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      A metabolomic approach to dry eye disorders. The role of oral supplements with antioxidants and omega 3 fatty acids

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          Abstract

          Purpose

          We used nuclear magnetic resonance spectroscopy of hydrogen-1 nuclei ( 1H NMR S) to analyze the metabolic profile of reflex tears from patients with dry eye disorders.

          Methods

          We performed a prospective case-control study involving 90 participants: 55 patients diagnosed with dry eye syndrome (DESG) and 35 healthy subjects (control group, CG). From the DESG, two subgroups were formed: mild DES (n=22) and moderate DES (n=33). Participants were prescribed an oral nutraceutic supplementation containing antioxidants and essential polyunsaturated fatty acids to be taken as three capsules per day for 3 months. Reflex tears (20–30 µl) were collected from the tear meniscus of both eyes of each subject with a microglass pipette. Nuclear magnetic resonance (NMR) spectra were acquired with a standard one-dimensional pulse sequence with water suppression; 256 free induction decays were collected into 64,000 data points with 14 ppm spectral width.

          Results

          Basal tears showed a differential metabolomic profile between groups. Almost 50 metabolites were identified by H cholesterol, N-acetylglucosamine, glutamate, amino-n-butyrate, choline, glucose, and formate were detected before supplementation and choline/acetylcholine after supplementation. The metabolic profile of the tears was statistically different between groups, as well as before and after supplementation.

          Conclusions

          Our data indicate that DES induces changes in the tear metabolic profile that can be modified with appropriate oral supplementation with antioxidants and essential polyunsaturated fatty acids.

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          Most cited references43

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          Tear cytokine profiles in dysfunctional tear syndrome.

          To compare tear cytokine and chemokine concentrations in asymptomatic control and Dysfunctional Tear syndrome (DTS) patients and determine the correlations between tear inflammatory mediators and clinical severity. Prospective observational cohort study. Concentrations of epidermal growth factor (EGF), interleukin (IL)-1 alpha (1alpha), 1 beta (1beta), 6, 10, 12, and 13, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and chemokines: IL-8 (CXC); macrophage inflammatory protein-1 alpha (MIP-1alpha) (CCL3); and regulated upon activation, normal T-cell expressed and secreted (RANTES CCL5) were measured by a multiplex immunobead assay in an asymptomatic control group and DTS patients with and without meibomian gland disease (MGD). Spearman correlations between tear cytokines and severity of irritation symptoms and ocular surface signs were calculated. Tear concentrations of IL-6, IL-8 and TNF-alpha were significantly higher in DTS with and without MGD and EGF was significantly reduced in the DTS without MGD group compared with the control group. MIP-1alpha was greater in entire DTS and DTS without MGD groups than the control group and RANTES was greater in DTS with MGD than the control and DTS without MGD groups. IL-12 was significantly higher in the DTS with MGD than the DTS without MGD subgroup. Significant correlations were observed between IL-6 and irritation symptoms and between a number of cytokines and chemokines and clinical parameters. As predicted, patients with DTS have higher levels of inflammatory mediators in their tears that show correlation with clinical disease parameters. Furthermore, different tear cytokine/chemokine profiles were observed in DTS patients with and without MGD groups.
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            An objective approach to dry eye disease severity.

            A prospective, multisite clinical study (10 sites in the European Union and the United States) evaluated the clinical utility of commonly used tests and tear osmolarity for assessing dry eye disease severity. Three hundred fourteen consecutive subjects between the ages of 18 and 82 years were recruited from the general patient population, 299 of which qualified with complete datasets. Osmolarity testing, Schirmer test without anesthesia, tear film breakup time (TBUT), corneal staining, meibomian dysfunction assessment, and conjunctival staining were performed bilaterally. A symptom questionnaire, the Ocular Surface Disease Index (OSDI), was also administered to each patient. Distributions of clinical signs and symptoms against a continuous composite severity index were evaluated. Osmolarity was found to have the highest correlation coefficient to disease severity (r(2) = 0.55), followed by conjunctival staining (r(2) = 0.47), corneal staining (r(2) = 0.43), OSDI (r(2) = 0.41), meibomian score (r(2) = 0.37), TBUT (r(2) = 0.30), and Schirmer result (r(2) = 0.17). A comparison of standard threshold-based classification with the composite severity index revealed significant overlap between the disease severities of prospectively defined normal and dry eye groups. Fully 63% of the subjects were found to be poorly classified by combinations of clinical thresholds. Tear film osmolarity was found to be the single best marker of disease severity across normal, mild/moderate, and severe categories. Other tests were found to be informative in the more severe forms of disease; thus, clinical judgment remains an important element in the clinical assessment of dry eye severity. The results also indicate that the initiation and progression of dry eye is multifactorial and supports the rationale for redefining severity on the basis of a continuum of clinical signs. (ClinicalTrials.gov number, NCT00848198.).
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              Tear analysis in ocular surface diseases.

              The thin layer of tears covering the ocular surface are a complex body fluid containing thousands of molecules of varied form and function of several origins. In this review, we have discussed some key issues in the analysis of tears in the context of understanding and diagnosing eye disease using current technologies of proteomics and metabolomics, and for their potential for clinical application. In the last several years, advances in proteomics/metabolomics/lipidomics technologies have greatly expanded our knowledge of the chemical composition of tear fluid. The quickened pace of studies has shown that tears as a complex extra-cellular fluid of the ocular surface contains a great deal of molecular information useful for the diagnosis, prognosis, and treatment of ocular surface diseases that has the ability to addresses the emphasis on personalized medicine and biomarkers of disease. Future research directions will likely include (1) standardize tear collection, storage, extraction, and sample preparation; (2) quantitative proteomic analysis of tear proteins using multiple reaction monitoring (MRM)-based mass spectrometry; (3) population based studies of human tear proteomics/metabolomics; (4) tear proteomics/metabolomics for systemic diseases; and (5) functional studies of tear proteins. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Mol Vis
                Mol. Vis
                MV
                Molecular Vision
                Molecular Vision
                1090-0535
                2015
                11 May 2015
                : 21
                : 555-567
                Affiliations
                [1 ]Ophthalmic Research Unit “Santiago grisolía,” Valencia, Spain
                [2 ]Ophthalmic Research Unit, Faculty of Medicine, University of Valencia, Spain
                [3 ]Spanish Collaborative Network of Ocular Pathology (OFTARED)
                [4 ]University and Polytechnic hospital La Fe, Valencia, Spain
                [5 ]Central Unit of Research in Medicine, University of Valencia, Valencia, Spain
                [6 ]Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Valencia, Spain
                [7 ]Department of Preventive Medicine and CIBER Fisiopatología de la Obesidad y Nutrición, School of Medicine, University of Valencia, Spain
                Author notes
                Correspondence to: Maria Dolores Pinazo-Durán, Ophthalmic Research Unit “Santiago grisolía,” University hospital Doctor Peset. Ave/ gaspar Aguilar 90; 46017, Valencia, Spain. Phone: +34 961622497; FAX: +34 961622748; email: dolores.pinazo@ 123456uv.es
                Article
                50 2014MOLVIS0652
                4431415
                25999682
                f26b2f81-3bc2-4b8a-8f6e-7cdb257a2b5f
                Copyright © 2015 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.

                History
                : 17 December 2014
                : 08 May 2015
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                Vision sciences
                Vision sciences

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