Cornea

Foulsham W, Marmalidou A, Amouzegar A, Coco G, Chen Y, Dana R. Review: The function of regulatory T cells at the ocular surface. Ocul Surf 2017;15(4):652-659.Abstract
Regulatory T cells (Tregs) are critical modulators of immune homeostasis. Tregs maintain peripheral tolerance to self-antigens, thereby preventing autoimmune disease. Furthermore, Tregs suppress excessive immune responses deleterious to the host. Recent research has deepened our understanding of how Tregs function at the ocular surface. This manuscript describes the classification, the immunosuppressive mechanisms, and the phenotypic plasticity of Tregs. We review the contribution of Tregs to ocular surface autoimmune disease, as well as the function of Tregs in allergy and infection at the ocular surface. Finally, we review the role of Tregs in promoting allotolerance in corneal transplantation.
González-Andrades M, Mata R, González-Gallardo MDC, Medialdea S, Arias-Santiago S, Martínez-Atienza J, Ruiz-García A, Pérez-Fajardo L, Lizana-Moreno A, Garzón I, Campos A, Alaminos M, Carmona G, Cuende N. A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment. BMJ Open 2017;7(9):e016487.Abstract
INTRODUCTION: There is a need to find alternatives to the use of human donor corneas in transplants because of the limited availability of donor organs, the incidence of graft complications, as well as the inability to successfully perform corneal transplant in patients presenting limbal deficiency, neo-vascularized or thin corneas, etc. We have designed a clinical trial to test a nanostructured fibrin-agarose corneal substitute combining allogeneic cells that mimics the anterior human native cornea in terms of optical, mechanical and biological behaviour. METHODS AND ANALYSIS: This is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in ten Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of this bioengineered human corneal substitute in adults with severe trophic corneal ulcers refractory to conventional treatment, or with sequelae of previous ulcers. In the initial phase of the trial (n=5), patients were sequentially recruited, with a safety period of 45 days, receiving the bioengineered corneal graft. In the second phase of the trial (currently ongoing), subjects are block randomised (2:1) to receive either the corneal graft (n=10), or amniotic membrane (n=5), as the control treatment. Adverse events, implant status, infection signs and induced neovascularization are evaluated as determinants of safety and feasibility of the bioengineered graft (main outcomes). Study endpoints are measured along a follow-up period of 24 months, including 27 post-implant assessment visits according to a decreasing frequency. Intention to treat, and per protocol, and safety analysis will be performed. ETHICS AND DISSEMINATION: The trial protocol received written approval by the corresponding Ethics Committee and the Spanish Regulatory Authority and is currently recruiting subjects. On completion of the trial, manuscripts with the results of phases I and II of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION: CT.gov identifier: NCT01765244 (Jan2013). EudraCT number: 2010-024290-40 (Dec2012).
Syed ZA, Tran JA, Jurkunas UV. Peripheral Endothelial Cell Count Is a Predictor of Disease Severity in Advanced Fuchs Endothelial Corneal Dystrophy. Cornea 2017;36(10):1166-1171.Abstract
PURPOSE: In advanced Fuchs endothelial corneal dystrophy (FECD), central endothelial changes do not correlate with disease severity. The peripheral endothelial cell count (ECC) has not been studied as a marker of FECD severity. The goal of this study was to determine the relationship between the peripheral ECC and known clinical markers of FECD in advanced cases. METHODS: Patients with FECD examined between January 1, 2013, and September 1, 2016, by 1 cornea specialist were identified. Medical records from all previous visits were reviewed to include eyes with high-quality central and peripheral in vivo confocal microscopy images performed on the same day as a clinical evaluation. Endothelial photographs were used to perform manual cell counts centrally and peripherally. Clinical grading of FECD from 1 to 4 was performed at the slit-lamp. RESULTS: We identified 154 eyes of 126 patients that met criteria for inclusion. With higher disease grades, central ECC and peripheral ECC decreased, visual acuity worsened, and central corneal thickness (CCT) increased (all P < 0.05). In patients with advanced disease (defined as either grade 3 or 4, CCT >700, or central ECC <350), the peripheral ECC was the best predictor of disease severity and had the highest number of statistically significant correlations with other clinical markers compared with competing variables. CONCLUSIONS: In advanced FECD, severity is best determined by the peripheral ECC compared with the central ECC, visual acuity, clinical disease grade, and CCT. The peripheral ECC should be added to the clinical parameters used to evaluate FECD severity.
Ousler GW, Rimmer D, Smith LM, Abelson MB. Use of the Controlled Adverse Environment (CAE) in Clinical Research: A Review. Ophthalmol Ther 2017;6(2):263-276.Abstract
The many internal and external factors that contribute to the pathophysiology of dry eye disease (DED) create a difficult milieu for its study and complicate its clinical diagnosis and treatment. The controlled adverse environment (CAE®) model has been developed to minimize the variability that arises from exogenous factors and to exacerbate the signs and symptoms of DED by stressing the ocular surface in a safe, standardized, controlled, and reproducible manner. By integrating sensitive, specific, and clinically relevant endpoints, the CAE has proven to be a unique and adaptable model for both identifying study-specific patient populations with modifiable signs and symptoms, and for tailoring the evaluation of interventions in clinical research studies.
Corcoran P, Hollander DA, Ousler GW, Angjeli E, Rimmer D, Lane K, Abelson MB. Dynamic Sensitivity of Corneal TRPM8 Receptors to Menthol Instillation in Dry Eye Versus Normal Subjects. J Ocul Pharmacol Ther 2017;33(9):686-692.Abstract
PURPOSE: To assess the sensitivity of corneal cold receptors to a known transient receptor potential melastatin 8 (TRPM8) agonist, menthol, in dry eye and normals, and to determine whether factors such as disease duration or age affect responses. METHODS: Dry eye disease (DED) (N = 33) and normal (N = 15) subjects were randomly assigned to receive Rohto® Hydra (0.01% menthol) or Systane® Ultra treatments (OU) in a prospective, double-blind, crossover study. DED subjects had documented disease and symptom response scores >2 on a 0- to 5-point scale. Normals had no history of DED and scores <2 on the same scale. Endpoints included mean cooling score (0 = not cool and 10 = very cool) evaluated at 0, 0.5, 1, 2, 3, and 4 min post-instillation, sum cooling scores (5 time points, range 0-60), and ocular signs and symptoms. RESULTS: Mean (±SD) ages were similar, 62.2 ± 8.6-year (DED) versus 53.5 ± 7.6-year (normal). Corneal sensitivity scores were not different between groups. Mean cooling scores at 0.5-4 min post-menthol instillation were significantly higher in DED subjects (P ≤ 0.03). Sum cooling scores were significantly higher (P = 0.04) in DED subjects with a disease duration <10 years (N = 18, 28.3 ± 2.58) versus ≥10 years (N = 15, 20.2 ± 2.76). Age did not affect cooling response in either group. CONCLUSION: DED subjects had greater sensitivity to cold than normal subjects. DED duration, and not age, was critical to cooling sensitivity. The finding that cooling scores were higher in subjects with DED for less than 10 years compared to more than 10 years suggests that corneal cold receptor sensitivity decreases as the duration of DED increases.
Lippestad M, Hodges RR, Utheim TP, Serhan CN, Dartt DA. Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways. Invest Ophthalmol Vis Sci 2017;58(11):4530-4544.Abstract
Purpose: Goblet cells in the conjunctiva secrete mucin into the tear film protecting the ocular surface. The proresolution mediator resolvin D1 (RvD1) regulates mucin secretion to maintain homeostasis during physiological conditions and in addition, actively terminates inflammation. We determined the signaling mechanisms used by RvD1 in cultured rat conjunctival goblet cells to increase intracellular [Ca2+] ([Ca2+]i) and induce glycoconjugate secretion. Methods: Increase in [Ca2+]i were measured using fura 2/AM and glycoconjugate secretion determined using an enzyme-linked lectin assay with the lectin Ulex Europaeus Agglutinin 1. Signaling pathways activated by RvD1 were studied after goblet cells were pretreated with signaling pathway inhibitors before stimulation with RvD1. The results were compared with results when goblet cells were stimulated with RvD1 alone and percent inhibition calculated. Results: The increase in [Ca2+]i stimulated by RvD1 was blocked by inhibitors to phospholipases (PL-) -D, -C, -A2, protein kinase C (PKC), extracellular signal-regulated kinases (ERK)1/2 and Ca2+/calmodulin-dependent kinase (Ca2+/CamK). Glycoconjugate secretion was significantly inhibited by PLD, -C, -A2, ERK1/2 and Ca2+/CamK, but not PKC. Conclusions: We conclude that RvD1 increases glycoconjugate secretion from goblet cells via multiple signaling pathways including PLC, PLD, and PLA2, as well as their signaling components ERK1/2 and Ca2+/CamK to preserve the mucous layer and maintain homeostasis by protecting the eye from desiccating stress, allergens, and pathogens.
Davies EC, Pineda R. Complications of Scleral-Fixated Intraocular Lenses. Semin Ophthalmol 2017;:1-6.Abstract
INTRODUCTION: Understanding the evolution of complications after scleral-fixated lens placement demonstrates advantageous surgical techniques and suitable candidates. MATERIALS/METHODS: A literature search in PubMed for several terms, including "scleral intraocular lens complication," yielded 17 relevant articles. RESULTS: Reviewing complication trends over time, lens tilt and suture erosion have decreased, cystoid macular edema has increased, and retinal detachment has remained the same after scleral-fixated lens placement. The successful reduction in complications are attributed to several alterations in technique, including positioning sclerotomy sites 180 degrees apart and using scleral flaps or pockets to bury sutures. Possible reduction in retinal risks have been proposed by performing an anterior vitrectomy prior to lens placement in certain settings. DISCUSSION: Complications after scleral-fixated lens placement should assist patient selection. Elderly patients with a history of hypertension should be counseled regarding risk of suprachoroidal hemorrhage, while young patients and postocular trauma patients should be considered for concurrent anterior vitrectomy.
Evangelista CB, Hatch KM. Corneal Collagen Cross-Linking Complications. Semin Ophthalmol 2017;:1-7.Abstract
Corneal cross-linking was approved by United States Food and Drug Administration for the treatment of progressive keratoconus in April 2016. As this approach becomes more widely used for the treatment of keratoconus and post-laser in situ keratomileusis (LASIK) ectasia, the medical community is becoming more familiar with potential complications associated with this procedure. This article aims to review the reported complications of collagen cross-linking for the treatment of keratoconus and post-LASIK ectasia.
Jackson CJ, Reppe S, Eidet JR, Eide L, Tønseth KA, Bergersen LH, Dartt DA, Griffith M, Utheim TP. Optimization of Storage Temperature for Retention of Undifferentiated Cell Character of Cultured Human Epidermal Cell Sheets. Sci Rep 2017;7(1):8206.Abstract
Cultured epidermal cell sheets (CES) containing undifferentiated cells are useful for treating skin burns and have potential for regenerative treatment of other types of epithelial injuries. The undifferentiated phenotype is therefore important for success in both applications. This study aimed to optimize a method for one-week storage of CES for their widespread distribution and use in regenerative medicine. The effect of storage temperatures 4 °C, 8 °C, 12 °C, 16 °C, and 24 °C on CES was evaluated. Analyses included assessment of viability, mitochondrial reactive oxygen species (ROS), membrane damage, mitochondrial DNA (mtDNA) integrity, morphology, phenotype and cytokine secretion into storage buffer. Lowest cell viability was seen at 4 °C. Compared to non-stored cells, ABCG2 expression increased between temperatures 8-16 °C. At 24 °C, reduced ABCG2 expression coincided with increased mitochondrial ROS, as well as increased differentiation, cell death and mtDNA damage. P63, C/EBPδ, CK10 and involucrin fluorescence combined with morphology observations supported retention of undifferentiated cell phenotype at 12 °C, transition to differentiation at 16 °C, and increased differentiation at 24 °C. Several cytokines relevant to healing were upregulated during storage. Importantly, cells stored at 12 °C showed similar viability and undifferentiated phenotype as the non-stored control suggesting that this temperature may be ideal for storage of CES.
Craig JP, Nelson DJ, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Report Executive Summary. Ocul Surf 2017;15(4):802-812.Abstract
This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org.
Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, Na K-S, Schaumberg D, Uchino M, Vehof J, Viso E, Vitale S, Jones L. TFOS DEWS II Epidemiology Report. Ocul Surf 2017;15(3):334-365.Abstract
The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non-modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.
Willcox MDP, Argüeso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, Papas EB, Rolland JP, Schmidt TA, Stahl U, Suarez T, Subbaraman LN, Uçakhan OÖ, Jones L. TFOS DEWS II Tear Film Report. Ocul Surf 2017;15(3):366-403.Abstract
The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED). The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED. Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased evaporation of tears from the ocular surface. The tear film is composed of many substances including lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to other components such as proteins and mucins can be used as biomarkers for DED. The Subcommittee recommended areas for future research to advance our understanding of the tear film and how this changes with DED. The final report was written after review by all Subcommittee members and the entire TFOS DEWS II membership.
Sullivan DA, Rocha EM, Aragona P, Clayton JA, Ding J, Golebiowski B, Hampel U, McDermott AM, Schaumberg DA, Srinivasan S, Versura P, Willcox MDP. TFOS DEWS II Sex, Gender, and Hormones Report. Ocul Surf 2017;15(3):284-333.Abstract
One of the most compelling features of dry eye disease (DED) is that it occurs more frequently in women than men. In fact, the female sex is a significant risk factor for the development of DED. This sex-related difference in DED prevalence is attributed in large part to the effects of sex steroids (e.g. androgens, estrogens), hypothalamic-pituitary hormones, glucocorticoids, insulin, insulin-like growth factor 1 and thyroid hormones, as well as to the sex chromosome complement, sex-specific autosomal factors and epigenetics (e.g. microRNAs). In addition to sex, gender also appears to be a risk factor for DED. "Gender" and "sex" are words that are often used interchangeably, but they have distinct meanings. "Gender" refers to a person's self-representation as a man or woman, whereas "sex" distinguishes males and females based on their biological characteristics. Both gender and sex affect DED risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization, and myriad other facets of eye health. Overall, sex, gender and hormones play a major role in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The purpose of this Subcommittee report is to review and critique the nature of this role, as well as to recommend areas for future research to advance our understanding of the interrelationships between sex, gender, hormones and DED.
Novack GD, Asbell P, Barabino S, Bergamini MVW, Ciolino JB, Foulks GN, Goldstein M, Lemp MA, Schrader S, Woods C, Stapleton F. TFOS DEWS II Clinical Trial Design Report. Ocul Surf 2017;15(3):629-649.Abstract
The development of novel therapies for Dry Eye Disease (DED) is formidable, and relatively few treatments evaluated have been approved for marketing. In this report, the Subcommittee reviewed challenges in designing and conducting quality trials, with special reference to issues in trials in patients with DED and present the regulatory perspective on DED therapies. The Subcommittee reviewed the literature and while there are some observations about the possible reasons why so many trials have failed, there is no obvious single reason other than the lack of correlation between signs and symptoms in DED. Therefore the report advocates for conducting good quality studies, as described, going forward. A key recommendation for future studies is conduct consistent with Good Clinical Practice (GCP), including use of Good Manufacturing Practice (GMP) quality clinical trial material. The report also recommends that the design, treatments, and sample size be consistent with the investigational treatment, the objectives of the study, and the phase of development. Other recommendations for pivotal studies are a priori selection of the outcome measure, and an appropriate sample size.

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