Original article
Treatment with Quinoline-3-carboxamide does not successfully prevent immune-mediated glomerulonephritis in mice
El tratamiento con 3-carboxamina-quinolina no previene con éxito una glomerulonefritis immuno-mediada en un modelo experimental en ratones
Read
6865
Timeswas read the article
2241
Total PDF
4624
Total HTML
Share statistics
array:25 [ "pii" => "S2013251416300736" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2016.08.004" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "183" "copyright" => "Sociedad Española de Nefrología" "copyrightAnyo" => "2016" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2016;36:687-93" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2967 "formatos" => array:3 [ "EPUB" => 317 "HTML" => 2066 "PDF" => 584 ] ] "Traduccion" => array:1 [ "en" => array:20 [ "pii" => "S0211699516300157" "issn" => "02116995" "doi" => "10.1016/j.nefro.2016.03.012" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "183" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2016;36:687-93" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5254 "formatos" => array:3 [ "EPUB" => 417 "HTML" => 3929 "PDF" => 908 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Treatment with Quinoline-3-carboxamide does not successfully prevent immune-mediated glomerulonephritis in mice" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "687" "paginaFinal" => "693" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El tratamiento con 3-carboxamina-quinolina no previene con éxito una glomerulonefritis immuno-mediada en un modelo experimental en ratones" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1798 "Ancho" => 3417 "Tamanyo" => 219503 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by (a) serum creatinine and (b) urea and (c) urinary protein excretion in control and Paquinimod-treated animals; Renal histology assessed by (d) percentage glomerular crescents and (e) glomerular thrombosis score in control and Paquinimod-treated animals. Medians shown. Paquinimod was administered at a dosage of 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg per day.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juliana Draibe, Ruth J. Pepper, Alan D. Salama" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Juliana" "apellidos" => "Draibe" ] 1 => array:2 [ "nombre" => "Ruth J." "apellidos" => "Pepper" ] 2 => array:2 [ "nombre" => "Alan D." "apellidos" => "Salama" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2013251416300736" "doi" => "10.1016/j.nefroe.2016.08.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251416300736?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699516300157?idApp=UINPBA000064" "url" => "/02116995/0000003600000006/v1_201611240148/S0211699516300157/v1_201611240148/en/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2013251416300761" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2016.09.002" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "194" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2016;36:694-700" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3734 "formatos" => array:3 [ "EPUB" => 318 "HTML" => 2560 "PDF" => 856 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "The relationship between dietary salt intake and ambulatory blood pressure variability in non-diabetic hypertensive patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "694" "paginaFinal" => "700" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Relación entre el consumo de sal y la variabilidad de la presión arterial ambulatoria en pacientes hipertensos no diabéticos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "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" => 1247 "Ancho" => 1588 "Tamanyo" => 158191 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The correlation with nighttime systolic ARV and log(24-h urinary sodium).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Nihal Ozkayar, Fatih Dede, Ihsan Ates, Fatma Akyel, Tolga Yildirim, Bulent Altun" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Nihal" "apellidos" => "Ozkayar" ] 1 => array:2 [ "nombre" => "Fatih" "apellidos" => "Dede" ] 2 => array:2 [ "nombre" => "Ihsan" "apellidos" => "Ates" ] 3 => array:2 [ "nombre" => "Fatma" "apellidos" => "Akyel" ] 4 => array:2 [ "nombre" => "Tolga" "apellidos" => "Yildirim" ] 5 => array:2 [ "nombre" => "Bulent" "apellidos" => "Altun" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251416300761?idApp=UINPBA000064" "url" => "/20132514/0000003600000006/v1_201702210030/S2013251416300761/v1_201702210030/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S201325141730007X" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2017.01.007" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "251" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2016;36:679-86" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4450 "formatos" => array:3 [ "EPUB" => 364 "HTML" => 3263 "PDF" => 823 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Delphi consensus on the diagnosis and management of dyslipidaemia in chronic kidney disease patients: A post hoc analysis of the DIANA study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "679" "paginaFinal" => "686" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Consenso Delphi sobre el diagnóstico y manejo de la dislipidemia en pacientes con enfermedad renal crónica: análisis <span class="elsevierStyleItalic">post-hoc</span> del estudio DIANA" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 356 "Ancho" => 1653 "Tamanyo" => 67332 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Score scale and levels of agreement and disagreement.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Aleix Cases Amenós, Juan Pedro-Botet Montoya, Vicente Pascual Fuster, Vivencio Barrios Alonso, Xavier Pintó Sala, Juan F. Ascaso Gimilio, Jesús Millán Nuñez-Cortés, Adalberto Serrano Cumplido" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Aleix" "apellidos" => "Cases Amenós" ] 1 => array:2 [ "nombre" => "Juan" "apellidos" => "Pedro-Botet Montoya" ] 2 => array:2 [ "nombre" => "Vicente" "apellidos" => "Pascual Fuster" ] 3 => array:2 [ "nombre" => "Vivencio" "apellidos" => "Barrios Alonso" ] 4 => array:2 [ "nombre" => "Xavier" "apellidos" => "Pintó Sala" ] 5 => array:2 [ "nombre" => "Juan F." "apellidos" => "Ascaso Gimilio" ] 6 => array:2 [ "nombre" => "Jesús" "apellidos" => "Millán Nuñez-Cortés" ] 7 => array:2 [ "nombre" => "Adalberto" "apellidos" => "Serrano Cumplido" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699516301163" "doi" => "10.1016/j.nefro.2016.07.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699516301163?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S201325141730007X?idApp=UINPBA000064" "url" => "/20132514/0000003600000006/v1_201702210030/S201325141730007X/v1_201702210030/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Treatment with Quinoline-3-carboxamide does not successfully prevent immune-mediated glomerulonephritis in mice" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "687" "paginaFinal" => "693" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juliana Draibe, Ruth J. Pepper, Alan D. Salama" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juliana" "apellidos" => "Draibe" "email" => array:1 [ 0 => "jbordignon@bellvitgehospital.cat" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Ruth J." "apellidos" => "Pepper" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Alan D." "apellidos" => "Salama" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Hospital de Bellvitge, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "UCL Centre for Nephrology, Royal Free Hospital, London, UK" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El tratamiento con 3-carboxamina-quinolina no previene con éxito una glomerulonefritis immuno-mediada en un modelo experimental en ratones" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1798 "Ancho" => 3417 "Tamanyo" => 246126 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by (a) serum creatinine and (b) urea and (c) urinary protein excretion in control and Paquinimod-treated animals; Renal histology assessed by (d) percentage glomerular crescents and (e) glomerular thrombosis score in control and Paquinimod-treated animals. Medians shown. Paquinimod was administered at a dosage of 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg per day.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Paquinimod belongs to the class of quinoline-3-carboximide derivatives, compounds that have demonstrated efficacy in treating autoimmune diseases in both humans and mice.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1–5</span></a> Linomide, the first compound of this class, was effective in treatment of multiple sclerosis (MS) in phase II studies; however, cardiovascular toxicity during phase III studies led to premature trial termination.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6,7</span></a> Subsequently, two new compounds with improved safety profiles and increased potency were investigated. The first, Laquinimod exhibited clinical efficacy as well as favourable safety in MS patients<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8–10</span></a> and is still being investigated for the treatment of MS. The second, Paquinimod effectively inhibited disease in experimental lupus prone mice, and was well tolerated (in doses up to 3<span class="elsevierStyleHsp" style=""></span>mg/day) in SLE patients with low disease activity, however, at higher doses (up to 6<span class="elsevierStyleHsp" style=""></span>mg/day) systemic adverse effects consisting of myalgias and arthralgias were reported. In addition, transient increases in inflammatory cells and acute phase reactants were seen at all doses, but most marked at the higher dose range.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The S100A9 protein has been identified as one target molecule of Paquinimod, disrupting binding of this protein to one of its receptors, TLR-4 but not to the advanced glycosylation end product-specific receptor (RAGE).<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> In association with S100A8, S100A9 forms the heterodimer S100A8/S100A9, termed calprotectin. Calprotectin is found abundantly in neutrophils, monocytes and early differentiated macrophages and is involved in calcium-dependent signalling, cell differentiation, cell cycle progression and cytoskeleton-membrane interactions.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> Upon phagocyte activation with the inflamed endothelium, calprotectin is secreted, binds to endothelial cells stimulating the secretion of pro-inflammatory cytokines such as interleukin-8 (IL8) and increasing the expression of Intercellular adhesion molecule 1(ICAM-1), involved in the further recruitment of leucocytes, promoting the impairment of endothelial monolayer integrity and inducing apoptosis and necrosis.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">14–16</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Calprotectin has been demonstrated to be upregulated in many inflammatory disorders, such as SLE, RA, idiopathic juvenile arthritis, Kawasaki's disease and AAV.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17–22</span></a> In patients with active SLE, serum calprotectin levels correlate with disease activity assessed by laboratory and clinical parameters.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> In patients with limited systemic AAV, failure to suppress serum calprotectin whilst on immunosuppressive treatment was associated with subsequent disease relapse, suggesting that calprotectin may be a useful biomarker to predict future flares.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In animal models of autoimmunity, calprotectin and its TLR4 receptor have been implicated in mediating disease. In accelerated NTN, a model of immune mediated glomerulonephritis, wild-type (WT) mice with glomerulonephritis have increased serum levels of S100A8/A9, while mice deficient in S100A9 (S100A9<span class="elsevierStyleSup">−/−</span>) or the TLR4 receptor (TLR4<span class="elsevierStyleSup">−/−</span>) are significantly protected from disease.<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">23,24</span></a> In a model of autoimmunity in mice overexpressing CD40L, S100A8/S100A9 was critical for the induction of dermatitis and nephritis, as well as the expansion of autoreactive CD8 T-cells, and the development of autoantibodies.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> Together these data suggest that S100A8/A9 blockade could be a promising therapeutic target in human glomerulonephritis including lupus nephritis and ANCA associated glomerulonephritis. In the present study we assessed the efficacy of Paquinimod in the prevention and treatment of murine NTN.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Animals, induction of accelerated nephrotoxic nephritis (NTN) and treatment with Paquinimod</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male C57BL/6 mice were between 8 and 12 weeks of age, and were bred in house. All experiments were performed under the terms of the Animals (Scientific Procedures) Act 1986, under UK Home Office animal welfare licences</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Nephrotoxic nephritis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Sheep anti-mouse nephrotoxic serum (NTS) was generated according to previously published methods.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Disease was induced by pre-immunising mice sub-cutaneously with sheep IgG (0.2<span class="elsevierStyleHsp" style=""></span>mg) in Complete Freund's Adjunvant (CFA, Sigma). Five days later (day 0), mice were injected intravenously with 200<span class="elsevierStyleHsp" style=""></span>μl of sheep NTS (diluted 1:3 in sterile 0.9% NaCl) and intraperitoneal lipopolysaccharide (LPS, 0.1<span class="elsevierStyleHsp" style=""></span>μg/mouse). Mice were sacrificed 8 days later. Groups of 7–10 mice were used per treatment cohort.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Treatment with different doses of Paquinimod</span><p id="par0035" class="elsevierStylePara elsevierViewall">Mice were treated with Paquinimod (from Active Biotech AB, Lund, Sweden) dissolved in drinking water available ad libitum, after assessment of the average daily fluid intake of the mice. In the first experiment, the compound was used at dosage of 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg per day starting at day 0 in the treatment group (10 mice: paquinimod), while control mice drank normal water (10 mice: controls). In the second experiment, a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg/kg per day was used, starting at day 0 (prevention group: PaqP, 7 mice), or day 2 (therapeutic group: PaqT, 7 mice) or untreated (Control, 7 mice). Mice were placed in metabolic cages overnight, the day before sacrifice and urine collected.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Assessment of renal injury</span><p id="par0040" class="elsevierStylePara elsevierViewall">Serum creatinine, urea, ALT and albumin were measured in the clinical pathology laboratory, Mary Lyon Centre, Medical research Council, Harwell. In all experiments, urine was collected after housing mice in metabolic cages overnight with free access to food and water. Urinary protein was measured by the sulfosalicylic acid method.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a></p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Histology and immunohistochemistry</span><p id="par0045" class="elsevierStylePara elsevierViewall">Kidneys were removed, fixed in formalin and embedded in paraffin for periodic acid-Schiff (PAS) and immunohistochemical staining. Immunoperoxidase staining for mouse calprotectin and macrophages was performed using a rat anti-mouse calprotectin monoclonal antibody (clone 2B10 at 1.2<span class="elsevierStyleHsp" style=""></span>mg/ml, a gift from Prof Nancy Hogg) and a rat anti-mouse MAC2 (at 1<span class="elsevierStyleHsp" style=""></span>mg/ml), respectively. Renal sections were analysed for the percentages of glomerular crescents (0–100%) and the degree of glomerular thrombosis using a standard scoring system (0<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>no PAS material, 1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0–25% of glomerulus affected, 2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>25–50%, 3<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>50–75% and 4<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>75–100%).</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using GraphPad prism 6.0 (GraphPad Software, San Diego, CA, USA). A Mann–Whitney test was used when comparing 2 groups. When comparing 3 groups, a one-way ANOVA test was used. Results were considered significant when <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Low dose preventative Paquinimod treatment</span><p id="par0055" class="elsevierStylePara elsevierViewall">In the first experiment, a dose of paquinimod of 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg per day was administered from day 0, based on the previously published data demonstrating efficacy in a lupus mouse model.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> All mice tolerated this dose, with no fatalities. Renal function, assessed by serum urea and creatinine, as well as urinary protein excretion, were not significantly different between Paquinmod-treated (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) and control (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) mice (median serum urea Paquinimod 14.8<span class="elsevierStyleHsp" style=""></span>mmol/l (range 6.9–98.0) vs control 8.2<span class="elsevierStyleHsp" style=""></span>mmol/l (range 5.8–120); median serum creatinine Paquinimod treated 36.6<span class="elsevierStyleHsp" style=""></span>μmol/l (range 25.6–76.3) vs control 34.3<span class="elsevierStyleHsp" style=""></span>μmol/l (range 29.1–86.6); median proteinuria in Paquinimod-treated animals 9.3<span class="elsevierStyleHsp" style=""></span>mg/ml (range 6.3–14.5) vs controls 6.8<span class="elsevierStyleHsp" style=""></span>mg/ml (range 1.1–9.1) (all p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>NS)) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a–c).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Similarly, renal histology, revealed no significant differences between the two groups with regards percentages of glomerular crescents (median % crescents paquinimod 8% (range 0–60%) vs controls 10% (range 0–44) or thrombosis scores (median thrombosis score Paquinimod 0.53 (range 0–3.5) vs controls 0.1 (range 0–2.84) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>d and e).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">High-dose prevention and treatment Paquinimod therapy</span><p id="par0065" class="elsevierStylePara elsevierViewall">In the second series of experiments, the dose of Paquinimod was increased to 25<span class="elsevierStyleHsp" style=""></span>mg/kg per day, based on further published data showing efficacy in the treatment of experimental autoimmune encephalomyelitis.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> After 8 days, 4 mice had died; 2 from the control group, 1 from the prevention group and 1 from the treatment group.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Renal function and proteinuria (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a–c) were similar between the three groups(median serum creatinine control 12.1<span class="elsevierStyleHsp" style=""></span>μmol/l (range 10.4–13.7) vs Paq P 17.3<span class="elsevierStyleHsp" style=""></span>μmol/l (range 10.8–55.7) vs Paq T 16.7<span class="elsevierStyleHsp" style=""></span>μmol/l (range 15.2–18.10); median serum urea control 9.5<span class="elsevierStyleHsp" style=""></span>mmol/l (range 9.0–14.1) vs Paq P 35.1<span class="elsevierStyleHsp" style=""></span>mmol/l (range 10.9–148.8) vs Paq T 42.7<span class="elsevierStyleHsp" style=""></span>mmol/l (range 8.1–77.3); Renal histological damage was also similar in all three groups with regards percentages of glomerular crescents (median % crescents control 0% (range 0–20) vs Paq P 4% (range 0–75) vs Paq T 0% (range 0–50) and glomerular thrombosis scores median thrombosis score control 0.1 (range 0–0.49) vs Paq P 0.39 (range 0–0.97) vs Paq T 0.02 (range 0–0.22) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>d and e).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">As the drug has direct binding effect in the S100A9 and calprotectin is abundantly expressed in early inflammatory macrophages, we performed an immunoperoxidase staining for calprotectin and macrophages (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>a and b) and quantification of these showed a trend for increased glomerular calprotectin expression, and a similar trend in glomerular macrophage numbers, (mean glomerular calprotectin cell expression control 0.22<span class="elsevierStyleHsp" style=""></span>cells/glomerulus (SEM 0.1) vs Paq P 1.25 (SEM 0.6) vs Paq T 0.45 (SEM 0.2); mean glomerular macrophage number control 2.2<span class="elsevierStyleHsp" style=""></span>cells/glomerulus (SEM 0.1) vs Paq P 3.6 (SEM 1.0) vs Paq T 4.1 (SEM 0.7)).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Previous studies in lupus prone mice,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> experimental autoimmune encephalomyelitis<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> and collagenase induced osteoarthritis<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> have demonstrated a significant reduction in glomerular, central nervous system and joint inflammation respectively following the use of prophylactic low and high doses of Paquinimod, a compound that inhibits S100A9 but not S100A8, binding to TLR4. We have previously shown that serum S100A8/A9 levels are elevated during NTN and that S100A9 deficiency significantly attenuates disease, in part by inhibiting release of proinflammatory cytokines and chemokines.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> We found no effect of S100A9 deficiency on glomerular neutrophil recruitment, but noted a significant reduction in glomerular macrophage infiltration. In this report, we show that using the same NTN model, different doses of Paquinimod administered at the time of, or following, disease induction were not efficacious in attenuating disease. We found a non-significant trend of increased glomerular calprotectin expression in those animals given the highest dose of Paquinimod, and a similar trend in the number of glomerular macrophages.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Denoric et al.,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> demonstrated that Paquinimod reduced the accumulation of Ly6C<span class="elsevierStyleSup">hi</span> inflammatory monocytes and eosinophils, but not neutrophils in the omentum or at subcutaneous sites of inflammation. While, in alum-induced inflammation, in which neutrophils were the predominant cell population, Paquinimod failed to reduce the accumulation of inflammatory cells. Therefore our NTN model, which relies on early transient neutrophil recruitment followed by monocyte/macrophage infiltration into the kidney by day 3, may not be easily attenuated by Paquinimod. Another possible explanation for our observations may relate to the findings of Vandal et al.,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> who investigated the role of S100A8 and S100A9 on neutrophil migration into a murine air pouch in response to LPS. They found that LPS led to S100A8, S100A9 and S100A8/A9 in the pouch exudates that preceded the neutrophil accumulation. Blocking S100A8 inhibited neutrophil migration 3<span class="elsevierStyleHsp" style=""></span>h after LPS injection, but blocking S100A9 had no significant effect. It is therefore possible that LPS used in induction of our NTN model resulted in an increase of S100A8 expressing inflammatory cells early on in the course of disease.</p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition, Paquinimod appears to induce a transient increase in levels of inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate, reported in Paquinimod-treated SLE patients.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> These changes were more evident with higher dosages of Paquinimod (4.5<span class="elsevierStyleHsp" style=""></span>mg/day and 6.0<span class="elsevierStyleHsp" style=""></span>mg/day compared to 3.0<span class="elsevierStyleHsp" style=""></span>mg/day). Similar increases in inflammatory markers, were also reported in the first weeks of treatment from clinical trials with Laquinimod.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8,9</span></a> The mechanisms that cause these changes remain unclear and are being investigated, but if replicated in our NTN model could explain the lack of efficacy observed in a short term animal model. It is noteworthy that the efficacy of Paquinimod in other experimental models have utilised more prolonged time courses compared to ours. Our NTN model may evolve too rapidly to dissect out any transient increase and subsequent reduction in inflammation that may occur with this compound, in contrast to genetic deficiency of S100A9.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion, we could not show a benefit from Paquinimod in prevention or treatment of a murine NTN model, despite having previously shown a benefit from complete S100A9 deficiency using the same model. However, due to the transient proinflammatory action of this compound, a murine glomerulonephritis model of longer duration may be necessary to fully test the efficacy of this drug, or the drug may need to be used in combination therapy with other anti-inflammatories such as corticosteroids which could suppress the early inflammatory response.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors’ contribution</span><p id="par0100" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">JB: performed animal work, participated in the design of the study, performed the statistical analysis and drafted the manuscript.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">RP: performed animal work.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">AS: performed animal work, conceived of the study, and participated in its design and coordination.</p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interests</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that they have no competing interests.</p><p id="par0125" class="elsevierStylePara elsevierViewall">All authors read and approved the final manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres803838" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 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" => "xpalclavsec802026" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec802025" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres803839" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec802024" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Animals, induction of accelerated nephrotoxic nephritis (NTN) and treatment with Paquinimod" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Animals" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Nephrotoxic nephritis" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Treatment with different doses of Paquinimod" ] ] ] 1 => array:3 [ "identificador" => "sec0035" "titulo" => "Assessment of renal injury" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Histology and immunohistochemistry" ] ] ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Statistical analysis" ] ] ] 7 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Low dose preventative Paquinimod treatment" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "High-dose prevention and treatment Paquinimod therapy" ] ] ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Authors’ contribution" ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-11-26" "fechaAceptado" => "2016-03-16" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec802026" "palabras" => array:4 [ 0 => "Glomerulonephritis" 1 => "Animal model" 2 => "Calprotectin" 3 => "Paquinimod" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec802025" "palabras" => array:19 [ 0 => "TLR-4" 1 => "ANCA" 2 => "AAV" 3 => "SLE" 4 => "RA" 5 => "MS" 6 => "RAGE" 7 => "IL8" 8 => "ICAM-1" 9 => "WT" 10 => "S100A9<span class="elsevierStyleSup">−/−</span>" 11 => "TLR4<span class="elsevierStyleSup">−/−</span>" 12 => "NTS" 13 => "CFA" 14 => "LPS" 15 => "PaqP" 16 => "PaqT" 17 => "PAS" 18 => "CPR" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec802024" "palabras" => array:4 [ 0 => "Glomerulonefritis" 1 => "Modelo animal" 2 => "Calprotectina" 3 => "Paquinimod" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Quinoline-3-carboximide compounds, such as paquinimod, which targets the protein S100A9, have demonstrated efficacy in treating autoimmune diseases. S100A9, in association with S100A8, forms the heterodimer S100A8/S100A9, known as calprotectin; that has been shown to be upregulated in numerous inflammatory disorders. We had previously demonstrated protection from glomerular disease in S100A9-deficient mice. The aim of this study was to assess the efficacy of paquinimod in the prevention and treatment of experimental glomerulonephritis.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Nephrotoxic nephritis (NTN) was induced in C57BL/6 mice according to our standard protocol. Mice were treated with different doses of paquinimod either at disease induction (prevention group) or two days following induction (therapeutic group) and sacrificed 8 days following induction. Disease was assessed histologically (number of glomerular crescents, degree of glomerular thrombosis, number of infiltrating leucocytes and calprotectin expression) and biochemically (serum creatinine and urea levels, and urinary levels of protein).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Neither treatment with low (0.5<span class="elsevierStyleHsp" style=""></span>mg/kg) or high (25<span class="elsevierStyleHsp" style=""></span>mg/kg) doses of paquinimod, given preventatively or therapeutically, led to disease attenuation, as assessed by biochemical or histological parameters. Additionally, we found trends for an increase in renal glomerular calprotectin expression in the high dose groups, suggesting a possible feedback regulation of calprotectin expression.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our results show that paquinimod does not successfully prevent or treat mice with NTN. Other models of immune-mediated glomerulonephritis need to be tested to investigate the therapeutic potential of this compound in renal disease.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 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" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los compuestos relacionados con la 3-carboxamina-quinolina han demostrado eficacia en el tratamiento de enfermedades autoinmunes. Uno de estos compuestos, el paquinimod, ejerce su función a través del targeting de la proteína S100A9. La proteína S100A9, en asociación con S100A8, forma el heterodímero S100A8/S100A9, conocido como calprotectina, que se ha demostrado que está elevada en variadas enfermedades inflamatorias. Habíamos demostrado anteriormente la protección contra la enfermedad glomerular en ratones deficientes de S100A9. El objetivo de este estudio fue evaluar la eficacia de paquinimod en la prevención y el tratamiento de la glomerulonefritis experimental.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La nefritis nefrotóxica (NTN) se indujo en ratones C57BL/6 de acuerdo con el protocolo estándar. Los ratones fueron tratados con diferentes dosis de paquinimod en el momento de la inducción de la enfermedad (grupo de prevención) o 2 días después de la inducción (grupo terapéutico)y se sacrificaron 8 días después de la inducción. La enfermedad se evaluó histológicamente (número de semilunas glomerulares, el grado de trombosis glomerular, número de leucocitos infiltrantes y de expresión de calprotectina) y bioquímico (niveles séricos de creatinina y urea, y los niveles urinarios de proteínas).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Ninguno de los tratamientos con bajas (0,5<span class="elsevierStyleHsp" style=""></span>mg/kg) o altas (25<span class="elsevierStyleHsp" style=""></span>mg/kg) dosis de paquinimod, administrados preventiva o terapéuticamente, resultaron en la atenuación de la enfermedad,según los parámetros bioquímicos o histológicos. Además, encontramos una tendencia al aumento en la expresión renal de la calprotectina glomerular en los grupos con dosis altas, lo que indica una posible regulación de la retroalimentación de la expresión de calprotectina.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados muestran que el paquinimod no puede prevenir ni tratar con éxito la NTN en los ratones. Otros modelos de glomerulonefritis inmunomediadas necesitan ser testados para investigar el potencial terapéutico de este compuesto en la enfermedad renal.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1798 "Ancho" => 3417 "Tamanyo" => 246126 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by (a) serum creatinine and (b) urea and (c) urinary protein excretion in control and Paquinimod-treated animals; Renal histology assessed by (d) percentage glomerular crescents and (e) glomerular thrombosis score in control and Paquinimod-treated animals. Medians shown. Paquinimod was administered at a dosage of 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg per day.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1800 "Ancho" => 3417 "Tamanyo" => 264965 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by (a) serum creatinine and (b) urea and (c) urinary protein excretion in controls and animals treated with Paquinimod prophylactically (Paq-P)or therapeutically (Paq-T); Renal histology assessed by (d) percentage glomerular crescents and (e) glomerular thrombosis score in control and Paquinimod-treated animals. Medians shown. Paquinimod was administered at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg/kg per day.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2273 "Ancho" => 3333 "Tamanyo" => 626529 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemistry for (a) calprotectin expressing cells and (c) macrophages. (b) Quantification of mean calprotectin positive cells per glomerulus and (d) mean glomerular macrophage number in Control, and Paquinimod treated animals (prevention group (Paq P) and therapeutic group (PaqT)). Paquinimod administered at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg/kg per day.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paradoxical effects of LS-2616 (linomide) treatment type II collagen arthritis model in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Björk" 1 => "S. Kleinau" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Agents Actions" "fecha" => "1989" "volumen" => "27" "paginaInicial" => "319" "paginaFinal" => "321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2801316" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0160" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The new orally active immunoregulator laquinimod (ABR- 215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Brunmark" 1 => "A. Runström" 2 => "L. Ohlsson" 3 => "B. Sparre" 4 => "T. Brodin" 5 => "M. Aström" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Neuroimmunol" "fecha" => "2002" "volumen" => "130" "paginaInicial" => "163" "paginaFinal" => "172" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12225898" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0165" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Runström" 1 => "T. Leanderson" 2 => "L. Ohlsson" 3 => "B. Axelsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jneuroim.2005.11.023" "Revista" => array:6 [ "tituloSerie" => "J Neuroimmunol" "fecha" => "2006" "volumen" => "173" "paginaInicial" => "69" "paginaFinal" => "78" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16472873" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0170" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Wegner" 1 => "C. Stadelmann" 2 => "R. Pförtner" 3 => "E. Raymond" 4 => "S. Feigelson" 5 => "R. Alon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jneuroim.2010.07.009" "Revista" => array:6 [ "tituloSerie" => "J Neuroimmunol" "fecha" => "2010" "volumen" => "227" "paginaInicial" => "133" "paginaFinal" => "143" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20684995" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0175" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amelioration of experimental autoimmune encephalomyelitis by the quinoline-3-carboxamide Paquinimod" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Helmersson" 1 => "A. Sundstedt" 2 => "A. Deronic" 3 => "T. Leanderson" 4 => "F. Ivars" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Immunopathol Infect Dis" "fecha" => "2013" "volumen" => "182" "paginaInicial" => "1671" "paginaFinal" => "1680" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0180" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.H. Noseworthy" 1 => "J.S. Wolinsly" 2 => "F.D. Lublin" 3 => "J.N. Whitaker" 4 => "A. Linde" 5 => "P. Gjorstrup" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurology" "fecha" => "2000" "volumen" => "54" "paginaInicial" => "1726" "paginaFinal" => "1733" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10802775" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0185" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Linomide in treatment of multiple sclerosis: MRI results from premature terminated phase III trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "I.L. Tan" 1 => "G.J. Lycklama a Njicholt" 2 => "C.H. Polman" 3 => "H.J. Ader" 4 => "F. Barkof" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/135245850000600208" "Revista" => array:6 [ "tituloSerie" => "Mult Scler" "fecha" => "2000" "volumen" => "6" "paginaInicial" => "99" "paginaFinal" => "104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10773855" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0190" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Comi" 1 => "A. Pulizzi" 2 => "M. Rovaris" 3 => "O. Abramsky" 4 => "T. Arbizu" 5 => "A. Boiko" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(08)60918-6" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2008" "volumen" => "371" "paginaInicial" => "2085" "paginaFinal" => "2092" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18572078" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0195" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ 0 => "C. Polman" 1 => "F. Barkhof" 2 => "M. Sandberg-Wollheim" 3 => "A. Linde" 4 => "O. Nordle" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1212/01.WNL.0000154520.48391.69" "Revista" => array:6 [ "tituloSerie" => "Neurology" "fecha" => "2005" "volumen" => "64" "paginaInicial" => "987" "paginaFinal" => "991" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15781813" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0200" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Comi" 1 => "O. Abramsky" 2 => "T. Arbizu" 3 => "A. Boyko" 4 => "R. Gold" 5 => "E. Havrdová" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1352458510378127" "Revista" => array:6 [ "tituloSerie" => "Mult Scler" "fecha" => "2010" "volumen" => "16" "paginaInicial" => "1360" "paginaFinal" => "1366" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20834039" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0205" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.A. Bengtsson" 1 => "G. Sturfelt" 2 => "C. Lood" 3 => "L. Rönnblom" 4 => "R.F. van Vollenhoven" 5 => "B. Axelsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.33493" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2012" "volumen" => "64" "paginaInicial" => "1579" "paginaFinal" => "1588" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22131101" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0210" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3- carboxamides" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Björk" 1 => "A. Björk" 2 => "T. Vogl" 3 => "M. Stenström" 4 => "D. Liberg" 5 => "A. Olsson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "PLoS Biol" "fecha" => "2009" "volumen" => "7" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0215" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The S100 family of EF-hand calcium-binding proteins: functions and pathology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B.W. Schäfer" 1 => "C.W. Heizmann" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Trends Biochem Sci" "fecha" => "1996" "volumen" => "21" "paginaInicial" => "134" "paginaFinal" => "140" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8701470" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0220" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Frosch" 1 => "A. Strey" 2 => "T. Vogl" 3 => "N.M. Wulffraat" 4 => "W. Kuis" 5 => "C. Sunderkötter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(200003)43:3<628::AID-ANR20>3.0.CO;2-X" "Revista" => array:7 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2000" "volumen" => "43" "numero" => "3" "paginaInicial" => "628" "paginaFinal" => "637" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10728757" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0225" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Viemnann" 1 => "A. Atrey" 2 => "A. Janning" 3 => "K. Jurk" 4 => "K. Klimmek" 5 => "T. Vogl" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2004-07-2520" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2005" "volumen" => "105" "paginaInicial" => "2955" "paginaFinal" => "2962" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15598812" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0230" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MRP8/MRP14 impairs endotelial integrity and induces a capase-dependent and -independent cell death program" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Viemnann" 1 => "K. Barczyk" 2 => "T. Vogl" 3 => "U. Fischer" 4 => "C. Sunderkötter" 5 => "K. Schulze-Osthoff" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2006-08-040444" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2007" "volumen" => "109" "paginaInicial" => "2453" "paginaFinal" => "2460" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17095618" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0235" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Calprotectin in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H.J. Haga" 1 => "J.G. Brun" 2 => "H.B. Berntzen" 3 => "R. Cervera" 4 => "M. Khamashta" 5 => "G.R. Hughes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/096120339300200108" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "1993" "volumen" => "2" "paginaInicial" => "47" "paginaFinal" => "50" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8485559" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0240" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.S. Soyfoo" 1 => "J. Roth" 2 => "T. Vogl" 3 => "R. Pochet" 4 => "G. Decaux" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3899/jrheum.081302" "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2009" "volumen" => "36" "paginaInicial" => "2190" "paginaFinal" => "2194" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19755614" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0245" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differential expression and response to anti-TNF alpha treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. De Rycke" 1 => "D. Baeten" 2 => "D. Foell" 3 => "E. Kruithof" 4 => "E.M. Veys" 5 => "J. Roth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/path.1758" "Revista" => array:6 [ "tituloSerie" => "J Pathol" "fecha" => "2005" "volumen" => "206" "paginaInicial" => "17" "paginaFinal" => "27" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15809977" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0250" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Frosch" 1 => "M. Ahlmann" 2 => "T. Vogl" 3 => "H. Wittkowski" 4 => "N. Wulffraat" 5 => "D. Foell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.24349" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2009" "volumen" => "60" "paginaInicial" => "883" "paginaFinal" => "891" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19248102" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0255" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of myeloid-related protein-8 and -14 in patients with acute Kawasaki disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Hirono" 1 => "D. Foell" 2 => "Y. Xing" 3 => "S. Miyagawa-Tomita" 4 => "F. Ye" 5 => "M. Ahlmann" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2006.02.077" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2006" "volumen" => "48" "paginaInicial" => "1257" "paginaFinal" => "1264" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16979015" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0260" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Leucocyte and serum calprotectin (S100A8/S100A9) expression reflect disease activity in ANCA associated vasculitis and glomerulonephritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Pepper" 1 => "S. Hamour" 2 => "K.M. Chavele" 3 => "N. Rasmussen" 4 => "S. Flint" 5 => "P.A. Lyons" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ki.2013.2" "Revista" => array:6 [ "tituloSerie" => "Kidney Int" "fecha" => "2013" "volumen" => "83" "paginaInicial" => "1150" "paginaFinal" => "1158" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23423260" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0265" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toll-like receptor 4 stimulation triggers crescentic glomerulonephritis by multiple mechanisms including a direct effect on renal cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Giorgini" 1 => "S.H. Brown HJm Sacks" 2 => "M.G. Robsons" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2353/ajpath.2010.091279" "Revista" => array:7 [ "tituloSerie" => "Am J Pathol" "fecha" => "2010" "volumen" => "177" "numero" => "2" "paginaInicial" => "644" "paginaFinal" => "653" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20566738" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0270" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "S100A8/A9 (calprotectin) is critical for development of glomerulonephritis promoting inflammatory leukocyte- renal cell interactions" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.J. Pepper" 1 => "H-H. Wang" 2 => "G.K. Rajakaruna" 3 => "E. Papakrivopoulou" 4 => "T. Vogl" 5 => "C.D. Pusey" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Pathol" "fecha" => "2015" "volumen" => "185" "numero" => "5" "paginaInicial" => "1" "paginaFinal" => "11" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0275" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Toll-like receptor 4ligand MRP8 and MRp14 are crucial in development of autoreactive Cd8+ T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Loser" 1 => "T. Vogl" 2 => "M. Vosork" 3 => "A. Lueken" 4 => "V. Kupas" 5 => "W. Nacken" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nm1638" "Revista" => array:7 [ "tituloSerie" => "Nat Med" "fecha" => "2007" "volumen" => "13" "numero" => "9" "paginaInicial" => "1042" "paginaFinal" => "1049" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17767165" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0280" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.S. Topham" 1 => "V. Csizmadia" 2 => "D. Soler" 3 => "D. Hines" 4 => "C.J. Gerard" 5 => "D.J. Salant" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI7707" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1999" "volumen" => "104" "paginaInicial" => "1549" "paginaFinal" => "1557" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10587518" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0285" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Th2 responses induce humorally mediated injury in experimental anti-glomerular basement membrane glomerulonephritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "X.R. Huang" 1 => "S.R. Holdsworth" 2 => "P.G. Tipping" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Am Soc Nephrol" "fecha" => "1997" "volumen" => "8" "paginaInicial" => "1101" "paginaFinal" => "1108" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9219159" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0290" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "May 12" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.F. Schelbergen" 1 => "E.J. Geven" 2 => "M.H. van den Bosch" 3 => "H. Eriksson" 4 => "T. Leanderson" 5 => "T. Vogl" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2015" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0295" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The quinoline-3-carboxamide pquinimod (ABR-215757) reduces leucocyte recruitment during sterile inflammation: Leukocyte-and context-specific effects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Denoric" 1 => "S. Helmersson" 2 => "T. Leanderson" 3 => "F. Ivars" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Int Immunopharm" "fecha" => "2014" "volumen" => "18" "paginaInicial" => "290" "paginaFinal" => "297" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0300" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K. Vandal" 1 => "P. Rouleau" 2 => "A. Boivin" 3 => "C. Ryckman" 4 => "M. Talbot" 5 => "P.A. Tessier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Immunol" "fecha" => "2003" "volumen" => "171" "numero" => "5" "paginaInicial" => "2602" "paginaFinal" => "2609" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12928412" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003600000006/v1_201702210030/S2013251416300736/v1_201702210030/en/main.assets" "Apartado" => array:4 [ "identificador" => "42660" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003600000006/v1_201702210030/S2013251416300736/v1_201702210030/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251416300736?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 4 | 6 |
| 2024 October | 40 | 34 | 74 |
| 2024 September | 53 | 29 | 82 |
| 2024 August | 65 | 57 | 122 |
| 2024 July | 36 | 27 | 63 |
| 2024 June | 54 | 29 | 83 |
| 2024 May | 59 | 32 | 91 |
| 2024 April | 49 | 32 | 81 |
| 2024 March | 50 | 19 | 69 |
| 2024 February | 37 | 32 | 69 |
| 2024 January | 42 | 25 | 67 |
| 2023 December | 16 | 19 | 35 |
| 2023 November | 43 | 36 | 79 |
| 2023 October | 33 | 29 | 62 |
| 2023 September | 26 | 24 | 50 |
| 2023 August | 38 | 24 | 62 |
| 2023 July | 34 | 29 | 63 |
| 2023 June | 37 | 15 | 52 |
| 2023 May | 48 | 29 | 77 |
| 2023 April | 38 | 13 | 51 |
| 2023 March | 58 | 17 | 75 |
| 2023 February | 45 | 20 | 65 |
| 2023 January | 48 | 23 | 71 |
| 2022 December | 81 | 23 | 104 |
| 2022 November | 91 | 25 | 116 |
| 2022 October | 56 | 30 | 86 |
| 2022 September | 41 | 31 | 72 |
| 2022 August | 59 | 47 | 106 |
| 2022 July | 43 | 45 | 88 |
| 2022 June | 39 | 25 | 64 |
| 2022 May | 38 | 32 | 70 |
| 2022 April | 33 | 41 | 74 |
| 2022 March | 45 | 38 | 83 |
| 2022 February | 61 | 33 | 94 |
| 2022 January | 36 | 47 | 83 |
| 2021 December | 43 | 38 | 81 |
| 2021 November | 44 | 43 | 87 |
| 2021 October | 52 | 33 | 85 |
| 2021 September | 30 | 37 | 67 |
| 2021 August | 41 | 35 | 76 |
| 2021 July | 34 | 31 | 65 |
| 2021 June | 63 | 38 | 101 |
| 2021 May | 69 | 46 | 115 |
| 2021 April | 81 | 60 | 141 |
| 2021 March | 48 | 52 | 100 |
| 2021 February | 48 | 34 | 82 |
| 2021 January | 58 | 22 | 80 |
| 2020 December | 24 | 17 | 41 |
| 2020 November | 31 | 14 | 45 |
| 2020 October | 25 | 20 | 45 |
| 2020 September | 29 | 12 | 41 |
| 2020 August | 40 | 11 | 51 |
| 2020 July | 25 | 16 | 41 |
| 2020 June | 36 | 28 | 64 |
| 2020 May | 38 | 16 | 54 |
| 2020 April | 32 | 18 | 50 |
| 2020 March | 71 | 16 | 87 |
| 2020 February | 49 | 24 | 73 |
| 2020 January | 41 | 26 | 67 |
| 2019 December | 32 | 26 | 58 |
| 2019 November | 41 | 15 | 56 |
| 2019 October | 28 | 12 | 40 |
| 2019 September | 27 | 17 | 44 |
| 2019 August | 24 | 14 | 38 |
| 2019 July | 30 | 20 | 50 |
| 2019 June | 25 | 15 | 40 |
| 2019 May | 19 | 23 | 42 |
| 2019 April | 63 | 30 | 93 |
| 2019 March | 42 | 25 | 67 |
| 2019 February | 27 | 16 | 43 |
| 2019 January | 31 | 23 | 54 |
| 2018 December | 136 | 61 | 197 |
| 2018 November | 194 | 14 | 208 |
| 2018 October | 93 | 16 | 109 |
| 2018 September | 77 | 15 | 92 |
| 2018 August | 40 | 23 | 63 |
| 2018 July | 45 | 14 | 59 |
| 2018 June | 52 | 17 | 69 |
| 2018 May | 69 | 18 | 87 |
| 2018 April | 81 | 8 | 89 |
| 2018 March | 86 | 17 | 103 |
| 2018 February | 122 | 10 | 132 |
| 2018 January | 46 | 4 | 50 |
| 2017 December | 125 | 13 | 138 |
| 2017 November | 51 | 12 | 63 |
| 2017 October | 27 | 7 | 34 |
| 2017 September | 45 | 6 | 51 |
| 2017 August | 54 | 8 | 62 |
| 2017 July | 49 | 9 | 58 |
| 2017 June | 56 | 7 | 63 |
| 2017 May | 64 | 10 | 74 |
| 2017 April | 51 | 2 | 53 |
| 2017 March | 27 | 6 | 33 |
| 2017 February | 19 | 6 | 25 |
Show all
