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      Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

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          Abstract

          In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual.

          This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown.

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          Most cited references166

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          The lack of association between signs and symptoms in patients with dry eye disease.

          The purpose of this report was to examine the relation between clinical tests and dry eye symptoms in patients with dry eye disease. Seventy-five patients with dry eye disease (ICD-9 code 375.15) were included in these analyses. There was no specific entry criterion for enrollment in addition to a previous dry eye diagnosis in this clinic-based sample. Patients represented varying types and severity of dry eye disease and were previously diagnosed by clinic attending doctors in this university clinic setting. The study examination included a symptom interview that assessed dryness, grittiness, soreness, redness, and ocular fatigue. The interview was followed by a clinical dry eye examination conducted in the following sequence: meibomian gland assessment, tear meniscus height, tear breakup time test, fluorescein staining, the phenol red thread test, Schirmer test, and rose bengal staining. Partial Spearman correlation coefficients, the Wilcoxon rank sum test, chi 2 test, and multivariate logistic regression were used to evaluate the relationship between dry eye tests and symptoms. Symptoms were generally not associated with clinical signs in patients with dry eye disease. There were no significant correlations between signs and symptoms after adjustment for age and artificial tear use. The rank of each clinical test result did not statistically differ when stratified by the presence of patient symptoms in Wilcoxon rank sum analyses. Likewise, the frequency of patient symptoms did not differ statistically when stratified by a positive clinical test result in chi 2 analyses. In multivariate logistic regression analyses, no clinical test significantly predicted frequently reported symptoms after adjustment for age and artificial tear use. These results suggest a poor relation between dry eye tests and symptoms, which represents a quandary in dry eye clinical research and practice.
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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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              Trachoma.

              Trachoma is the most common infectious cause of blindness. Repeated episodes of infection with Chlamydia trachomatis in childhood lead to severe conjunctival inflammation, scarring, and potentially blinding inturned eyelashes (trichiasis or entropion) in later life. Trachoma occurs in resource-poor areas with inadequate hygiene, where children with unclean faces share infected ocular secretions. Much has been learnt about the epidemiology and pathophysiology of trachoma. Integrated control programmes are implementing the SAFE Strategy: surgery for trichiasis, mass distribution of antibiotics, promotion of facial cleanliness, and environmental improvement. This strategy has successfully eliminated trachoma in several countries and global efforts are underway to eliminate blinding trachoma worldwide by 2020.
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                Author and article information

                Contributors
                +44-141-3318657 , +44 (0)141 331 3387 , suzanne.hagan@gcu.ac.uk
                Journal
                EPMA J
                EPMA J
                The EPMA Journal
                BioMed Central (London )
                1878-5077
                1878-5085
                13 July 2016
                13 July 2016
                2016
                : 7
                : 15
                Affiliations
                [ ]Department of Life Sciences, Vision Sciences, Glasgow Caledonian University (GCU ), G4 0BA Glasgow, Scotland, UK
                [ ]Institute of Applied Ophthalmobiology (IOBA), University of Valladolid, Valladolid, Spain
                [ ]Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain
                Author information
                http://orcid.org/0000-0001-9836-159X
                Article
                65
                10.1186/s13167-016-0065-3
                4942926
                27413414
                af9ad817-47d3-4fb1-8ac8-5c8b1d2f7f9c
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 April 2016
                : 3 June 2016
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                Molecular medicine
                biomarkers,tear fluid,proteome,metabolome,predictive preventive personalised medicine (pppm),dry eye,glaucoma,diabetic retinopathy,cancer,neurological disorders

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