta-9-tetrahydrocannabinol (THC), abnormal cannabidiol, synthetic cannabinoid, and cannabidiol (CDB). The outcomes most studied were neuroretinal dysfunction, followed by vascular effects. The studies also included investigation of neuroprotective and anti-inflammatory effects and teratogenic effects. This review suggests that cannabinoids may have an important role in retinal processing and function.
Zhang Y, Wang K, Pan J, Yang S, Yao H, Li M, Li H, Lei H, Jin H, Wang F. Exosomes mediate an epithelial-mesenchymal transition cascade in retinal pigment epithelial cells: Implications for proliferative vitreoretinopathy. J Cell Mol Med 2020;Abstract
Exosomes have recently emerged as a pivotal mediator of many physiological and pathological processes. However, the role of exosomes in proliferative vitreoretinopathy (PVR) has not been reported. In this study, we aimed to investigate the role of exosomes in PVR. Transforming growth factor beta 2 (TGFß-2) was used to induce epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, as an in vitro model of PVR. Exosomes from normal and EMTed RPE cells were extracted and identified. We incubated extracted exosomes with recipient RPE cells, and co-cultured EMTed RPE cells and recipient RPE cells in the presence of the exosome inhibitor GW4869. Both experiments suggested that there are further EMT-promoting effects of exosomes from EMTed RPE cells. MicroRNA sequencing was also performed to identify the miRNA profiles in exosomes from both groups. We identified 34 differentially expressed exosomal miRNAs (P <. 05). Importantly, miR-543 was found in exosomes from EMTed RPE cells, and miR-543-enriched exosomes significantly induced the EMT of recipient RPE cells. Our study demonstrates that exosomal miRNA is differentially expressed in RPE cells during EMT and that these exosomal miRNAs may play pivotal roles in EMT induction. Our results highlight the importance of exosomes as cellular communicators within the microenvironment of PVR.
Zheng Q, Jones FK, Leavitt SV, Ung L, Labrique AB, Peters DH, Lee EC, Azman AS, Azman AS. HIT-COVID, a global database tracking public health interventions to COVID-19. Sci Data 2020;7(1):286.Abstract
The COVID-19 pandemic has sparked unprecedented public health and social measures (PHSM) by national and local governments, including border restrictions, school closures, mandatory facemask use and stay at home orders. Quantifying the effectiveness of these interventions in reducing disease transmission is key to rational policy making in response to the current and future pandemics. In order to estimate the effectiveness of these interventions, detailed descriptions of their timelines, scale and scope are needed. The Health Intervention Tracking for COVID-19 (HIT-COVID) is a curated and standardized global database that catalogues the implementation and relaxation of COVID-19 related PHSM. With a team of over 200 volunteer contributors, we assembled policy timelines for a range of key PHSM aimed at reducing COVID-19 risk for the national and first administrative levels (e.g. provinces and states) globally, including details such as the degree of implementation and targeted populations. We continue to maintain and adapt this database to the changing COVID-19 landscape so it can serve as a resource for researchers and policymakers alike.
Zhu Y, Cui Y, Wang JC, Lu Y, Zeng R, Katz R, Wu DM, Eliott D, Vavvas DG, Husain D, Miller JW, Kim LA, Miller JB. Different Scan Protocols Affect the Detection Rates of Diabetic Retinopathy Lesions by Wide-Field Swept-Source Optical Coherence Tomography Angiography. Am J Ophthalmol 2020;215:72-80.Abstract
PURPOSE: To compare different scan protocols of wide-field swept-source optical coherence tomography angiography (SS-OCTA) for the detection of diabetic retinopathy (DR) lesions. DESIGN: Comparison of diagnostic approaches. METHODS: A prospective, observational study was conducted at Massachusetts Eye and Ear from December 2018 to July 2019. Proliferative diabetic retinopathy (PDR), nonproliferative diabetic retinopathy (NPDR), and diabetic patients without DR were included. All patients were imaged using SS-OCTA using the following scan protocol: 3- × 3-mm Angio centered on the fovea; 6- × 6-mm Angio centered on the fovea and the optic disc; 15- × 9-mm Montage; and 12- × 12-mm Angio centered on the fovea and the optic disc. Images were independently evaluated by 2 graders for the presence or absence of DR lesions including microaneurysms, intraretinal microvascular abnormalities, neovascularization, nonperfusion areas, venous looping, and hard exudates. All statistical analyses were performed using commercial software. RESULTS: A total of 176 eyes in 119 participants were included in the study. The detection rate of neovascularization on 6- × 6-mm Angio centered on the fovea was approximately one-half that on 15- × 9-mm Montage (P < .05) imaging. Combining 6- × 6-mm Angio imaging centered on the fovea and the optic disc could increase the rate to approximately two-thirds (P < .05). The 12- × 12-mm Angio imaging centered on the combination of fovea and optic disc had detection rates comparable to those of 15- × 9-mm Montage imaging for all DR lesions (P > .05). For microaneurysms, 6- × 6-mm Angio had better performance than 15- × 9-mm Montage (P < .05). CONCLUSIONS: Wide-field SS-OCTA images were useful in detecting DR lesions. The 12- × 12-mm Angio imaging centered on the fovea and on the optic disc may be an optimal balance between speed and efficacy for evaluation of DR in clinical practice.
Zieske JD, Hutcheon AEK, Guo X. Extracellular Vesicles and Cell-Cell Communication in the Cornea. Anat Rec (Hoboken) 2020;303(6):1727-1734.Abstract
One question that has intrigued cell biologists for many years is, "How do cells interact to influence one another's activity?" The discovery of extracellular vesicles (EVs) and the fact that they carry cargo, which directs cells to undergo changes in morphology and gene expression, has revolutionized this field of research. Little is known regarding the role of EVs in the cornea; however, we have demonstrated that EVs isolated from corneal epithelial cells direct corneal keratocytes to initiate fibrosis. Intriguingly, our data suggest that EVs do not penetrate epithelial basement membrane (BM), perhaps providing a mechanism explaining the importance of BM in the lack of scarring in scrape wounds. Since over 100-million people worldwide suffer from visual impairment as a result of corneal scarring, the role of EVs may be vital to understanding the mechanisms of wound repair. Therefore, we investigated EVs in ex vivo and in vivo-like three-dimensional cultures of human corneal cells using transmission electron microscopy. Some of the major findings were all three major cell types (epithelial, fibroblast, and endothelial cells) appear to release EVs, EVs can be identified using TEM, and EVs appeared to be involved in cell-cell communication. Interestingly, while our previous publication suggests that EVs do not penetrate the epithelial BM, it appears that EVs penetrate the much thicker endothelial BM (Descemet's membrane). These findings indicate the huge potential of EV research in the cornea and wound healing, and suggest that during homeostasis the endothelium and stromal cells are in communication. Anat Rec, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
Zucker CL, Bernstein PS, Schalek RL, Lichtman JW, Dowling JE. A connectomics approach to understanding a retinal disease. Proc Natl Acad Sci U S A 2020;117(31):18780-18787.Abstract
Macular telangiectasia type 2 (MacTel), a late-onset macular degeneration, has been linked to a loss in the retina of Müller glial cells and the amino acid serine, synthesized by the Müller cells. The disease is confined mainly to a central retinal region called the MacTel zone. We have used electron microscopic connectomics techniques, optimized for disease analysis, to study the retina from a 48-y-old woman suffering from MacTel. The major observations made were specific changes in mitochondrial structure within and outside the MacTel zone that were present in all retinal cell types. We also identified an abrupt boundary of the MacTel zone that coincides with the loss of Müller cells and macular pigment. Since Müller cells synthesize retinal serine, we propose that a deficiency of serine, required for mitochondrial maintenance, causes mitochondrial changes that underlie MacTel development.
van Zyl T, Yan W, McAdams A, Peng Y-R, Shekhar K, Regev A, Juric D, Sanes JR. Cell atlas of aqueous humor outflow pathways in eyes of humans and four model species provides insight into glaucoma pathogenesis. Proc Natl Acad Sci U S A 2020;117(19):10339-10349.Abstract
Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single-cell RNA sequencing (scRNAseq). From ∼24,000 single-cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (), rhesus macaque (), pig (), and mouse (). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma and for using model systems to assess mechanisms and potential interventions.

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