Determination of inmune response and inflammation mediators in tears: Changes in dry eye and glaucoma as compared to healthy controls | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Benitez-del-Castillo Sánchez, M.D. Morillo-Rojas, C. Galbis-Estrada, M.D. Pinazo-Duran" "autores" => array:4 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Benitez-del-Castillo Sánchez" "email" => array:1 [ 0 => "javier.benitezdelcastillo@uca.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M.D." "apellidos" => "Morillo-Rojas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "Galbis-Estrada" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "M.D." "apellidos" => "Pinazo-Duran" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Oftalmología, Hospital de Jerez, Jerez de la Frontera, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Investigación de Oftalmología Santiago Grisolía, Hospital Universitario Dr. Peset, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Determinación de mediadores de la respuesta inmune e inflamación en lágrimas: cambios en ojo seco y glaucoma frente a población sana" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 732 "Ancho" => 1372 "Tamanyo" => 31965 ] ] "descripcion" => array:1 [ "en" => "Statistically significant differences of inflammation marker molecules and immune response in tears between the glaucoma and controls. POAGG: primary open angle glaucoma treatment group; CG: control group; IL-6: interleukin 6; pg/mg/ml: picograms per ml per miligram." ] ] ] "textoCompleto" => "IntroductionThe dry eye disease (DE) is a complex dysfunction of the ocular surface<a class="elsevierStyleCrossRef" href="#bib0210">1</a> comprising 2 distinct etiopathogenies: one due to insufficient lacrimal production (aqueous deficient) and the other due to increased elimination (evaporative), although both are frequently combined.<a class="elsevierStyleCrossRefs" href="#bib0215">2,3</a> DE usually affects patients over 60. In addition, dryness can occur in the ocular surface due to external or internal factors such as menopause, the use of topical or systemic medicaments, exposure to light, computer screens, environmental contaminants and air-conditioning.<a class="elsevierStyleCrossRefs" href="#bib0210">1,3</a>Glaucoma is a group of diseases characterized by high intraocular pressure as main risk factor that produces progressive and irreversible deterioration of the visual field due to the loss of retinal ganglion cells and optic nerve fibers.<a class="elsevierStyleCrossRef" href="#bib0225">4</a> The most prevalent form is primary open angle glaucoma (POAG) that accounts for nearly 80% of all types.<a class="elsevierStyleCrossRefs" href="#bib0230">5,6</a> The estimated prevalence of glaucoma in Western populations over 40 is between 1.1 and 3.0%. In addition, glaucoma continues to be the first cause of irreversible blindness in the world, and the second in industrialized countries.<a class="elsevierStyleCrossRefs" href="#bib0235">6,7</a> The first treatment measure for POAG is typically topical medication.Both glaucoma and DE are related to age. In fact, it is not infrequent to find patients in chronic hypotensor treatment presenting with clinic expressions of DE in varying degrees. Some authors describe that 66% of patients with severe DE also have POAG<a class="elsevierStyleCrossRef" href="#bib0245">8</a> while others report that approximately 60% of patients that utilize daily antiglaucoma eyedrops refer DE symptoms<a class="elsevierStyleCrossRefs" href="#bib0250">9,10</a> that appear after beginning hypotensor treatment.<a class="elsevierStyleCrossRefs" href="#bib0260">11,12</a>Eyes are continually exposed to environmental irritating agents that stimulate immune response and give rise to chronic inflammation processes (IIR). The mean mediators of said processes are leukocytes and other cellular phenotypes involved in innate immunity such as T and B lymphocytes as well as natural killer cells. The interaction between all these cell types are regulated by a range of molecules such as cytokins, chemokines, cell adhesion molecules and others.<a class="elsevierStyleCrossRef" href="#bib0270">13</a> Uncontrolled acute or chronic inflammation produces tissue damage. Accordingly, alterations in the levels of IIR mediators in blood, aqueous humor, vitreous and ocular tissue has given scientific evidence that IIR is involved in the pathogenesis of ocular diseases of the anterior as well as the posterior segment.<a class="elsevierStyleCrossRefs" href="#bib0275">14–17</a> Developments in biotechnology such as multiplex analysis with flow cytometry can improve our knowledge about the pathogenesis and progression mechanisms of ocular diseases<a class="elsevierStyleCrossRefs" href="#bib0295">18,19</a> particularly for DE and POAG.The authors proposed to quantify the inflammatory component in ocular surface structures of patients with and without DE diagnostic in chronic treatment with anti-glaucoma eyedrops. The objective of the present study was to analyze the expression of IIR molecules in tears of patients with slight or moderate DE and in patients with suspected or diagnosed POAG, in the initial or intermediate stages and in treatment with hypotensor eyedrops in order to compare these with data obtained from healthy subjects.Material and methodsA prospective observational cohort study approved by the Ethics and Biomedical Research Committee of the S.A.S. Jerez de la Frontera Hospital (Cádiz, Spain). Informed consent was obtained from patients and all procedures were in accordance with the AMM Helsinki declaration for research with humans (version 2008). On the basis of the inclusion and exclusion criteria summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, 107 participants were recruited and distributed in the following groups: patients with DE (DEG; n=30), glaucoma or suspected glaucoma with hypotensor ocular treatment (POAGG; n=41) and healthy controls (CG; n=36), all males and females in the age range between 25 and 80 who visited practices in the hospitals of the study, i.e., S.A.S. hospital, Jerez de la Frontera (Cádiz, Spain) and the Santiago Grisolía Ophthalmological Research Unit (Valencia, Spain).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The study included only patients with slight or moderate bilateral DE according to the survey and score of the Ocular Surface Disease Index (OSDI)<a class="elsevierStyleCrossRef" href="#bib0305">20</a> and diagnosed one year or more before study baseline.The study only included patients with POAG with slight-moderate visual field defects<a class="elsevierStyleCrossRef" href="#bib0310">21</a> or patients with suspected POAG and normal visual fields in treatment over 6 months only with a prostaglandin analog available in the market as topical ocular hypotensor medicament but who had been previously diagnosed with DE.The study participants were requested to suspend any treatment with local or systemic anti-inflammatory or antihistaminic drugs as well as other treatments focused on DE or glandular Meibomium dysfunction such as antibiotics, NSAIDs and corticoids prior to the first visit. The DEG patients were allowed to maintain treatment with artificial tears but diminishing their use up to maximum tolerance and to refrain from instilling them 2–3 days before the scheduled visit for obtaining samples.In the first visit of the study, patients were given appointments between 9:00am and 12:00pm in order to complete the data of the interview carried out during the selection process and to perform the ophthalmological examination that included Schirmer test type I, slitlamp examination of the anterior and posterior segment of the eye and surrounding areas and fluorescein tear breakup time (FBUT). Subsequently, the patients were asked to return a few days later in order to obtain the reflex tear samples of the inferior meniscus of both eyes through capillarity using a 60μL Pasteur micropipette. A mean quantity of 32±7μL were drawn from both eyes and immediately frozen at −80°C up to processing time in order to analyze for each participant the expression of a specific set of cytokins in the samples by means of the multiplex flow cytometry system Luminex® R-200 (Luminex, Austin, TX, USA). Utilizing this system and with an approximate amount of 30μl per sample it is possible to perform immunodetection. In order to identify and quantify each antigen-antibody reaction, a Bio-Plex® suspension array flow-based system was used (Bio-Rad Laboratories, Hercules, CA, USA). The identification of analyzed molecules is based on grain color and emitting fluorescence, using fluorescence-marked informer molecules associated to each target protein. The concentration of cytokins and chemokins is calculated automatically by the Bio-Plex® software (Bio-Rad Laboratories, Hercules, CA, USA) utilizing a curve derived from a recombinant cytokin standard. Once said concentration has been found, corrections are made for obtaining the total initial protein concentration of each human tear sample during analysis. The IIR markers present in the tears were determined as follows: interleukins (IL) IL-1β, IL-2, IL-4, IL-5, IL-6 and IL-10. Tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF) and granulocyte macrophage colony stimulation factor (GM-CSF). All results are shown as mean±standard deviation (DE) of 2 determinations and expressed in picograms per milliliter and milligram.The data were collected in a spreadsheet designed for that purpose in Excel for Windows (Microsoft Corporation, Redmond, WA, USA), and analyzed with the statistical application SPSS 20.0 (IBM Corp SPSS Statistics for windows version 20.0. Armonk, NY, USA). The sociodemographic data and clinic characteristics were studied with the Chi square tests for qualitative variables and standard parametric test for quantitative variables. For comparing the cytokin concentration in 2 independent groups, the nonparametric Mann–Whitney U test was utilized assuming a nonhomogeneous distribution of said variables. All results were considered significant if p<0.05.ResultsOverall, 116 participants, comprising patients and healthy volunteers, were eligible for the study. Six patients with DE diagnostic and 3 patients with suspected POAG in treatment were not included due to the inability to obtain sufficient tear samples for study. The amount of tear samples extracted from patients allowed the analysis of 92.2% of participants. After these exclusions, the overall population of the study comprised 107 participants (214 eyes) distributed in the 3 following groups: patients diagnosed with slight-moderate DE (DEG; n=30), patients diagnosed and treated for suspected glaucoma or with initial POAG (POAGG; n=41) and a control group of healthy participants (CG; n=36).The mean age of participants was 52±15 years (mean±DE) in DEG patients, 57±18 years in POAGG patients and 50±12 years CG patients. No statistically significant differences were found between groups in what concerns age (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). As regards sex, the percentage of males and females was 30/70% in DEG, 31.7/68.3% in POAGG, and 30.5/69.5% in CG, respectively. No statistically significant differences were found between the groups on the basis of sex, although females predominated in a ratio of 1:2 among study participants (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The results of the Schirmer test were 4.26±0.59mm in DEG, 7.82±1.92mm in POAGG and 13.25±2.46mm in CG. Statistically significant differences between groups were found for this parameter (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).FBUT was 4.35±1.23s in DEG; 6.14±2.32s in POAGG and 14.24±3.22s in CG. Statistically significant differences were also found between groups for this parameter (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).As regards the expression of IIR markers, significantly higher levels were found in DEG tears in comparison with CG for the following molecules: IL-1β (p=0.0144), IL-6 (p<0.0001) and IL-10 (p=0.0392) in DEG than in CG. In contrast, significantly lower expression levels were found for VEGF (p=0.0042) in DEG than in CG (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>When comparing POAGG with CG tears, a significantly higher expression of IL-6 was found (p=0.0001) in patients in treatment for G (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Finally, a comparison of the values obtained from tears of DEG and POAGG patients demonstrated statistically significant differences between both: IL-4 (p=0.0012) were higher in DEG, and the POAGG group exhibited higher levels of IL-6 (p=0.0014), TNF-α (p=0.0048) and VEGF (p=0.0058) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionThe main objective of the present study was to analyze possible differences in the expression of IIR mediators in tears of patients with DE diagnostic and patients with suspected or diagnosed POAG in treatment with hypotensor ocular eyedrops, without previous DE diagnostic, and comparing them with healthy subjects in the CG group. To this end, a system based on flow cytometry with the capacity to simultaneously determine several molecules in a single microplate tray was utilized (Luminex® R-200 Multiplex system [Luminex, Austin, TX, USA]). The results have demonstrated differential expressions of the main IIR marker molecules in tears of patients with DE and POAG and against the data obtained from healthy subjects. Identified molecules with statistical significance were: IL-1β, IL-4, IL-6, IL-10, TNF-α, GM-CSF and VEGF. However, the molecule that demonstrated the highest statistical significance both in DEG and in POAGG vis-à-vis control subjects was IL-6. On the other hand, the comparison between both groups of patients (DEG vs. POAGG) demonstrated that the molecules with the highest statistical significance were IL-4 and again IL-6.The method for collecting reflexive human tears with capillary tubes was a useful, noninvasive and relatively easy procedure to achieve the objectives of the present study. The amounts of tears collected from each group (in all cases lower in patients with DE, followed by patients with POAG and finally the largest amount obtained from the CG) was sufficient to execute the methodology described above. The immediate freezing of the samples was crucial to address the protocol described for the assessments.DE is a frequent cause of visits to the ophthalmologist and a prevalent ocular disorder all over the world.<a class="elsevierStyleCrossRef" href="#bib0220">3</a> Ocular discomfort and vision alteration are characteristic of DE and produce difficulties for carrying out daily activities.<a class="elsevierStyleCrossRefs" href="#bib0210">1–3</a> Glaucoma is the first cause of irreversible blindness worldwide.<a class="elsevierStyleCrossRefs" href="#bib0225">4–7,21</a> The comorbidity of both processes (DE and POAG) is frequent in daily clinic as the risk of having both conditions increases with age. In addition, patients with POAG are treated with chronic eyedrops instillations that could give rise to ocular surface diseases.<a class="elsevierStyleCrossRef" href="#bib0315">22</a>In the present study, both groups of patients (DEG, POAGG) exhibited obvious changes related to ocular surface alterations in clinical examinations, even when glaucoma patients were not previously diagnosed with DE. Schirmer test results were significantly lower in DEG and POAGG in comparison with the CG, which shows a quantitative alteration of the lacrimal tear in relation to ocular surface dysfunction in both diseases. As regards BUT with fluorescein results in tears, it was significantly shorter in DEG and POAGG than in the CG, which clearly demonstrates the instability of the lacrimal tear in both diseases when compared to healthy controls.A large range of molecules in tears are known to be involved in maintaining the morphology and function of the ocular surface,<a class="elsevierStyleCrossRefs" href="#bib0320">23–26</a> and it is known that the qualitative or quantitative alteration thereof affects the integrity of the ocular surface and potentially induces changes in IIR with underlying inflammatory expressions regulated by cytokins-chemokins. It is known that locally produced cytokins can reach detectable levels during pathological processes. The results of the present study demonstrate significantly high levels of IL-1β, IL-6 and IL-10 in DEG patients. The increased expression of pro-inflammatory cytokins is an evident sign of activity and a marker of said process. However, some types are more important for reinforcing the innate immune response by focusing adaptive immunity toward Th1- or Th2-dependent response.<a class="elsevierStyleCrossRef" href="#bib0340">27</a> In this regard, pro-inflammatory IL-1β and IL-6 cytokins are fundamental for the synthesis of acute phase proteins and are produced in large amounts in response to infectious processes and to any type of stress. IL-10 is an anti-inflammatory cytokin synthesized by Th2 cells, B-monocytes and lymphocytes that inhibits the production of pro-inflammatory cytokins (as those described above). The presence of these 3 molecules in the tears of patients with DE confirm the activation of IIR processes in affected eyes. In fact, the results of the study essentially match those obtained by other authors<a class="elsevierStyleCrossRefs" href="#bib0290">17,26–30</a> despite the differences in the sample taking and processing. The levels of expression reached by IL-6 in the tears of the patients of this study confirm that this cytokin is a key molecule in DE pathogeny, with data similar to those of several authors,<a class="elsevierStyleCrossRefs" href="#bib0290">17,23,24,26–30</a> thus signaling its correlation with clinical parameters and their possible utilization as a biomarker to indicate the severity of the process.Data on the significant reduction of VEGF expression in DEG patients against CG patients are interesting and were also discussed by the authors<a class="elsevierStyleCrossRefs" href="#bib0320">23,24</a> and by Brignole-Badouin et al.<a class="elsevierStyleCrossRefs" href="#bib0355">30,31</a> among others. VEGF expression is closely regulated and its transcription responds to several signals such as IL-1β, IL-6 pro-inflammatory cytokins and oncoproteins, including the tyrosine kinase proto-oncogene (c-Src), murine sarcoma viral oncogene (v-Raf), the Ras proto-oncogene Ras and other signaling molecules.<a class="elsevierStyleCrossRefs" href="#bib0365">32–34</a> The function of VEGF has been studied in conjunctival biopsies and tears of inflammatory chronic diseases such as atopic keratoconjunctivitis,<a class="elsevierStyleCrossRef" href="#bib0380">35</a> which demonstrates that, in addition to its angiogenic action, VEGF could also perform as a pro-inflammatory mediator in the pathogenesis of rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0385">36</a> Other authors have described VEGF increases in tears of patients with moderate DE,<a class="elsevierStyleCrossRefs" href="#bib0335">26,37</a> where VEGF plays a role in the cross-communication between vessels and nerves, and the low expression of this molecule is related to neuro-regeneration processes.<a class="elsevierStyleCrossRef" href="#bib0375">34</a> For these reasons, the authors believe that diminished VEGF in the tears of the patients of this study could relate to the ocular discomfort and pain they may experience in response to the underlying neurotrophic epitheliopathy.The joint results of clinical exploration and IIR determination in glaucomatous tears of patients in chronic treatments with hypotensor eyedrops was very interesting as significantly higher levels of IL-6 were obtained when compared to the CG. These data confirm the IIR process of the ocular surface in the course of glaucoma and can be associated to the chronic administration of anti-hypotensive eyedrops that induce inflammatory activity influenced by IL-6. Similarly, Badouin et al.<a class="elsevierStyleCrossRef" href="#bib0390">37</a> demonstrated high IL-6 levels (in addition to IL-8 and IL-10), tears of glaucomatous patients in treatment when compared to normal subjects.The authors have described changes in the expression of IIR mediator molecules when comparing DEG with POAGG patients, with a highly significant increase of IL-4 in DEG, and IL-6, TNF-α and VEGF in POAGG. These results support the common inflammatory basis but, interestingly, with different molecules, which indicates that different signaling pathways are involved in these 2 processes. In this regard, analyzing differences in the protein profile of tears between the diseases of this study, other authors have reached similar results,<a class="elsevierStyleCrossRefs" href="#bib0385">36–39</a> which indicates that these molecules could be utilized for designing new therapies for patients with ocular surface dysfunctions.<a class="elsevierStyleCrossRef" href="#bib0405">40</a>The limitations of the present study include that the expression and tears of the majority of the IIR molecules as quantitative variables exhibited abnormal distribution in the data. For this reason, nonparametric tests were used for making comparisons between groups and this could reduce the potency of the study. An additional limitation is that the study was carried out with Caucasian patients with suspected or diagnosed slight or moderate POAG or with non-advanced DE. Accordingly, caution is advised in what concerns the external validity of the study in the population. On the other hand, the study has not included the differences between the hypotensor eyedrops utilized by POAGG patients or their respective compositions. In fact, this is the object of experiments the authors are carrying out at present. It is also possible that the technique utilized could influence the type of detected molecules, as pointed out by Dione et al.,<a class="elsevierStyleCrossRef" href="#bib0410">41</a> and this should be taken into account when designing new studies for these type of assessments.In conclusion, utilizing the noninvasive, nontraumatic method of extracting reflex human tears through capillarity and analyzing the expression of a range of cytokins through a multi-determination system based on flow cytometry, the differential profile of the expression of IIR marker molecules in patients with DE, suspected or diagnosed POAG in chronic antihypertensive treatment has been obtained and compared with healthy controls. This confirms the inflammatory activity in ocular surface dysfunctions and indicates that IL-6 can be utilized as a potential biomarker for this disease. These findings provide researchers with an opportunity to carry out broader studies that could help improve diagnosis and management of the 2 diseases discussed in this paper.Conflict of interestsNo conflict of interests was declared by the authors in what concerns instruments, materials or reactants utilized in the present study." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres833045" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec828968" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres833046" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec828969" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-08-28" "fechaAceptado" => "2016-12-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec828968" "palabras" => array:5 [ 0 => "Tears" 1 => "Cytokines" 2 => "Dry eye" 3 => "Glaucoma" 4 => "Inflammation and immune response" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec828969" "palabras" => array:5 [ 0 => "Lágrimas" 1 => "Citoquinas" 2 => "Ojo seco" 3 => "Glaucoma" 4 => "Inflamación y respuesta inmune" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo determine the expression profile of immune response and inflammation (IRI) mediator molecules in tears from patients with dry eye (DE), and those suspected of having or have primary open-angle glaucoma (POAG) under treatment and compare them with healthy controls. MethodsA prospective observational cohort study including 107 participants sub-divided into: healthy controls (CG; n=30), patients with DE (DEG; n=41) and patients suspected of having or have POAG and on hypotensive treatment (POAG-G; n=36). Tear samples were collected by capillary to be processed using a multi-immunoassay system based on flow cytometry (Luminex R-200®), in order to determine the interleukins (IL): 1β, 2, 4, 5, 6, and 10, and the growth factors: tumor necrosis alpha (TNF-α), vascular endothelial (VEGF), and granulocyte-macrophage colony stimulating (GM-CSF). Data were processed using the SPSS 20.0 program. ResultsMolecules that significantly increased in tears from DEG vs. POAG-G patients were: IL-1 (p=0.01), IL-6 (p=0.004), IL-10 (p=0.04), whereas VEGF significantly decreased in the DEG. The POAG-G showed significantly higher IL-6 values (p<0.0001) as compared to the CG. When comparing both the DEG and POAG-G, significant differences were observed in tear expression of IL-4 (p=0.004), IL-6 (p=0.002), TNF-α (p=0.03), GM-CSF (p=0.03), and VEGF (p=0.002). ConclusionsThe increased expression of IRI mediators in tears from patients with DE or POAG strongly demonstrated the importance of immune response in both pathologies. However, the different molecules involved also suggest distinct signaling pathways for these processes that still require further research." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoDeterminar el perfil de expresión de las moléculas mediadoras de inflamación y respuesta inmune (IRI) en lágrimas de pacientes con ojo seco (OS) y pacientes en tratamiento médico por sospecha o diagnóstico de glaucoma primario de ángulo abierto (GPAA) para compararlos con sujetos sanos. MétodoEstudio prospectivo observacional de cohortes de 107 participantes subdivididos en: pacientes con OS (GOS; n=30), pacientes con sospecha o diagnóstico de GPAA con tratamiento hipotensor ocular (GGPAA; n=41) y controles sanos (GC; n=36). Se obtuvieron muestras de lágrimas mediante capilaridad para analizarlas mediante sistema de multiinmunoanálisis basado en citometría de flujo (Luminex R-200®), determinando diversas interleucinas (IL): 1β, 2, 4, 5, 6 y 10, y también los factores de necrosis tumoral alfa (TNF-α), de crecimiento endotelial vascular (VEGF) y de crecimiento de colonias de granulocitos y macrófagos (GM-CSF). Los datos se procesaron mediante el programa SPSS 20.0. ResultadosLas moléculas que aumentaron significativamente en lágrimas de pacientes en el GOS versus GGPAA fueron: IL-1β (p=0.01), IL-6 (p=0,004), IL-10 (p=0,04), mientras que el VEGF disminuyó significativamente en el GOS. El GGPAA mostró aumento significativo de IL-6 (p<0,0001) frente al GC. Comparando GOS y GGPAA, observamos diferencias significativas para IL-4 (p=0,004), IL-6 (p=0,002), TNF-α (p=0,03), GM-CSF (p=0,03) y VEGF (p=0,002). ConclusionesEl aumento de expresión de los mediadores de IRI en lágrimas de pacientes con OS o GPAA demuestra la importancia de estos procesos en ambas enfermedades, aunque las distintas moléculas implicadas indican diferentes vías de señalización para ambas, que requieren más investigaciones." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Benitez-del-Castillo Sánchez J, Morillo-Rojas MD, Galbis-Estrada C, Pinazo-Duran MD. Determinación de mediadores de la respuesta inmune e inflamación en lágrimas: cambios en ojo seco y glaucoma frente a población sana. Arch Soc Esp Oftalmol. 2017;92:210–217." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "This paper was awarded the First Galo Leoz Prize for Research at the Congress of the Ophthalmology Society of Spain held in Málaga (September 2016)." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 967 "Ancho" => 2469 "Tamanyo" => 67492 ] ] "descripcion" => array:1 [ "en" => "Statistically significant differences of inflammation marker molecules and immune response in tears between the dry eye and control groups. CG: control group; DEG: dry eye group; IL: interleukin; pg/mg/ml: picograms per ml per miligram; VEGF: vascular endothelial growth factor." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 732 "Ancho" => 1372 "Tamanyo" => 31965 ] ] "descripcion" => array:1 [ "en" => "Statistically significant differences of inflammation marker molecules and immune response in tears between the glaucoma and controls. POAGG: primary open angle glaucoma treatment group; CG: control group; IL-6: interleukin 6; pg/mg/ml: picograms per ml per miligram." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1022 "Ancho" => 2428 "Tamanyo" => 73979 ] ] "descripcion" => array:1 [ "en" => "Statistically significant differences of inflammation marker molecules and immune response in tears between the dry eye and glaucoma groups. POAGG: primary open angle glaucoma treatment group; DEG: dry eye group; IL: interleukin; pg/mg/ml: picograms per ml per miligram; TNF-α: tumor necrosis factor alpha; VEGF: vascular endothelial growth factor." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "POAGG: primary open angle glaucoma group of patients; CG: control group; DEG: dry eye group of patients; POAG: primary open angle glaucoma; DE: dry eye." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inclusion criteria \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Exclusion criteria \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age 25–80 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Age <25 years or >80 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosed with slight-moderate DE disease (for DEG) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Atopia or other allergic diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosed with suspected or non-advanced POAG (for POAGG) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Use of contact lenses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Healthy controls (for CG) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractive surgery history \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Able to participate in the study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Systemic diseases or treatments that could alter the ocular surface \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Informed consent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Palpebral abnormalities, severe blepharitis or meibomitis, lacrimal point occlusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Other ocular diseases and use of eyedrops other than artificial tears (without preservatives) or PG analog ocular hypotensors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Previous diagnostic of coexistence of DE and POAG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not able to participate in the study \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1403200.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Inclusion/exclusion criteria for study participants." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Differences between study groups in age, Schirmer and FBUT with T for student test for independent samples. Sex differences with Chi square test. Significance if p<0.05.DE: standard deviation; FBUT: fluorescein breakup time; POAGG: primary open angle glaucoma group; CG: control group; DEG: dry eye group; mm: millimeters; s: seconds." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Overall study population (n=107 participants)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG (n=30) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG (n=41) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">CG (n=36) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-CG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG-CG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-POAGG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age in years (mean±DE) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52±15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">57±18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Sex [%]</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Males \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 (n=9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31.7 (n=13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30.5 (n=11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Females \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70 (n=21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">68.3 (n=28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">69.5 (n=25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.89 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.91 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Schirmer in mm (mean±DE) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.26±0.59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.82±1.82 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13.25±2.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FBUT in s (mean±DE) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.35±1.23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.14±2.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.24±3.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0002 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1403201.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of the study population." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Differences between study groups with a Mann–Whitney U test. Values ‡ significant if p<0.05.SD: standard deviation; POAGG: primary open angle glaucoma group; CG: control group; GM-CSF: granulocyte-macrophage colony-stimulating factor; DEG: dry eye group; IL: interleukin; pg/mg/ml: picograms per ml per miligram; TNF-α: tumor necrosis factor alpha; VEGF: vascular endothelial growth factor." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Overall study population (n=107)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG (n=30) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG (n=41) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">CG (n=36) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-CG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG-CG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-POAGG difference: p value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-1β (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.88±6.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12±10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9±10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0144 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4907 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0828 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-2 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.66±3.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4±0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1189 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0941 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6262 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-4 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21.79±9.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2±2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20±7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2706 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0012 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-5 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.97±3.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4±3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3±3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0845 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0928 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1301 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-6 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17.95±6.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27±16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12±9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0145 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-8 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">496.3±750.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">508.19±680 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">447.85±548.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3594 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6533 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4472 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-10 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.3±2.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.96±2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.92±1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0392 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9407 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0518 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-12 (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">51.27±63.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38.68±9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38.76±1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8274 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7285 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8983 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TNF-α (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.27±7.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17.93±7.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16.33±6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2436 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3170 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0048 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VEGF (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">367.75±290.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">609.28±329.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">581.6±257.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0042 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3855 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0058 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GM-CSF (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.16±3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.91±1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.76±3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2491 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8221 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1328 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IFNy (mean±SD) [pg/mg/ml] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.14±1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.81±0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.89±0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.7732 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1705 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4493 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1403199.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Expression profile of inflammation marker molecules and immune response in the tears of the studied population." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:41 [ 0 => array:3 [ "identificador" => "bib0210" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dry eye disease: pathophysiology, classification, and diagnosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "H.D. 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Determination of inmune response and inflammation mediators in tears: Changes in dry eye and glaucoma as compared to healthy controls

Determinación de mediadores de la respuesta inmune e inflamación en lágrimas: cambios en ojo seco y glaucoma frente a población sana

J. Benitez-del-Castillo Sáncheza,

Corresponding author

javier.benitezdelcastillo@uca.es

Corresponding author.

, M.D. Morillo-Rojasa, C. Galbis-Estradab, M.D. Pinazo-Duranb

a Departamento de Oftalmología, Hospital de Jerez, Jerez de la Frontera, Spain

b Unidad de Investigación de Oftalmología Santiago Grisolía, Hospital Universitario Dr. Peset, Valencia, Spain

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environmental contaminants and air-conditioning&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">1&#44;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Glaucoma is a group of diseases characterized by high intraocular pressure as main risk factor that produces progressive and irreversible deterioration of the visual field due to the loss of retinal ganglion cells and optic nerve fibers&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a> The most prevalent form is primary open angle glaucoma &#40;POAG&#41; that accounts for nearly 80&#37; of all types&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">5&#44;6</span></a> The estimated prevalence of glaucoma in Western populations over 40 is between 1&#46;1 and 3&#46;0&#37;&#46; In addition&#44; glaucoma continues to be the first cause of irreversible blindness in the world&#44; and the second in industrialized countries&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">6&#44;7</span></a> The first treatment measure for POAG is typically topical medication&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Both glaucoma and DE are related to age&#46; 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The interaction between all these cell types are regulated by a range of molecules such as cytokins&#44; chemokines&#44; cell adhesion molecules and others&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> Uncontrolled acute or chronic inflammation produces tissue damage&#46; Accordingly&#44; alterations in the levels of IIR mediators in blood&#44; aqueous humor&#44; vitreous and ocular tissue has given scientific evidence that IIR is involved in the pathogenesis of ocular diseases of the anterior as well as the posterior segment&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">14&#8211;17</span></a> Developments in biotechnology such as multiplex analysis with flow cytometry can improve our knowledge about the pathogenesis and progression mechanisms of ocular diseases<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">18&#44;19</span></a> particularly for DE and POAG&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The authors proposed to quantify the inflammatory component in ocular surface structures of patients with and without DE diagnostic in chronic treatment with anti-glaucoma eyedrops&#46; The objective of the present study was to analyze the expression of IIR molecules in tears of patients with slight or moderate DE and in patients with suspected or diagnosed POAG&#44; in the initial or intermediate stages and in treatment with hypotensor eyedrops in order to compare these with data obtained from healthy subjects&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0040" class="elsevierStylePara elsevierViewall">A prospective observational cohort study approved by the Ethics and Biomedical Research Committee of the S&#46;A&#46;S&#46; Jerez de la Frontera Hospital &#40;C&#225;diz&#44; Spain&#41;&#46; Informed consent was obtained from patients and all procedures were in accordance with the AMM Helsinki declaration for research with humans &#40;version 2008&#41;&#46; On the basis of the inclusion and exclusion criteria summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; 107 participants were recruited and distributed in the following groups&#58; patients with DE &#40;DEG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#44; glaucoma or suspected glaucoma with hypotensor ocular treatment &#40;POAGG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; and healthy controls &#40;CG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#44; all males and females in the age range between 25 and 80 who visited practices in the hospitals of the study&#44; i&#46;e&#46;&#44; S&#46;A&#46;S&#46; hospital&#44; Jerez de la Frontera &#40;C&#225;diz&#44; Spain&#41; and the Santiago Grisol&#237;a Ophthalmological Research Unit &#40;Valencia&#44; Spain&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The study included only patients with slight or moderate bilateral DE according to the survey and score of the Ocular Surface Disease Index &#40;OSDI&#41;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a> and diagnosed one year or more before study baseline&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The study only included patients with POAG with slight-moderate visual field defects<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a> or patients with suspected POAG and normal visual fields in treatment over 6 months only with a prostaglandin analog available in the market as topical ocular hypotensor medicament but who had been previously diagnosed with DE&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The study participants were requested to suspend any treatment with local or systemic anti-inflammatory or antihistaminic drugs as well as other treatments focused on DE or glandular Meibomium dysfunction such as antibiotics&#44; NSAIDs and corticoids prior to the first visit&#46; The DEG patients were allowed to maintain treatment with artificial tears but diminishing their use up to maximum tolerance and to refrain from instilling them 2&#8211;3 days before the scheduled visit for obtaining samples&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In the first visit of the study&#44; patients were given appointments between 9&#58;00<span class="elsevierStyleHsp" style=""></span>am and 12&#58;00<span class="elsevierStyleHsp" style=""></span>pm in order to complete the data of the interview carried out during the selection process and to perform the ophthalmological examination that included Schirmer test type <span class="elsevierStyleSmallCaps">I</span>&#44; slitlamp examination of the anterior and posterior segment of the eye and surrounding areas and fluorescein tear breakup time &#40;FBUT&#41;&#46; Subsequently&#44; the patients were asked to return a few days later in order to obtain the reflex tear samples of the inferior meniscus of both eyes through capillarity using a 60<span class="elsevierStyleHsp" style=""></span>&#956;L Pasteur micropipette&#46; A mean quantity of 32<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7<span class="elsevierStyleHsp" style=""></span>&#956;L were drawn from both eyes and immediately frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C up to processing time in order to analyze for each participant the expression of a specific set of cytokins in the samples by means of the multiplex flow cytometry system Luminex<span class="elsevierStyleSup">&#174;</span> R-200 &#40;Luminex&#44; Austin&#44; TX&#44; USA&#41;&#46; Utilizing this system and with an approximate amount of 30<span class="elsevierStyleHsp" style=""></span>&#956;l per sample it is possible to perform immunodetection&#46; In order to identify and quantify each antigen-antibody reaction&#44; a Bio-Plex<span class="elsevierStyleSup">&#174;</span> suspension array flow-based system was used &#40;Bio-Rad Laboratories&#44; Hercules&#44; CA&#44; USA&#41;&#46; The identification of analyzed molecules is based on grain color and emitting fluorescence&#44; using fluorescence-marked informer molecules associated to each target protein&#46; The concentration of cytokins and chemokins is calculated automatically by the Bio-Plex<span class="elsevierStyleSup">&#174;</span> software &#40;Bio-Rad Laboratories&#44; Hercules&#44; CA&#44; USA&#41; utilizing a curve derived from a recombinant cytokin standard&#46; Once said concentration has been found&#44; corrections are made for obtaining the total initial protein concentration of each human tear sample during analysis&#46; The IIR markers present in the tears were determined as follows&#58; interleukins &#40;IL&#41; IL-1&#946;&#44; IL-2&#44; IL-4&#44; IL-5&#44; IL-6 and IL-10&#46; Tumor necrosis factor alpha &#40;TNF-&#945;&#41;&#44; vascular endothelial growth factor &#40;VEGF&#41; and granulocyte macrophage colony stimulation factor &#40;GM-CSF&#41;&#46; All results are shown as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;DE&#41; of 2 determinations and expressed in picograms per milliliter and milligram&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The data were collected in a spreadsheet designed for that purpose in Excel for Windows &#40;Microsoft Corporation&#44; Redmond&#44; WA&#44; USA&#41;&#44; and analyzed with the statistical application SPSS 20&#46;0 &#40;IBM Corp SPSS Statistics for windows version 20&#46;0&#46; Armonk&#44; NY&#44; USA&#41;&#46; The sociodemographic data and clinic characteristics were studied with the Chi square tests for qualitative variables and standard parametric test for quantitative variables&#46; For comparing the cytokin concentration in 2 independent groups&#44; the nonparametric Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test was utilized assuming a nonhomogeneous distribution of said variables&#46; All results were considered significant if <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">Overall&#44; 116 participants&#44; comprising patients and healthy volunteers&#44; were eligible for the study&#46; Six patients with DE diagnostic and 3 patients with suspected POAG in treatment were not included due to the inability to obtain sufficient tear samples for study&#46; The amount of tear samples extracted from patients allowed the analysis of 92&#46;2&#37; of participants&#46; After these exclusions&#44; the overall population of the study comprised 107 participants &#40;214 eyes&#41; distributed in the 3 following groups&#58; patients diagnosed with slight-moderate DE &#40;DEG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#44; patients diagnosed and treated for suspected glaucoma or with initial POAG &#40;POAGG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; and a control group of healthy participants &#40;CG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The mean age of participants was 52<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15 years &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>DE&#41; in DEG patients&#44; 57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18 years in POAGG patients and 50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12 years CG patients&#46; No statistically significant differences were found between groups in what concerns age &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; As regards sex&#44; the percentage of males and females was 30&#47;70&#37; in DEG&#44; 31&#46;7&#47;68&#46;3&#37; in POAGG&#44; and 30&#46;5&#47;69&#46;5&#37; in CG&#44; respectively&#46; No statistically significant differences were found between the groups on the basis of sex&#44; although females predominated in a ratio of 1&#58;2 among study participants &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the Schirmer test were 4&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;59<span class="elsevierStyleHsp" style=""></span>mm in DEG&#44; 7&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;92<span class="elsevierStyleHsp" style=""></span>mm in POAGG and 13&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;46<span class="elsevierStyleHsp" style=""></span>mm in CG&#46; Statistically significant differences between groups were found for this parameter &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">FBUT was 4&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;23<span class="elsevierStyleHsp" style=""></span>s in DEG&#59; 6&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;32<span class="elsevierStyleHsp" style=""></span>s in POAGG and 14&#46;24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;22<span class="elsevierStyleHsp" style=""></span>s in CG&#46; Statistically significant differences were also found between groups for this parameter &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">As regards the expression of IIR markers&#44; significantly higher levels were found in DEG tears in comparison with CG for the following molecules&#58; IL-1&#946; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0144&#41;&#44; IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; and IL-10 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0392&#41; in DEG than in CG&#46; In contrast&#44; significantly lower expression levels were found for VEGF &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0042&#41; in DEG than in CG &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">When comparing POAGG with CG tears&#44; a significantly higher expression of IL-6 was found &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; in patients in treatment for G &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Finally&#44; a comparison of the values obtained from tears of DEG and POAGG patients demonstrated statistically significant differences between both&#58; IL-4 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0012&#41; were higher in DEG&#44; and the POAGG group exhibited higher levels of IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0014&#41;&#44; TNF-&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0048&#41; and VEGF &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0058&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> and <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">The main objective of the present study was to analyze possible differences in the expression of IIR mediators in tears of patients with DE diagnostic and patients with suspected or diagnosed POAG in treatment with hypotensor ocular eyedrops&#44; without previous DE diagnostic&#44; and comparing them with healthy subjects in the CG group&#46; To this end&#44; a system based on flow cytometry with the capacity to simultaneously determine several molecules in a single microplate tray was utilized &#40;Luminex<span class="elsevierStyleSup">&#174;</span> R-200 Multiplex system &#91;Luminex&#44; Austin&#44; TX&#44; USA&#93;&#41;&#46; The results have demonstrated differential expressions of the main IIR marker molecules in tears of patients with DE and POAG and against the data obtained from healthy subjects&#46; Identified molecules with statistical significance were&#58; IL-1&#946;&#44; IL-4&#44; IL-6&#44; IL-10&#44; TNF-&#945;&#44; GM-CSF and VEGF&#46; However&#44; the molecule that demonstrated the highest statistical significance both in DEG and in POAGG vis-&#224;-vis control subjects was IL-6&#46; On the other hand&#44; the comparison between both groups of patients &#40;DEG vs&#46; POAGG&#41; demonstrated that the molecules with the highest statistical significance were IL-4 and again IL-6&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The method for collecting reflexive human tears with capillary tubes was a useful&#44; noninvasive and relatively easy procedure to achieve the objectives of the present study&#46; The amounts of tears collected from each group &#40;in all cases lower in patients with DE&#44; followed by patients with POAG and finally the largest amount obtained from the CG&#41; was sufficient to execute the methodology described above&#46; The immediate freezing of the samples was crucial to address the protocol described for the assessments&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">DE is a frequent cause of visits to the ophthalmologist and a prevalent ocular disorder all over the world&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">3</span></a> Ocular discomfort and vision alteration are characteristic of DE and produce difficulties for carrying out daily activities&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">1&#8211;3</span></a> Glaucoma is the first cause of irreversible blindness worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">4&#8211;7&#44;21</span></a> The comorbidity of both processes &#40;DE and POAG&#41; is frequent in daily clinic as the risk of having both conditions increases with age&#46; In addition&#44; patients with POAG are treated with chronic eyedrops instillations that could give rise to ocular surface diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In the present study&#44; both groups of patients &#40;DEG&#44; POAGG&#41; exhibited obvious changes related to ocular surface alterations in clinical examinations&#44; even when glaucoma patients were not previously diagnosed with DE&#46; Schirmer test results were significantly lower in DEG and POAGG in comparison with the CG&#44; which shows a quantitative alteration of the lacrimal tear in relation to ocular surface dysfunction in both diseases&#46; As regards BUT with fluorescein results in tears&#44; it was significantly shorter in DEG and POAGG than in the CG&#44; which clearly demonstrates the instability of the lacrimal tear in both diseases when compared to healthy controls&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A large range of molecules in tears are known to be involved in maintaining the morphology and function of the ocular surface&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">23&#8211;26</span></a> and it is known that the qualitative or quantitative alteration thereof affects the integrity of the ocular surface and potentially induces changes in IIR with underlying inflammatory expressions regulated by cytokins-chemokins&#46; It is known that locally produced cytokins can reach detectable levels during pathological processes&#46; The results of the present study demonstrate significantly high levels of IL-1&#946;&#44; IL-6 and IL-10 in DEG patients&#46; The increased expression of pro-inflammatory cytokins is an evident sign of activity and a marker of said process&#46; However&#44; some types are more important for reinforcing the innate immune response by focusing adaptive immunity toward Th1- or Th2-dependent response&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">27</span></a> In this regard&#44; pro-inflammatory IL-1&#946; and IL-6 cytokins are fundamental for the synthesis of acute phase proteins and are produced in large amounts in response to infectious processes and to any type of stress&#46; IL-10 is an anti-inflammatory cytokin synthesized by Th2 cells&#44; B-monocytes and lymphocytes that inhibits the production of pro-inflammatory cytokins &#40;as those described above&#41;&#46; The presence of these 3 molecules in the tears of patients with DE confirm the activation of IIR processes in affected eyes&#46; In fact&#44; the results of the study essentially match those obtained by other authors<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">17&#44;26&#8211;30</span></a> despite the differences in the sample taking and processing&#46; The levels of expression reached by IL-6 in the tears of the patients of this study confirm that this cytokin is a key molecule in DE pathogeny&#44; with data similar to those of several authors&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">17&#44;23&#44;24&#44;26&#8211;30</span></a> thus signaling its correlation with clinical parameters and their possible utilization as a biomarker to indicate the severity of the process&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Data on the significant reduction of VEGF expression in DEG patients against CG patients are interesting and were also discussed by the authors<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">23&#44;24</span></a> and by Brignole-Badouin et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">30&#44;31</span></a> among others&#46; VEGF expression is closely regulated and its transcription responds to several signals such as IL-1&#946;&#44; IL-6 pro-inflammatory cytokins and oncoproteins&#44; including the tyrosine kinase proto-oncogene &#40;c-Src&#41;&#44; murine sarcoma viral oncogene &#40;v-Raf&#41;&#44; the Ras proto-oncogene Ras and other signaling molecules&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">32&#8211;34</span></a> The function of VEGF has been studied in conjunctival biopsies and tears of inflammatory chronic diseases such as atopic keratoconjunctivitis&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">35</span></a> which demonstrates that&#44; in addition to its angiogenic action&#44; VEGF could also perform as a pro-inflammatory mediator in the pathogenesis of rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">36</span></a> Other authors have described VEGF increases in tears of patients with moderate DE&#44;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">26&#44;37</span></a> where VEGF plays a role in the cross-communication between vessels and nerves&#44; and the low expression of this molecule is related to neuro-regeneration processes&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">34</span></a> For these reasons&#44; the authors believe that diminished VEGF in the tears of the patients of this study could relate to the ocular discomfort and pain they may experience in response to the underlying neurotrophic epitheliopathy&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The joint results of clinical exploration and IIR determination in glaucomatous tears of patients in chronic treatments with hypotensor eyedrops was very interesting as significantly higher levels of IL-6 were obtained when compared to the CG&#46; These data confirm the IIR process of the ocular surface in the course of glaucoma and can be associated to the chronic administration of anti-hypotensive eyedrops that induce inflammatory activity influenced by IL-6&#46; Similarly&#44; Badouin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> demonstrated high IL-6 levels &#40;in addition to IL-8 and IL-10&#41;&#44; tears of glaucomatous patients in treatment when compared to normal subjects&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have described changes in the expression of IIR mediator molecules when comparing DEG with POAGG patients&#44; with a highly significant increase of IL-4 in DEG&#44; and IL-6&#44; TNF-&#945; and VEGF in POAGG&#46; These results support the common inflammatory basis but&#44; interestingly&#44; with different molecules&#44; which indicates that different signaling pathways are involved in these 2 processes&#46; In this regard&#44; analyzing differences in the protein profile of tears between the diseases of this study&#44; other authors have reached similar results&#44;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">36&#8211;39</span></a> which indicates that these molecules could be utilized for designing new therapies for patients with ocular surface dysfunctions&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">40</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The limitations of the present study include that the expression and tears of the majority of the IIR molecules as quantitative variables exhibited abnormal distribution in the data&#46; For this reason&#44; nonparametric tests were used for making comparisons between groups and this could reduce the potency of the study&#46; An additional limitation is that the study was carried out with Caucasian patients with suspected or diagnosed slight or moderate POAG or with non-advanced DE&#46; Accordingly&#44; caution is advised in what concerns the external validity of the study in the population&#46; On the other hand&#44; the study has not included the differences between the hypotensor eyedrops utilized by POAGG patients or their respective compositions&#46; In fact&#44; this is the object of experiments the authors are carrying out at present&#46; It is also possible that the technique utilized could influence the type of detected molecules&#44; as pointed out by Dione et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a> and this should be taken into account when designing new studies for these type of assessments&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In conclusion&#44; utilizing the noninvasive&#44; nontraumatic method of extracting reflex human tears through capillarity and analyzing the expression of a range of cytokins through a multi-determination system based on flow cytometry&#44; the differential profile of the expression of IIR marker molecules in patients with DE&#44; suspected or diagnosed POAG in chronic antihypertensive treatment has been obtained and compared with healthy controls&#46; This confirms the inflammatory activity in ocular surface dysfunctions and indicates that IL-6 can be utilized as a potential biomarker for this disease&#46; These findings provide researchers with an opportunity to carry out broader studies that could help improve diagnosis and management of the 2 diseases discussed in this paper&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0160" class="elsevierStylePara elsevierViewall">No conflict of interests was declared by the authors in what concerns instruments&#44; materials or reactants utilized in the present study&#46;</p></span></span>"
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    "fechaRecibido" => "2016-08-28"
    "fechaAceptado" => "2016-12-05"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec828968"
          "palabras" => array:5 [
            0 => "Tears"
            1 => "Cytokines"
            2 => "Dry eye"
            3 => "Glaucoma"
            4 => "Inflammation and immune response"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec828969"
          "palabras" => array:5 [
            0 => "L&#225;grimas"
            1 => "Citoquinas"
            2 => "Ojo seco"
            3 => "Glaucoma"
            4 => "Inflamaci&#243;n y respuesta inmune"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the expression profile of immune response and inflammation &#40;IRI&#41; mediator molecules in tears from patients with dry eye &#40;DE&#41;&#44; and those suspected of having or have primary open-angle glaucoma &#40;POAG&#41; under treatment and compare them with healthy controls&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective observational cohort study including 107 participants sub-divided into&#58; healthy controls &#40;CG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#44; patients with DE &#40;DEG&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; and patients suspected of having or have POAG and on hypotensive treatment &#40;POAG-G&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#46; Tear samples were collected by capillary to be processed using a multi-immunoassay system based on flow cytometry &#40;Luminex R-200<span class="elsevierStyleSup">&#174;</span>&#41;&#44; in order to determine the interleukins &#40;IL&#41;&#58; 1&#946;&#44; 2&#44; 4&#44; 5&#44; 6&#44; and 10&#44; and the growth factors&#58; tumor necrosis alpha &#40;TNF-&#945;&#41;&#44; vascular endothelial &#40;VEGF&#41;&#44; and granulocyte-macrophage colony stimulating &#40;GM-CSF&#41;&#46; Data were processed using the SPSS 20&#46;0 program&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Molecules that significantly increased in tears from DEG vs&#46; POAG-G patients were&#58; IL-1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#44; IL-10 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&#44; whereas VEGF significantly decreased in the DEG&#46; The POAG-G showed significantly higher IL-6 values &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; as compared to the CG&#46; When comparing both the DEG and POAG-G&#44; significant differences were observed in tear expression of IL-4 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#44; IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#44; TNF-&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#44; GM-CSF &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#44; and VEGF &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The increased expression of IRI mediators in tears from patients with DE or POAG strongly demonstrated the importance of immune response in both pathologies&#46; However&#44; the different molecules involved also suggest distinct signaling pathways for these processes that still require further research&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Determinar el perfil de expresi&#243;n de las mol&#233;culas mediadoras de inflamaci&#243;n y respuesta inmune &#40;IRI&#41; en l&#225;grimas de pacientes con ojo seco &#40;OS&#41; y pacientes en tratamiento m&#233;dico por sospecha o diagn&#243;stico de glaucoma primario de &#225;ngulo abierto &#40;GPAA&#41; para compararlos con sujetos sanos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo observacional de cohortes de 107 participantes subdivididos en&#58; pacientes con OS &#40;GOS&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&#44; pacientes con sospecha o diagn&#243;stico de GPAA con tratamiento hipotensor ocular &#40;GGPAA&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; y controles sanos &#40;GC&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#46; Se obtuvieron muestras de l&#225;grimas mediante capilaridad para analizarlas mediante sistema de multiinmunoan&#225;lisis basado en citometr&#237;a de flujo &#40;Luminex R-200<span class="elsevierStyleSup">&#174;</span>&#41;&#44; determinando diversas interleucinas &#40;IL&#41;&#58; 1&#946;&#44; 2&#44; 4&#44; 5&#44; 6 y 10&#44; y tambi&#233;n los factores de necrosis tumoral alfa &#40;TNF-&#945;&#41;&#44; de crecimiento endotelial vascular &#40;VEGF&#41; y de crecimiento de colonias de granulocitos y macr&#243;fagos &#40;GM-CSF&#41;&#46; Los datos se procesaron mediante el programa SPSS 20&#46;0&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las mol&#233;culas que aumentaron significativamente en l&#225;grimas de pacientes en el GOS versus GGPAA fueron&#58; IL-1&#946; &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; IL-6 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; IL-10 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;04&#41;&#44; mientras que el VEGF disminuy&#243; significativamente en el GOS&#46; El GGPAA mostr&#243; aumento significativo de IL-6 &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; frente al GC&#46; Comparando GOS y GGPAA&#44; observamos diferencias significativas para IL-4 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; IL-6 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41;&#44; TNF-&#945; &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41;&#44; GM-CSF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41; y VEGF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El aumento de expresi&#243;n de los mediadores de IRI en l&#225;grimas de pacientes con OS o GPAA demuestra la importancia de estos procesos en ambas enfermedades&#44; aunque las distintas mol&#233;culas implicadas indican diferentes v&#237;as de se&#241;alizaci&#243;n para ambas&#44; que requieren m&#225;s investigaciones&#46;</p></span>"
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            "identificador" => "abst0025"
            "titulo" => "Objetivo"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todo"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Benitez-del-Castillo S&#225;nchez J&#44; Morillo-Rojas MD&#44; Galbis-Estrada C&#44; Pinazo-Duran MD&#46; Determinaci&#243;n de mediadores de la respuesta inmune e inflamaci&#243;n en l&#225;grimas&#58; cambios en ojo seco y glaucoma frente a poblaci&#243;n sana&#46; Arch Soc Esp Oftalmol&#46; 2017&#59;92&#58;210&#8211;217&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This paper was awarded the First Galo Leoz Prize for Research at the Congress of the Ophthalmology Society of Spain held in M&#225;laga &#40;September 2016&#41;&#46;</p>"
      ]
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Statistically significant differences of inflammation marker molecules and immune response in tears between the dry eye and glaucoma groups&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">POAGG&#58; primary open angle glaucoma treatment group&#59; DEG&#58; dry eye group&#59; IL&#58; interleukin&#59; pg&#47;mg&#47;ml&#58; picograms per ml per miligram&#59; TNF-&#945;&#58; tumor necrosis factor alpha&#59; VEGF&#58; vascular endothelial growth factor&#46;</p>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">POAGG&#58; primary open angle glaucoma group of patients&#59; CG&#58; control group&#59; DEG&#58; dry eye group of patients&#59; POAG&#58; primary open angle glaucoma&#59; DE&#58; dry eye&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inclusion criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Exclusion criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age 25&#8211;80 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Age &#60;25 years or &#62;80 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosed with slight-moderate DE disease &#40;for DEG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atopia or other allergic diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnosed with suspected or non-advanced POAG &#40;for POAGG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Use of contact lenses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Healthy controls &#40;for CG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractive surgery history&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Able to participate in the study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Systemic diseases or treatments that could alter the ocular surface&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Informed consent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Palpebral abnormalities&#44; severe blepharitis or meibomitis&#44; lacrimal point occlusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other ocular diseases and use of eyedrops other than artificial tears &#40;without preservatives&#41; or PG analog ocular hypotensors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Previous diagnostic of coexistence of DE and POAG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not able to participate in the study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Inclusion&#47;exclusion criteria for study participants&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Differences between study groups in age&#44; Schirmer and FBUT with <span class="elsevierStyleItalic">T</span> for student test for independent samples&#46; Sex differences with Chi square test&#46; Significance if <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">DE&#58; standard deviation&#59; FBUT&#58; fluorescein breakup time&#59; POAGG&#58; primary open angle glaucoma group&#59; CG&#58; control group&#59; DEG&#58; dry eye group&#59; mm&#58; millimeters&#59; s&#58; seconds&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Overall study population &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>107 participants&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">CG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-CG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG-CG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-POAGG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age in years &#40;mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DE&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Sex &#91;&#37;&#93;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Males&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#46;7 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#46;5 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Females&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&#46;3 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69&#46;5 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;91&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Schirmer in mm &#40;mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DE&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FBUT in s &#40;mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DE&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#46;24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Differences between study groups with a Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Values &#8225; significant if <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#59; POAGG&#58; primary open angle glaucoma group&#59; CG&#58; control group&#59; GM-CSF&#58; granulocyte-macrophage colony-stimulating factor&#59; DEG&#58; dry eye group&#59; IL&#58; interleukin&#59; pg&#47;mg&#47;ml&#58; picograms per ml per miligram&#59; TNF-&#945;&#58; tumor necrosis factor alpha&#59; VEGF&#58; vascular endothelial growth factor&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Overall study population &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>107&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">CG &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-CG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">POAGG-CG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">DEG-POAGG difference&#58; <span class="elsevierStyleItalic">p</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-1&#946; &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0144&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4907&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0828&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-2 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;66<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0941&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6262&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-4 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&#46;79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2706&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-5 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0845&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0928&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1301&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-6 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-8 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">496&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>750&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">508&#46;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>680&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">447&#46;85<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>548&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3594&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6533&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4472&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-10 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;92<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0392&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9407&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0518&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IL-12 &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>63&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8274&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7285&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8983&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TNF-&#945; &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2436&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0048&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">367&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>290&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">609&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>329&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">581&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>257&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0042&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;3855&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0058&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GM-CSF &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;91<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2491&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8221&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1328&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IFNy &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; &#91;pg&#47;mg&#47;ml&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;81<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;89<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7732&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1705&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4493&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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