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Evolving multidimensional pharmacological approaches to CNV therapy in AMD.
Ehrenberg, M, Benny, O
Current eye research. 2018;(2):147-154
Abstract
PURPOSE The leading cause of severe visual loss world-wide is age-related macular degeneration. Although anti-Vascular Endothelial Growth Factor agents have significantly led to the initial pharmacologic reversal of vision loss in many cases of exudative macular degeneration, there still has been recurrence of choroidal neovascularization, and/or the onset of chorioretinal atrophy with fibrosis. MATERIALS AND METHODS In this review we discuss the status of anti- Vascular Endothelial Growth Factor in age-related macular degeneration and describe different studies focused on new potential therapeutic targets beyond anti- Vascular Endothelial Growth Factor. RESULTS Further investigations have elicited that Vascular Endothelial Growth Factor is only one of many angiogenic, and pro-inflammatory factors that bring about the growth and leakage of active choroidal neovascularization. Various new multifaceted strategies, including inhibitors to down-stream targets of endothelial cell division, such as TNP-470, may lead to a more permanent inactivation of choroidal neovascularization. CONCLUSIONS Based on the accumulated results in the treatment of age-related macular degeneration, it is hoped that the appropriate combination of anti-Vascular Endothelial Growth Factor agents with longer-acting and multidimensional pharmaceuticals, such as Methionine Aminopeptidase-2 inhibitors, will more effectively control choroidal neovascularization, prevent atrophy and fibrosis, and reduce the burden of frequent intraocular injections in age-related macular degeneration.
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Anti-platelet effects of vitamin supplements in age-related macular degeneration: an in vitro study.
Moschos, MM, Laios, K, Androudi, S, Ladas, DS, Chatziralli, IP
Cutaneous and ocular toxicology. 2018;(3):207-209
Abstract
OBJECTIVE The purpose of this experimental study was to investigate the role of vitamin supplements (Ocuvite, Vitalux Omega, and Nutrof Total) as possible inhibitors of the onset of age-related macular degeneration (AMD). MATERIALS AND METHODS The anti-aggregating effect of each vitamin was determined against four accumulative factors namely, platelet activating factor (PAF), adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), and arachidonic acid (AA) in the platelet rich plasma (PRP) of healthy volunteers. RESULTS Ocuvite, Vitalux Omega, and Nutrof Total were more potent inhibitors against PAF and ADP compared to TRAP and AA. Among the three vitamins, Nutrof Total displayed more potent inhibitions against TRAP and AA, while against PAF and ADP all the three vitamins revealed similar IC50 values. CONCLUSIONS The vitamins Ocuvite, Vitalux Omega, and Nutrof Total have anti-aggregating effects and therefore can be used against AMD in healthy volunteers.
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The role of the intestinal microbiome in ocular inflammatory disease.
Lin, P
Current opinion in ophthalmology. 2018;(3):261-266
Abstract
PURPOSE OF REVIEW The intestinal commensal microbiota are important in shaping immune cell repertoire and are influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This review summarizes the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit. RECENT FINDINGS Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis. Two groups showed that altering the microbiota with oral antibiotics results in reduced uveitis severity, and another group demonstrated that a commensal bacterial antigen activates retina-specific autoreactive T cells, potentially indicating a commensal trigger for uveitis. We have found that commensal bacterial metabolites, short chain fatty acids, can suppress autoimmune uveitis. Age-related macular degeneration is associated with an intestinal dysbiosis, which can be influenced by genetic risk alleles and age-related eye disease study (AREDS) supplementation. Strategies that might be effective for targeting the intestinal microbiota might involve several approaches, including the use of antibiotics, drugs that supplement beneficial bacterial components or target inflammatory bacterial strains, dietary strategies or microbial transplantation. SUMMARY The intestinal microbiota are potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.
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Evaluation of Efficacy and Safety of Dexamethasone Intravitreal Implants of Vitrectomized and Nonvitrectomized Eyes in a Real-World Study.
Rezkallah, A, Malclès, A, Dot, C, Voirin, N, Agard, É, Vié, AL, Denis, P, Mathis, T, Kodjikian, L
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 2018;(8):596-602
Abstract
PURPOSE To compare the efficacy and safety of the dexamethasone (DEX) intravitreal implant of vitrectomized and nonvitrectomized eyes in real-world conditions. METHODS This was a retrospective, multicenter, observational study. All consecutive patients presenting with at least one 0.7-mg intravitreal injection of DEX implant were included in this study. A total of 186 eyes in 170 patients were analyzed. Fifty-nine eyes were vitrectomized at baseline and 127 eyes had no vitrectomy at the last visit. Among the baseline-vitrectomized eyes analyzed, 72.9% were treatment naive eyes, and 44.1% of nonvitrectomized eyes had no prior treatment. RESULTS There was no statistically significant difference in the variation in best-corrected visual acuity (BCVA) between the 2 groups (P = 0.343). Variations of BCVA and central macular thickness were not significantly different between nonvitrectomized eyes and baseline-vitrectomized eyes. The intraocular pressure profile was the same in both nonvitrectomized eyes and baseline-vitrectomized eyes. The mean interval between injections was 6.9 months (2; 27.7) for nonvitrectomized eyes and 5.2 months (4; 22.1) for baseline-vitrectomized eyes (P = 0.001). The mean number of IVIs was 2 (1; 6) for nonvitrectomized eyes and 2.3 (1; 10) for baseline-vitrectomized eyes (P = 0.188) during the total follow-up period. CONCLUSION This large cohort shows that vitrectomy does not seem to influence the efficacy and safety profile of dexamethasone intravitreal implant for DME.
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A new perspective on lipid research in age-related macular degeneration.
van Leeuwen, EM, Emri, E, Merle, BMJ, Colijn, JM, Kersten, E, Cougnard-Gregoire, A, Dammeier, S, Meester-Smoor, M, Pool, FM, de Jong, EK, et al
Progress in retinal and eye research. 2018;:56-86
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Abstract
There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.
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Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration.
Kersten, E, Paun, CC, Schellevis, RL, Hoyng, CB, Delcourt, C, Lengyel, I, Peto, T, Ueffing, M, Klaver, CCW, Dammeier, S, et al
Survey of ophthalmology. 2018;(1):9-39
Abstract
Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy, and risk assessment in multifactorial diseases, such as age-related macular degeneration (AMD). AMD is a highly prevalent progressive retinal disorder for which multiple genetic and environmental risk factors have been described, but the exact etiology is not yet fully understood. Many compounds have been evaluated for their association with AMD. We performed an extensive literature review of all compounds measured in serum, plasma, vitreous, aqueous humor, and urine of AMD patients. Over 3600 articles were screened, resulting in more than 100 different compounds analyzed in AMD studies, involved in neovascularization, immunity, lipid metabolism, extracellular matrix, oxidative stress, diet, hormones, and comorbidities (such as kidney disease). For each compound, we provide a short description of its function and discuss the results of the studies in relation to its usefulness as AMD biomarker. In addition, biomarkers identified by hypothesis-free techniques, including metabolomics, proteomics, and epigenomics, are covered. In summary, compounds belonging to the oxidative stress pathway, the complement system, and lipid metabolism are the most promising biomarker candidates for AMD. We hope that this comprehensive survey of the literature on systemic and ocular fluid compounds as potential biomarkers in AMD will provide a stepping stone for future research and possible implementation in clinical practice.
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AGE-RELATED MACULAR DEGENERATION AND THE RISK OF ALL-CAUSE AND CARDIOVASCULAR MORTALITY: A Meta-Analysis of Cohort Studies.
Xin, X, Sun, Y, Li, S, Xu, H, Zhang, D
Retina (Philadelphia, Pa.). 2018;(3):497-507
Abstract
PURPOSE We evaluated the association between age-related macular degeneration (AMD) and the risk of all-cause and cardiovascular mortality by meta-analyses of data from prospective studies. METHODS A literature search was performed in PubMed, Web of Science, Embase, Cocharne Library, and China National Knowledge Infrastructure for relevant articles published up to December 2016. We estimated hazard ratios with 95% confidence intervals with fixed-effect models and conducted meta-regression to explore the potential sources of heterogeneity. Small-study effect was estimated by Egger's test and funnel plot. RESULTS We identified 13 population-based prospective cohort studies that examined the relationship between AMD and all-cause and cardiovascular mortality. Overall, the hazard ratios (95% confidence intervals) of all-cause mortality and cardiovascular mortality associated with any AMD were 1.15 (1.05-1.27) and 1.05 (95% confidence intervals: 0.87-1.26), respectively. The risk of all-cause mortality and cardiovascular mortality associated with early AMD were 1.08 (1.00-1.18) and 1.05 (0.89-1.24), and the associations with late AMD were 1.23 (1.11-1.36) and 1.28 (1.04-1.57), respectively. No evidence of small-study effect was found. CONCLUSION This meta-analysis indicated that AMD, especially late AMD, was associated with increased risk of all-cause mortality and cardiovascular mortality based on comparisons with people who did not have AMD and who were of similar age and sex.
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Can Artificial Intelligence Make Screening Faster, More Accurate, and More Accessible?
Li, Z, Keel, S, Liu, C, He, M
Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2018;(6):436-441
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Abstract
Diabetic retinopathy, glaucoma, and age-related macular degeneration are leading causes of vision loss and blindness worldwide. They tend to be asymptomatic in the early phase of disease and therefore require active screening programs to identify the patients requiring referral and treatment. Deep learning-based artificial intelligence technology has recently become a major topic in the field of ophthalmology. This paper aimed to provide a general view of the major findings on the application of deep learning for the classification of eye diseases from common imaging modalities. In the future, it is expected that these technologies will be applied in real-world screening programs to improve their efficiency and affordability.
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The effects of zinc supplementation on primary human retinal pigment epithelium.
Pao, PJ, Emri, E, Abdirahman, SB, Soorma, T, Zeng, HH, Hauck, SM, Thompson, RB, Lengyel, I
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2018;:184-191
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Abstract
Population-based and interventional studies have shown that elevated zinc levels can reduce the progression to advanced age-related macular degeneration. The objective of this study was to assess whether elevated extracellular zinc has a direct effect on retinal pigment epithelial cells (RPE), by examining the phenotype and molecular characteristics of increased extracellular zinc on human primary RPE cells. Monolayers of human foetal primary RPE cells were grown on culture inserts and maintained in medium supplemented with increasing total concentrations of zinc (0, 75, 100, 125 and 150 μM) for up to 4 weeks. Changes in cell viability and differentiation as well as expression and secretion of proteins were investigated. RPE cells developed a confluent monolayer with cobblestone morphology and transepithelial resistance (TER) >200 Ω*cm2 within 4 weeks. There was a zinc concentration-dependent increase in TER and pigmentation, with the largest effects being achieved by the addition of 125 μM zinc to the culture medium, corresponding to 3.4 nM available (free) zinc levels. The cells responded to addition of zinc by significantly increasing the expression of Retinoid Isomerohydrolase (RPE65) gene; cell pigmentation; Premelanosome Protein (PMEL17) immunoreactivity; and secretion of proteins including Apolipoprotein E (APOE), Complement Factor H (CFH), and High-Temperature Requirement A Serine Peptidase 1 (HTRA1) without an effect on cell viability. This study shows that elevated extracellular zinc levels have a significant and direct effect on differentiation and function of the RPE cells in culture, which may explain, at least in part, the positive effects seen in clinical settings. The results also highlight that determining and controlling of available, as opposed to total added, zinc will be essential to be able to compare results obtained in different laboratories.
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Deep learning applications in ophthalmology.
Rahimy, E
Current opinion in ophthalmology. 2018;(3):254-260
Abstract
PURPOSE OF REVIEW To describe the emerging applications of deep learning in ophthalmology. RECENT FINDINGS Recent studies have shown that various deep learning models are capable of detecting and diagnosing various diseases afflicting the posterior segment of the eye with high accuracy. Most of the initial studies have centered around detection of referable diabetic retinopathy, age-related macular degeneration, and glaucoma. SUMMARY Deep learning has shown promising results in automated image analysis of fundus photographs and optical coherence tomography images. Additional testing and research is required to clinically validate this technology.