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Owen LA, Shakoor A, Morgan DJ, Hejazi AA, McEntire WM, Brown JJ, Farrer LA, Kim I, Vitale A, Deangelis MM. The Utah Protocol for Postmortem Eye Phenotyping and Molecular Biochemical Analysis. Invest Ophthalmol Vis Sci 2019;60(4):1204-1212.Abstract
Purpose: Current understanding of local disease pathophysiology in AMD is limited. Analysis of the human disease-affected tissue is most informative, as gene expression, expressed quantitative trait loci, microenvironmental, and epigenetic changes can be tissue, cell type, and location specific. Development of a novel translational treatment and prevention strategies particularly for earlier forms of AMD are needed, although access to human ocular tissue analysis is challenging. We present a standardized protocol to study rapidly processed postmortem donor eyes for molecular biochemical and genomic studies. Methods: We partnered with the Utah Lions Eye Bank to obtain donor human eyes, blood, and vitreous, within 6 hours postmortem. Phenotypic analysis was performed using spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. Macular and extramacular tissues were immediately isolated, and the neural retina and retinal pigment epithelium/choroid from each specimen were separated and preserved. Ocular disease phenotype was analyzed using clinically relevant grading criteria by a group of four ophthalmologists incorporating data from SD-OCT retinal images, fundus photographs, and medical records. Results: The use of multimodal imaging leads to greater resolution of retinal pathology, allowing greater phenotypic rigor for both interobserver phenotype and known clinical diagnoses. Further, our analysis resulted in excellent quality RNA, which demonstrated appropriate tissue segregation. Conclusions: The Utah protocol is a standardized methodology for analysis of disease mechanisms in AMD. It uniquely allows for simultaneous rigorous phenotypic, molecular biochemical, and genomic analysis of both systemic and local tissues. This better enables the development of disease biomarkers and therapeutic interventions.
Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE, and Group TILSCDW. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 2019;38(3):364-375.Abstract
PURPOSE: Despite extensive knowledge gained over the last 3 decades regarding limbal stem cell deficiency (LSCD), the disease is not clearly defined, and there is lack of agreement on the diagnostic criteria, staging, and classification system among treating physicians and research scientists working on this field. There is therefore an unmet need to obtain global consensus on the definition, classification, diagnosis, and staging of LSCD. METHODS: A Limbal Stem Cell Working Group was first established by The Cornea Society in 2012. The Working Group was divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to obtain agreement on a strategic plan and methodology from all participants after a comprehensive literature search, and final agreement was reached on the definition, classification, diagnosis, and staging of LSCD. A writing group was formed to draft the current manuscript, which has been extensively revised to reflect the consensus of the Working Group. RESULTS: A consensus was reached on the definition, classification, diagnosis, and staging of LSCD. The clinical presentation and diagnostic criteria of LSCD were clarified, and a staging system of LSCD based on clinical presentation was established. CONCLUSIONS: This global consensus provides a comprehensive framework for the definition, classification, diagnosis, and staging of LSCD. The newly established criteria will aid in the correct diagnosis and formulation of an appropriate treatment for different stages of LSCD, which will facilitate a better understanding of the condition and help with clinical management, research, and clinical trials in this area.
Bothun ED, Wilson EM, Traboulsi EI, Diehl NN, Plager DA, VanderVeen DK, Freedman SF, Yen KG, Weil NC, Loh AR, Morrison D, Anderson JS, Lambert SR, and (TAPS) TAPSG. Outcomes of Unilateral Cataracts in Infants and Toddlers 7 to 24 Months of Age: Toddler Aphakia and Pseudophakia Study (TAPS). Ophthalmology 2019;126(8):1189-1195.Abstract
PURPOSE: To evaluate outcomes of unilateral cataract surgery in children 7 to 24 months of age. DESIGN: Retrospective case series at 10 Infant Aphakia Treatment Study (IATS) sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent unilateral cataract surgery with or without intraocular lens (IOL) placement during the IATS enrollment years of 2004 and 2010. MAIN OUTCOME MEASURES: Intraoperative complications, adverse events (AEs), visual acuity, and strabismus. RESULTS: Fifty-six children were included with a mean postoperative follow-up of 47.6 months. Median age at cataract surgery was 13.9 months (range, 7.2-22.9). Ninety-two percent received a primary IOL. Intraoperative complications occurred in 4 patients (7%). At 5 years of age, visual acuity of treated eyes was very good (≥20/40) in 11% and poor (≤20/200) in 44%. Adverse events were identified in 24%, with a 4% incidence of glaucoma suspect. An additional unplanned intraocular surgery occurred in 14% of children. Neither AEs nor intraocular reoperations were more common for children with surgery at 7 to 12 months of age than for those who underwent surgery at 13 to 24 months of age (AE rate, 21% vs. 25% [P = 0.60]; reoperation rate, 13% vs. 16% [P = 1.00]). CONCLUSIONS: Although most children underwent IOL implantation concurrent with unilateral cataract removal, the incidence of complications, reoperations, and glaucoma was low when surgery was performed between 7 and 24 months of age and compared favorably with same-site IATS data for infants undergoing surgery before 7 months of age. Our study showed that IOL implantation is relatively safe in children older than 6 months and younger than 2 years.
Utheim OA, Pasovic L, Raeder S, Eidet JR, Fostad IG, Sehic A, Roald B, de la Paz MF, Lyberg T, Dartt DA, Utheim TP. Effects of explant size on epithelial outgrowth, thickness, stratification, ultrastructure and phenotype of cultured limbal epithelial cells. PLoS One 2019;14(3):e0212524.Abstract
PURPOSE: Transplantation of limbal stem cells is a promising therapy for limbal stem cell deficiency. Limbal cells can be harvested from either a healthy part of the patient's eye or the eye of a donor. Small explants are less likely to inflict injury to the donor site. We investigated the effects of limbal explant size on multiple characteristics known to be important for transplant function. METHODS: Human limbal epithelial cells were expanded from large versus small explants (3 versus 1 mm of the corneal circumference) for 3 weeks and characterized by light microscopy, immunohistochemistry, and transmission electron microscopy. Epithelial thickness, stratification, outgrowth, ultrastructure and phenotype were assessed. RESULTS: Epithelial thickness and stratification were similar between the groups. Outgrowth size correlated positively with explant size (r = 0.37; P = 0.01), whereas fold growth correlated negatively with explant size (r = -0.55; P < 0.0001). Percentage of cells expressing the limbal epithelial cell marker K19 was higher in cells derived from large explants (99.1±1.2%) compared to cells derived from small explants (93.2±13.6%, P = 0.024). The percentage of cells expressing ABCG2, integrin β1, p63, and p63α that are markers suggestive of an immature phenotype; Keratin 3, Connexin 43, and E-Cadherin that are markers of differentiation; and Ki67 and PCNA that indicate cell proliferation were equal in both groups. Desmosome and hemidesmosome densities were equal between the groups. CONCLUSION: For donor- and culture conditions used in the present study, large explants are preferable to small in terms of outgrowth area. As regards limbal epithelial cell thickness, stratification, mechanical strength, and the attainment of a predominantly immature phenotype, both large and small explants are sufficient.
Roohipoor R, Alvarez R, Brodowska K, Yaseri M, Kloek C, Riazi M, Nourinia R, Nikkhah H, Prajna VN, Krishnan C, Tuli S, Green L, Srikumaran D, Shah AS, Mantagos IS, Chiang M, Chan PRV, Loewenstein J. Evaluation of computer-based retinopathy of prematurity (ROP) education for ophthalmology residents: a randomized, controlled, multicenter study. J AAPOS 2019;Abstract
PURPOSE: To evaluate the effect of a computer-based training program-Massachusetts Eye & Ear ROP Trainer-on residents' knowledge of retinopathy of prematurity (ROP) management. METHODS: In this prospective, randomized study, ophthalmology residents from nine different training programs consented to participate. Those who completed the study were randomly assigned to either the Trainer or the control group. The ROP Trainer was created using clinical cases encompassing the stages of ROP in digital pictures and videos. It includes sections on screening decisions, examination techniques, and diagnosis, and a reference section with the expert video clips and a searchable image library. Subjects in the control group were asked to study standard print material on ROP. A pre- and post-test, consisting of theoretical and practical (diagnosis) questions, and a post-intervention satisfaction test were administered. Accuracy of ROP diagnosis was assessed. RESULTS: A total of 180 residents agreed to participate, of whom 60 completed the study. Residents in the Trainer group had statistically significant improvements (P = 0.003) in ROP knowledge and diagnostic ability (P = 0.005). Residents randomized to the Trainer group were more satisfied with the training materials than were those in the control group. There was no significant difference in improving knowledge by year of training, sex, or country. Considering all training levels, a statistically significant increase was observed in sensitivity for the diagnosis of preplus or worse, zone I or II, ROP stage, category, and aggressive posterior ROP in the Trainer group. CONCLUSIONS: In this study, the Trainer was shown to significantly improve ROP knowledge and diagnostic skills of residents, regardless of sex, year, of training, or country.
Gomes PJ, Abelson MB, Stein L, Viirre E, Villafranca EJ, Lasser EC. Iodixanol nasal solution reduces allergic rhinoconjunctivitis signs and symptoms in Allergen BioCube: a randomized clinical trial. J Asthma Allergy 2019;12:71-81.Abstract
Purpose: Allergic rhinitis (AR) affects ~20% of the population worldwide. The objectives of this study were to evaluate the safety and efficacy of iodixanol nasal solution (Nasapaque) for AR treatment, using the Allergen BioCube (ABC), an environmental exposure unit. Iodixanol is a commonly used contrast media agent that shows efficacy on the signs and symptoms of AR. Patients and methods: Seventy-three adult subjects with AR were randomized to iodixanol or placebo treatment in a double-masked efficacy and safety study conducted outside of ragweed pollen season. In-office treatment was administered after BioCube ragweed pollen exposure, and again 8 days later prior to ragweed exposure. Nasal and ocular efficacy and safety assessments were conducted before and after treatment. Results: Iodixanol treatment resulted in statistically significantly lower total nasal symptom scores as compared to placebo at several time points post-treatment and ABC exposure. Individual nasal and ocular symptoms, notably nasal itching and ocular itching, showed evidence of lower scores in the iodixanol group. Peak nasal inspiratory flow (PNIF) improved (9%-16%) with iodixanol from baseline as compared to PNIF in the placebo group which ranged from 3% worsening to improvement of 2%. Few (9) adverse events occurred. Conclusion: Iodixanol nasal solution demonstrated efficacy for relief of several nasal and ocular allergic rhinoconjunctivitis signs and symptoms, and was safe and well tolerated in this early Phase II exploratory trial. Further studies with iodixanol are warranted. Allergy challenge models such as the ABC provide valuable assessments of allergen exposures and drug efficacies. Study Identification Number: NCT02377895.
Busch C, Fraser-Bell S, Zur D, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, Fung AT, Gabrielle P-H, Giancipoli E, Chaikitmongkol V, Okada M, Laíns I, Santos AR, Kunavisarut P, Sala-Puigdollers A, Chhablani J, Ozimek M, Hilely A, Unterlauft JD, Loewenstein A, Iglicki M, Rehak M, Rehak M. Real-world outcomes of observation and treatment in diabetic macular edema with very good visual acuity: the OBTAIN study. Acta Diabetol 2019;56(7):777-784.Abstract
AIMS: To describe and compare the functional and anatomical outcomes of untreated and treated diabetic macular edema (DME) in eyes with very good baseline visual acuity (VA) in a real-world setting. METHODS: A 12-month, retrospective, multicenter, observational cohort study, including DME patients with baseline visual acuity (VA) ≤ 0.1 logMAR (≥ 20/25 Snellen) and central subfield thickness (CST) > 250 µm with intra- and/or subretinal fluid seen on optical coherence tomography. RESULTS: A total of 249 eyes were included, of which 155 were treated and 94 were non-treated during follow-up. Most eyes maintained vision (VA gain or VA loss < 5 letters) at 12 months (treated: 58.1%; non-treated: 73.4%). In non-treated eyes with stable VA within the first 6 months, VA was maintained throughout the follow-up in most cases (86.3%). In non-treated eyes with VA loss ≥ 5 letters within 6 months (36.7%), further observation led to worse visual outcome than treatment (- 4.2 vs. - 7.8 letters, p = 0.013). In eyes in which treatment was initiated at baseline (n = 102), treatment with 8-12 anti-VEGF injections led to better visual outcome compared to treatment with less injections (- 0.3 ± 3.6 letters vs. - 3.8 ± 6.2 letters, p = 0.003). CONCLUSION: In a real-world setting, the majority of DME patients with very good VA maintained vision at 12 months, regardless of whether the DME was treated or not. This study supports close observation of eyes with DME and very good VA with consideration of treatment when a one line drop in vision is observed.
Sheptulin V, Fedorov A, Prause J, Fay A, Grusha Y. Hyaluronic Acid Gel Biodegradation After Intrapalpebral and Intraorbital Injection in Experimental Study. Ophthalmic Plast Reconstr Surg 2019;35(6):558-561.Abstract
PURPOSE: Amid the increasing clinical application of hyaluronic acid (HA) fillers in the ocular adnexa is a paucity of histological data concerning the fate of the injected material. The current study documents the in vivo biodegradation of HA deposited in the eyelid and orbit. METHODS: The study included 22 chinchilla rabbits. The right upper eyelid of 12 rabbits received a single 0.2 ml Restylane (Galderma, Uppsala, Sweden) subcutaneous injection. In 10 different rabbits, the right orbit was injected with 1.0 ml Restylane SubQ (Galderma, Uppsala, Sweden) in the extraconal space. The rabbits in the eyelid group were euthanized at 2 weeks, 1 month, 2, 4, 6, and 9 months, while the rabbits in the orbit group were euthanized at 1 month, 3, 6, 12, and 18 months. Histological analysis was performed on the harvested samples. RESULTS: In the eyelid, the HA assumed a sponge-like structure that diminished gradually over time. At 9 months, the injected HA partially persisted, mainly in the peripheral areas of injection. A similar histologic pattern was observed in the injected orbits, with slow changes persisting at the eighteenth month. In both cohorts, clear signs of collagen deposition and pseudocapsule formation were observed around HA droplets, with no signs inflammation. CONCLUSIONS: HA injected subcutaneously into the eyelid and orbit of rabbits undergoes slow and gradual biodegradation, with HA persisting to no less than 9 months in the eyelid and 18 months in orbit. Neocollagen synthesis and lack of hyaluronidase activity could explain the unexpectedly prolonged HA persistence.
North VS, Habib L, Yoon MK. Merkel Cell Carcinoma of the Eyelid: a Review. Surv Ophthalmol 2019;Abstract
Merkel cell carcinoma (MCC) is a rare, aggressive tumor of both epithelial and neuroendocrine origin that carries a mortality rate of up to 40%. MCC tumors typically present as painless, expanding nodules on the sun-exposed skin areas of older, white patients. Eyelid and periocular tumors comprise approximately 2.5% of all cases of MCC and may be mistaken for chalazia or basal cell carcinomas. Immunosuppression is a significant risk factor, particularly in solid-organ transplant recipients, patients with chronic lymphocytic leukemia, and patients with HIV. Sentinel lymph node biopsy is often employed for accurate staging of head and neck MCC. Treatment includes wide-local excision, commonly with the addition of radiotherapy for improved locoregional disease control. Historically, adjuvant chemotherapy had been reserved for metastatic disease, but immunotherapy and targeted chemotherapies are currently being investigated for use in primary disease. The clinical characteristics of all available published cases of eyelid MCC are summarized .
Ichhpujani P, Singh RB, Foulsham W, Thakur S, Lamba AS. Visual implications of digital device usage in school children: a cross-sectional study. BMC Ophthalmol 2019;19(1):76.Abstract
PURPOSE: To evaluate the use of digital devices, reading habits and the prevalence of eyestrain among urban Indian school children, aged 11-17 years. METHODS: The study included 576 adolescents attending urban schools who were surveyed regarding their electronic device usage. Additional information on the factors that may have an effect on ocular symptoms was collected. RESULTS: Twenty percent of students aged 11 in the study population use digital devices on a daily basis, in comparison with 50% of students aged 17. In addition to using these devices as homework aids, one third of study participants reported using digital devices for reading instead of conventional textbooks. The majority of students preferred sitting on a chair while reading (77%; 445 students), with only 21% (123 students) preferring to lie on the bed and 8 students alternating between chair and bed. There was a significant association between the students who preferred to lie down and those who experienced eyestrain, as reported by a little over one fourth of the student population (27%). Out of 576 students, 18% (103) experienced eyestrain at the end of the day after working on digital devices. CONCLUSIONS: The increased use of digital devices by adolescents brings a new challenge of digital eyestrain at an early age. Our study reports the patterns of electronic device usage by school children, evaluates factors associated with eyestrain and highlights the need for further investigation of these issues.
Chung DC, Bertelsen M, Lorenz B, Pennesi ME, Leroy BP, Hamel CP, Pierce E, Sallum J, Larsen M, Stieger K, Preising M, Weleber R, Yang P, Place E, Liu E, Schaefer G, DiStefano-Pappas J, Elci OU, McCague S, Wellman JA, High KA, Reape KZ. The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. Am J Ophthalmol 2019;199:58-70.Abstract
PURPOSE: To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses. DESIGN: Global, multicenter, retrospective chart review. METHODS: Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD. PROCEDURES: Data were extracted from patient charts. MEASUREMENTS: Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available). RESULTS: VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships. CONCLUSIONS: The number of clinical diagnoses and lack of a consistent RPE65 mutation-to-phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations.
Al-Moujahed A, Tian B, Efstathiou NE, Konstantinou EK, Hoang M, Lin H, Miller JW, Vavvas DG. Receptor interacting protein kinase 3 (RIP3) regulates iPSCs generation through modulating cell cycle progression genes. Stem Cell Res 2019;35:101387.Abstract
The molecular mechanisms involved in induced pluripotent stem cells (iPSCs) generation are poorly understood. The cell death machinery of apoptosis-inducing caspases have been shown to facilitate the process of iPSCs reprogramming. However, the effect of other cell death processes, such as programmed necrosis (necroptosis), on iPSCs induction has not been studied. In this study, we investigated the role of receptor-interacting protein kinase 3 (RIP3), an essential regulator of necroptosis, in reprogramming mouse embryonic fibroblast cells (MEFs) into iPSCs. RIP3 was found to be upregulated in iPSCs compared to MEFs. Deletion of RIP3 dramatically suppressed the reprogramming of iPSCs (~82%). RNA-seq analysis and qRT-PCR showed that RIP3 KO MEFs expressed lower levels of genes that control cell cycle progression and cell division and higher levels of extracellular matrix-regulating genes. The growth rate of RIP3 KO MEFs was significantly slower than WT MEFs. These findings can partially explain the inhibitory effects of RIP3 deletion on iPSCs generation and show for the first time that the necroptosis kinase RIP3 plays an important role in iPSC reprogramming. In contrast to RIP3, the kinase and scaffolding functions of RIPK1 appeared to have distinct effects on reprogramming.

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