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disrupting binding of this protein to one of its receptors&#44; TLR-4 but not to the advanced glycosylation end product-specific receptor &#40;RAGE&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> In association with S100A8&#44; S100A9 forms the heterodimer S100A8&#47;S100A9&#44; termed calprotectin&#46; Calprotectin is found abundantly in neutrophils&#44; monocytes and early differentiated macrophages and is involved in calcium-dependent signalling&#44; cell differentiation&#44; cell cycle progression and cytoskeleton-membrane interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> Upon phagocyte activation with the inflamed endothelium&#44; calprotectin is secreted&#44; binds to endothelial cells stimulating the secretion of pro-inflammatory cytokines such as interleukin-8 &#40;IL8&#41; and increasing the expression of Intercellular adhesion molecule 1&#40;ICAM-1&#41;&#44; involved in the further recruitment of leucocytes&#44; promoting the impairment of endothelial monolayer integrity and inducing apoptosis and necrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">14&#8211;16</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Calprotectin has been demonstrated to be upregulated in many inflammatory disorders&#44; such as SLE&#44; RA&#44; idiopathic juvenile arthritis&#44; Kawasaki&#39;s disease and AAV&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17&#8211;22</span></a> In patients with active SLE&#44; serum calprotectin levels correlate with disease activity assessed by laboratory and clinical parameters&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> In patients with limited systemic AAV&#44; failure to suppress serum calprotectin whilst on immunosuppressive treatment was associated with subsequent disease relapse&#44; suggesting that calprotectin may be a useful biomarker to predict future flares&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In animal models of autoimmunity&#44; calprotectin and its TLR4 receptor have been implicated in mediating disease&#46; In accelerated NTN&#44; a model of immune mediated glomerulonephritis&#44; wild-type &#40;WT&#41; mice with glomerulonephritis have increased serum levels of S100A8&#47;A9&#44; while mice deficient in S100A9 &#40;S100A9<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#41; or the TLR4 receptor &#40;TLR4<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#41; are significantly protected from disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">23&#44;24</span></a> In a model of autoimmunity in mice overexpressing CD40L&#44; S100A8&#47;S100A9 was critical for the induction of dermatitis and nephritis&#44; as well as the expansion of autoreactive CD8 T-cells&#44; and the development of autoantibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> Together these data suggest that S100A8&#47;A9 blockade could be a promising therapeutic target in human glomerulonephritis including lupus nephritis and ANCA associated glomerulonephritis&#46; In the present study we assessed the efficacy of Paquinimod in the prevention and treatment of murine NTN&#46;</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&#44; induction of accelerated nephrotoxic nephritis &#40;NTN&#41; 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&#47;6 mice were between 8 and 12 weeks of age&#44; and were bred in house&#46; All experiments were performed under the terms of the Animals &#40;Scientific Procedures&#41; Act 1986&#44; 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 &#40;NTS&#41; was generated according to previously published methods&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Disease was induced by pre-immunising mice sub-cutaneously with sheep IgG &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#41; in Complete Freund&#39;s Adjunvant &#40;CFA&#44; Sigma&#41;&#46; Five days later &#40;day 0&#41;&#44; mice were injected intravenously with 200<span class="elsevierStyleHsp" style=""></span>&#956;l of sheep NTS &#40;diluted 1&#58;3 in sterile 0&#46;9&#37; NaCl&#41; and intraperitoneal lipopolysaccharide &#40;LPS&#44; 0&#46;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mouse&#41;&#46; Mice were sacrificed 8 days later&#46; Groups of 7&#8211;10 mice were used per treatment cohort&#46;</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 &#40;from Active Biotech AB&#44; Lund&#44; Sweden&#41; dissolved in drinking water available ad libitum&#44; after assessment of the average daily fluid intake of the mice&#46; In the first experiment&#44; the compound was used at dosage of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day starting at day 0 in the treatment group &#40;10 mice&#58; paquinimod&#41;&#44; while control mice drank normal water &#40;10 mice&#58; controls&#41;&#46; In the second experiment&#44; a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day was used&#44; starting at day 0 &#40;prevention group&#58; PaqP&#44; 7 mice&#41;&#44; or day 2 &#40;therapeutic group&#58; PaqT&#44; 7 mice&#41; or untreated &#40;Control&#44; 7 mice&#41;&#46; Mice were placed in metabolic cages overnight&#44; the day before sacrifice and urine collected&#46;</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&#44; urea&#44; ALT and albumin were measured in the clinical pathology laboratory&#44; Mary Lyon Centre&#44; Medical research Council&#44; Harwell&#46; In all experiments&#44; urine was collected after housing mice in metabolic cages overnight with free access to food and water&#46; Urinary protein was measured by the sulfosalicylic acid method&#46;<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&#44; fixed in formalin and embedded in paraffin for periodic acid-Schiff &#40;PAS&#41; and immunohistochemical staining&#46; Immunoperoxidase staining for mouse calprotectin and macrophages was performed using a rat anti-mouse calprotectin monoclonal antibody &#40;clone 2B10 at 1&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#44; a gift from Prof Nancy Hogg&#41; and a rat anti-mouse MAC2 &#40;at 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41;&#44; respectively&#46; Renal sections were analysed for the percentages of glomerular crescents &#40;0&#8211;100&#37;&#41; and the degree of glomerular thrombosis using a standard scoring system &#40;0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no PAS material&#44; 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#8211;25&#37; of glomerulus affected&#44; 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#8211;50&#37;&#44; 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#8211;75&#37; and 4<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>75&#8211;100&#37;&#41;&#46;</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&#46;0 &#40;GraphPad Software&#44; San Diego&#44; CA&#44; USA&#41;&#46; A Mann&#8211;Whitney test was used when comparing 2 groups&#46; When comparing 3 groups&#44; a one-way ANOVA test was used&#46; Results were considered significant when <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</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&#44; a dose of paquinimod of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day was administered from day 0&#44; based on the previously published data demonstrating efficacy in a lupus mouse model&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> All mice tolerated this dose&#44; with no fatalities&#46; Renal function&#44; assessed by serum urea and creatinine&#44; as well as urinary protein excretion&#44; were not significantly different between Paquinmod-treated &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; and control &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; mice &#40;median serum urea Paquinimod 14&#46;8<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 6&#46;9&#8211;98&#46;0&#41; vs control 8&#46;2<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 5&#46;8&#8211;120&#41;&#59; median serum creatinine Paquinimod treated 36&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 25&#46;6&#8211;76&#46;3&#41; vs control 34&#46;3<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 29&#46;1&#8211;86&#46;6&#41;&#59; median proteinuria in Paquinimod-treated animals 9&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;ml &#40;range 6&#46;3&#8211;14&#46;5&#41; vs controls 6&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;ml &#40;range 1&#46;1&#8211;9&#46;1&#41; &#40;all p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>a&#8211;c&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Similarly&#44; renal histology&#44; revealed no significant differences between the two groups with regards percentages of glomerular crescents &#40;median &#37; crescents paquinimod 8&#37; &#40;range 0&#8211;60&#37;&#41; vs controls 10&#37; &#40;range 0&#8211;44&#41; or thrombosis scores &#40;median thrombosis score Paquinimod 0&#46;53 &#40;range 0&#8211;3&#46;5&#41; vs controls 0&#46;1 &#40;range 0&#8211;2&#46;84&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>d and e&#41;&#46;</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&#44; the dose of Paquinimod was increased to 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#44; based on further published data showing efficacy in the treatment of experimental autoimmune encephalomyelitis&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> After 8 days&#44; 4 mice had died&#59; 2 from the control group&#44; 1 from the prevention group and 1 from the treatment group&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Renal function and proteinuria &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#8211;c&#41; were similar between the three groups&#40;median serum creatinine control 12&#46;1<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 10&#46;4&#8211;13&#46;7&#41; vs Paq P 17&#46;3<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 10&#46;8&#8211;55&#46;7&#41; vs Paq T 16&#46;7<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 15&#46;2&#8211;18&#46;10&#41;&#59; median serum urea control 9&#46;5<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 9&#46;0&#8211;14&#46;1&#41; vs Paq P 35&#46;1<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 10&#46;9&#8211;148&#46;8&#41; vs Paq T 42&#46;7<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 8&#46;1&#8211;77&#46;3&#41;&#59; Renal histological damage was also similar in all three groups with regards percentages of glomerular crescents &#40;median &#37; crescents control 0&#37; &#40;range 0&#8211;20&#41; vs Paq P 4&#37; &#40;range 0&#8211;75&#41; vs Paq T 0&#37; &#40;range 0&#8211;50&#41; and glomerular thrombosis scores median thrombosis score control 0&#46;1 &#40;range 0&#8211;0&#46;49&#41; vs Paq P 0&#46;39 &#40;range 0&#8211;0&#46;97&#41; vs Paq T 0&#46;02 &#40;range 0&#8211;0&#46;22&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>d and e&#41;&#46;</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&#44; we performed an immunoperoxidase staining for calprotectin and macrophages &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a and b&#41; and quantification of these showed a trend for increased glomerular calprotectin expression&#44; and a similar trend in glomerular macrophage numbers&#44; &#40;mean glomerular calprotectin cell expression control 0&#46;22<span class="elsevierStyleHsp" style=""></span>cells&#47;glomerulus &#40;SEM 0&#46;1&#41; vs Paq P 1&#46;25 &#40;SEM 0&#46;6&#41; vs Paq T 0&#46;45 &#40;SEM 0&#46;2&#41;&#59; mean glomerular macrophage number control 2&#46;2<span class="elsevierStyleHsp" style=""></span>cells&#47;glomerulus &#40;SEM 0&#46;1&#41; vs Paq P 3&#46;6 &#40;SEM 1&#46;0&#41; vs Paq T 4&#46;1 &#40;SEM 0&#46;7&#41;&#41;&#46;</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&#44;<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&#44; central nervous system and joint inflammation respectively following the use of prophylactic low and high doses of Paquinimod&#44; a compound that inhibits S100A9 but not S100A8&#44; binding to TLR4&#46; We have previously shown that serum S100A8&#47;A9 levels are elevated during NTN and that S100A9 deficiency significantly attenuates disease&#44; in part by inhibiting release of proinflammatory cytokines and chemokines&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> We found no effect of S100A9 deficiency on glomerular neutrophil recruitment&#44; but noted a significant reduction in glomerular macrophage infiltration&#46; In this report&#44; we show that using the same NTN model&#44; different doses of Paquinimod administered at the time of&#44; or following&#44; disease induction were not efficacious in attenuating disease&#46; We found a non-significant trend of increased glomerular calprotectin expression in those animals given the highest dose of Paquinimod&#44; and a similar trend in the number of glomerular macrophages&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Denoric et al&#46;&#44;<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&#44; but not neutrophils in the omentum or at subcutaneous sites of inflammation&#46; While&#44; in alum-induced inflammation&#44; in which neutrophils were the predominant cell population&#44; Paquinimod failed to reduce the accumulation of inflammatory cells&#46; Therefore our NTN model&#44; which relies on early transient neutrophil recruitment followed by monocyte&#47;macrophage infiltration into the kidney by day 3&#44; may not be easily attenuated by Paquinimod&#46; Another possible explanation for our observations may relate to the findings of Vandal et al&#46;&#44;<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&#46; They found that LPS led to S100A8&#44; S100A9 and S100A8&#47;A9 in the pouch exudates that preceded the neutrophil accumulation&#46; Blocking S100A8 inhibited neutrophil migration 3<span class="elsevierStyleHsp" style=""></span>h after LPS injection&#44; but blocking S100A9 had no significant effect&#46; 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&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition&#44; Paquinimod appears to induce a transient increase in levels of inflammatory markers&#44; such as C-reactive protein &#40;CRP&#41; and erythrocyte sedimentation rate&#44; reported in Paquinimod-treated SLE patients&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> These changes were more evident with higher dosages of Paquinimod &#40;4&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day and 6&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;day compared to 3&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46; Similar increases in inflammatory markers&#44; were also reported in the first weeks of treatment from clinical trials with Laquinimod&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;9</span></a> The mechanisms that cause these changes remain unclear and are being investigated&#44; but if replicated in our NTN model could explain the lack of efficacy observed in a short term animal model&#46; It is noteworthy that the efficacy of Paquinimod in other experimental models have utilised more prolonged time courses compared to ours&#46; Our NTN model may evolve too rapidly to dissect out any transient increase and subsequent reduction in inflammation that may occur with this compound&#44; in contrast to genetic deficiency of S100A9&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; we could not show a benefit from Paquinimod in prevention or treatment of a murine NTN model&#44; despite having previously shown a benefit from complete S100A9 deficiency using the same model&#46; However&#44; due to the transient proinflammatory action of this compound&#44; a murine glomerulonephritis model of longer duration may be necessary to fully test the efficacy of this drug&#44; 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&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors&#8217; 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&#58; performed animal work&#44; participated in the design of the study&#44; performed the statistical analysis and drafted the manuscript&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">RP&#58; performed animal work&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">AS&#58; performed animal work&#44; conceived of the study&#44; and participated in its design and coordination&#46;</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&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">All authors read and approved the final manuscript&#46;</p></span></span>"
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            3 => "SLE"
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            11 => "TLR4<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>"
            12 => "NTS"
            13 => "CFA"
            14 => "LPS"
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      "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&#44; such as paquinimod&#44; which targets the protein S100A9&#44; have demonstrated efficacy in treating autoimmune diseases&#46; S100A9&#44; in association with S100A8&#44; forms the heterodimer S100A8&#47;S100A9&#44; known as calprotectin&#59; that has been shown to be upregulated in numerous inflammatory disorders&#46; We had previously demonstrated protection from glomerular disease in S100A9-deficient mice&#46; The aim of this study was to assess the efficacy of paquinimod in the prevention and treatment of experimental glomerulonephritis&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Nephrotoxic nephritis &#40;NTN&#41; was induced in C57BL&#47;6 mice according to our standard protocol&#46; Mice were treated with different doses of paquinimod either at disease induction &#40;prevention group&#41; or two days following induction &#40;therapeutic group&#41; and sacrificed 8 days following induction&#46; Disease was assessed histologically &#40;number of glomerular crescents&#44; degree of glomerular thrombosis&#44; number of infiltrating leucocytes and calprotectin expression&#41; and biochemically &#40;serum creatinine and urea levels&#44; and urinary levels of protein&#41;&#46;</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 &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; or high &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; doses of paquinimod&#44; given preventatively or therapeutically&#44; led to disease attenuation&#44; as assessed by biochemical or histological parameters&#46; Additionally&#44; we found trends for an increase in renal glomerular calprotectin expression in the high dose groups&#44; suggesting a possible feedback regulation of calprotectin expression&#46;</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&#46; Other models of immune-mediated glomerulonephritis need to be tested to investigate the therapeutic potential of this compound in renal disease&#46;</p></span>"
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          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
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            "titulo" => "Methods"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los compuestos relacionados con la 3-carboxamina-quinolina han demostrado eficacia en el tratamiento de enfermedades autoinmunes&#46; Uno de estos compuestos&#44; el paquinimod&#44; ejerce su funci&#243;n a trav&#233;s del targeting de la prote&#237;na S100A9&#46; La prote&#237;na S100A9&#44; en asociaci&#243;n con S100A8&#44; forma el heterod&#237;mero S100A8&#47;S100A9&#44; conocido como calprotectina&#44; que se ha demostrado que est&#225; elevada en variadas enfermedades inflamatorias&#46; Hab&#237;amos demostrado anteriormente la protecci&#243;n contra la enfermedad glomerular en ratones deficientes de S100A9&#46; El objetivo de este estudio fue evaluar la eficacia de paquinimod en la prevenci&#243;n y el tratamiento de la glomerulonefritis experimental&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La nefritis nefrot&#243;xica &#40;NTN&#41; se indujo en ratones C57BL&#47;6 de acuerdo con el protocolo est&#225;ndar&#46; Los ratones fueron tratados con diferentes dosis de paquinimod en el momento de la inducci&#243;n de la enfermedad &#40;grupo de prevenci&#243;n&#41; o 2 d&#237;as despu&#233;s de la inducci&#243;n &#40;grupo terap&#233;utico&#41;y se sacrificaron 8 d&#237;as despu&#233;s de la inducci&#243;n&#46; La enfermedad se evalu&#243; histol&#243;gicamente &#40;n&#250;mero de semilunas glomerulares&#44; el grado de trombosis glomerular&#44; n&#250;mero de leucocitos infiltrantes y de expresi&#243;n de calprotectina&#41; y bioqu&#237;mico &#40;niveles s&#233;ricos de creatinina y urea&#44; y los niveles urinarios de prote&#237;nas&#41;&#46;</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 &#40;0&#44;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; o altas &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; dosis de paquinimod&#44; administrados preventiva o terap&#233;uticamente&#44; resultaron en la atenuaci&#243;n de la enfermedad&#44;seg&#250;n los par&#225;metros bioqu&#237;micos o histol&#243;gicos&#46; Adem&#225;s&#44; encontramos una tendencia al aumento en la expresi&#243;n renal de la calprotectina glomerular en los grupos con dosis altas&#44; lo que indica una posible regulaci&#243;n de la retroalimentaci&#243;n de la expresi&#243;n de calprotectina&#46;</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 &#233;xito la NTN en los ratones&#46; Otros modelos de glomerulonefritis inmunomediadas necesitan ser testados para investigar el potencial terap&#233;utico de este compuesto en la enfermedad renal&#46;</p></span>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by &#40;a&#41; serum creatinine and &#40;b&#41; urea and &#40;c&#41; urinary protein excretion in control and Paquinimod-treated animals&#59; Renal histology assessed by &#40;d&#41; percentage glomerular crescents and &#40;e&#41; glomerular thrombosis score in control and Paquinimod-treated animals&#46; Medians shown&#46; Paquinimod was administered at a dosage of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by &#40;a&#41; serum creatinine and &#40;b&#41; urea and &#40;c&#41; urinary protein excretion in controls and animals treated with Paquinimod prophylactically &#40;Paq-P&#41;or therapeutically &#40;Paq-T&#41;&#59; Renal histology assessed by &#40;d&#41; percentage glomerular crescents and &#40;e&#41; glomerular thrombosis score in control and Paquinimod-treated animals&#46; Medians shown&#46; Paquinimod was administered at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#46;</p>"
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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
Juliana Draibea,b,
Autor para correspondencia
, Ruth J. Pepperb, Alan D. Salamab
a Hospital de Bellvitge, Barcelona, Spain
b UCL Centre for Nephrology, Royal Free Hospital, London, UK
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    "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&#44; compounds that have demonstrated efficacy in treating autoimmune diseases in both humans and mice&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1&#8211;5</span></a> Linomide&#44; the first compound of this class&#44; was effective in treatment of multiple sclerosis &#40;MS&#41; in phase II studies&#59; however&#44; cardiovascular toxicity during phase III studies led to premature trial termination&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;7</span></a> Subsequently&#44; two new compounds with improved safety profiles and increased potency were investigated&#46; The first&#44; Laquinimod exhibited clinical efficacy as well as favourable safety in MS patients<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#8211;10</span></a> and is still being investigated for the treatment of MS&#46; The second&#44; Paquinimod effectively inhibited disease in experimental lupus prone mice&#44; and was well tolerated &#40;in doses up to 3<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; in SLE patients with low disease activity&#44; however&#44; at higher doses &#40;up to 6<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; systemic adverse effects consisting of myalgias and arthralgias were reported&#46; In addition&#44; transient increases in inflammatory cells and acute phase reactants were seen at all doses&#44; but most marked at the higher dose range&#46;<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&#44; disrupting binding of this protein to one of its receptors&#44; TLR-4 but not to the advanced glycosylation end product-specific receptor &#40;RAGE&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> In association with S100A8&#44; S100A9 forms the heterodimer S100A8&#47;S100A9&#44; termed calprotectin&#46; Calprotectin is found abundantly in neutrophils&#44; monocytes and early differentiated macrophages and is involved in calcium-dependent signalling&#44; cell differentiation&#44; cell cycle progression and cytoskeleton-membrane interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> Upon phagocyte activation with the inflamed endothelium&#44; calprotectin is secreted&#44; binds to endothelial cells stimulating the secretion of pro-inflammatory cytokines such as interleukin-8 &#40;IL8&#41; and increasing the expression of Intercellular adhesion molecule 1&#40;ICAM-1&#41;&#44; involved in the further recruitment of leucocytes&#44; promoting the impairment of endothelial monolayer integrity and inducing apoptosis and necrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">14&#8211;16</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Calprotectin has been demonstrated to be upregulated in many inflammatory disorders&#44; such as SLE&#44; RA&#44; idiopathic juvenile arthritis&#44; Kawasaki&#39;s disease and AAV&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17&#8211;22</span></a> In patients with active SLE&#44; serum calprotectin levels correlate with disease activity assessed by laboratory and clinical parameters&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> In patients with limited systemic AAV&#44; failure to suppress serum calprotectin whilst on immunosuppressive treatment was associated with subsequent disease relapse&#44; suggesting that calprotectin may be a useful biomarker to predict future flares&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In animal models of autoimmunity&#44; calprotectin and its TLR4 receptor have been implicated in mediating disease&#46; In accelerated NTN&#44; a model of immune mediated glomerulonephritis&#44; wild-type &#40;WT&#41; mice with glomerulonephritis have increased serum levels of S100A8&#47;A9&#44; while mice deficient in S100A9 &#40;S100A9<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#41; or the TLR4 receptor &#40;TLR4<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#41; are significantly protected from disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">23&#44;24</span></a> In a model of autoimmunity in mice overexpressing CD40L&#44; S100A8&#47;S100A9 was critical for the induction of dermatitis and nephritis&#44; as well as the expansion of autoreactive CD8 T-cells&#44; and the development of autoantibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> Together these data suggest that S100A8&#47;A9 blockade could be a promising therapeutic target in human glomerulonephritis including lupus nephritis and ANCA associated glomerulonephritis&#46; In the present study we assessed the efficacy of Paquinimod in the prevention and treatment of murine NTN&#46;</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&#44; induction of accelerated nephrotoxic nephritis &#40;NTN&#41; 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&#47;6 mice were between 8 and 12 weeks of age&#44; and were bred in house&#46; All experiments were performed under the terms of the Animals &#40;Scientific Procedures&#41; Act 1986&#44; 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 &#40;NTS&#41; was generated according to previously published methods&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Disease was induced by pre-immunising mice sub-cutaneously with sheep IgG &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#41; in Complete Freund&#39;s Adjunvant &#40;CFA&#44; Sigma&#41;&#46; Five days later &#40;day 0&#41;&#44; mice were injected intravenously with 200<span class="elsevierStyleHsp" style=""></span>&#956;l of sheep NTS &#40;diluted 1&#58;3 in sterile 0&#46;9&#37; NaCl&#41; and intraperitoneal lipopolysaccharide &#40;LPS&#44; 0&#46;1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mouse&#41;&#46; Mice were sacrificed 8 days later&#46; Groups of 7&#8211;10 mice were used per treatment cohort&#46;</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 &#40;from Active Biotech AB&#44; Lund&#44; Sweden&#41; dissolved in drinking water available ad libitum&#44; after assessment of the average daily fluid intake of the mice&#46; In the first experiment&#44; the compound was used at dosage of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day starting at day 0 in the treatment group &#40;10 mice&#58; paquinimod&#41;&#44; while control mice drank normal water &#40;10 mice&#58; controls&#41;&#46; In the second experiment&#44; a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day was used&#44; starting at day 0 &#40;prevention group&#58; PaqP&#44; 7 mice&#41;&#44; or day 2 &#40;therapeutic group&#58; PaqT&#44; 7 mice&#41; or untreated &#40;Control&#44; 7 mice&#41;&#46; Mice were placed in metabolic cages overnight&#44; the day before sacrifice and urine collected&#46;</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&#44; urea&#44; ALT and albumin were measured in the clinical pathology laboratory&#44; Mary Lyon Centre&#44; Medical research Council&#44; Harwell&#46; In all experiments&#44; urine was collected after housing mice in metabolic cages overnight with free access to food and water&#46; Urinary protein was measured by the sulfosalicylic acid method&#46;<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&#44; fixed in formalin and embedded in paraffin for periodic acid-Schiff &#40;PAS&#41; and immunohistochemical staining&#46; Immunoperoxidase staining for mouse calprotectin and macrophages was performed using a rat anti-mouse calprotectin monoclonal antibody &#40;clone 2B10 at 1&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#44; a gift from Prof Nancy Hogg&#41; and a rat anti-mouse MAC2 &#40;at 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41;&#44; respectively&#46; Renal sections were analysed for the percentages of glomerular crescents &#40;0&#8211;100&#37;&#41; and the degree of glomerular thrombosis using a standard scoring system &#40;0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no PAS material&#44; 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#8211;25&#37; of glomerulus affected&#44; 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#8211;50&#37;&#44; 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#8211;75&#37; and 4<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>75&#8211;100&#37;&#41;&#46;</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&#46;0 &#40;GraphPad Software&#44; San Diego&#44; CA&#44; USA&#41;&#46; A Mann&#8211;Whitney test was used when comparing 2 groups&#46; When comparing 3 groups&#44; a one-way ANOVA test was used&#46; Results were considered significant when <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</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&#44; a dose of paquinimod of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day was administered from day 0&#44; based on the previously published data demonstrating efficacy in a lupus mouse model&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> All mice tolerated this dose&#44; with no fatalities&#46; Renal function&#44; assessed by serum urea and creatinine&#44; as well as urinary protein excretion&#44; were not significantly different between Paquinmod-treated &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; and control &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; mice &#40;median serum urea Paquinimod 14&#46;8<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 6&#46;9&#8211;98&#46;0&#41; vs control 8&#46;2<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 5&#46;8&#8211;120&#41;&#59; median serum creatinine Paquinimod treated 36&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 25&#46;6&#8211;76&#46;3&#41; vs control 34&#46;3<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 29&#46;1&#8211;86&#46;6&#41;&#59; median proteinuria in Paquinimod-treated animals 9&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;ml &#40;range 6&#46;3&#8211;14&#46;5&#41; vs controls 6&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;ml &#40;range 1&#46;1&#8211;9&#46;1&#41; &#40;all p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>a&#8211;c&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Similarly&#44; renal histology&#44; revealed no significant differences between the two groups with regards percentages of glomerular crescents &#40;median &#37; crescents paquinimod 8&#37; &#40;range 0&#8211;60&#37;&#41; vs controls 10&#37; &#40;range 0&#8211;44&#41; or thrombosis scores &#40;median thrombosis score Paquinimod 0&#46;53 &#40;range 0&#8211;3&#46;5&#41; vs controls 0&#46;1 &#40;range 0&#8211;2&#46;84&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>d and e&#41;&#46;</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&#44; the dose of Paquinimod was increased to 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#44; based on further published data showing efficacy in the treatment of experimental autoimmune encephalomyelitis&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> After 8 days&#44; 4 mice had died&#59; 2 from the control group&#44; 1 from the prevention group and 1 from the treatment group&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Renal function and proteinuria &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#8211;c&#41; were similar between the three groups&#40;median serum creatinine control 12&#46;1<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 10&#46;4&#8211;13&#46;7&#41; vs Paq P 17&#46;3<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 10&#46;8&#8211;55&#46;7&#41; vs Paq T 16&#46;7<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;range 15&#46;2&#8211;18&#46;10&#41;&#59; median serum urea control 9&#46;5<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 9&#46;0&#8211;14&#46;1&#41; vs Paq P 35&#46;1<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 10&#46;9&#8211;148&#46;8&#41; vs Paq T 42&#46;7<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;range 8&#46;1&#8211;77&#46;3&#41;&#59; Renal histological damage was also similar in all three groups with regards percentages of glomerular crescents &#40;median &#37; crescents control 0&#37; &#40;range 0&#8211;20&#41; vs Paq P 4&#37; &#40;range 0&#8211;75&#41; vs Paq T 0&#37; &#40;range 0&#8211;50&#41; and glomerular thrombosis scores median thrombosis score control 0&#46;1 &#40;range 0&#8211;0&#46;49&#41; vs Paq P 0&#46;39 &#40;range 0&#8211;0&#46;97&#41; vs Paq T 0&#46;02 &#40;range 0&#8211;0&#46;22&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>d and e&#41;&#46;</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&#44; we performed an immunoperoxidase staining for calprotectin and macrophages &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a and b&#41; and quantification of these showed a trend for increased glomerular calprotectin expression&#44; and a similar trend in glomerular macrophage numbers&#44; &#40;mean glomerular calprotectin cell expression control 0&#46;22<span class="elsevierStyleHsp" style=""></span>cells&#47;glomerulus &#40;SEM 0&#46;1&#41; vs Paq P 1&#46;25 &#40;SEM 0&#46;6&#41; vs Paq T 0&#46;45 &#40;SEM 0&#46;2&#41;&#59; mean glomerular macrophage number control 2&#46;2<span class="elsevierStyleHsp" style=""></span>cells&#47;glomerulus &#40;SEM 0&#46;1&#41; vs Paq P 3&#46;6 &#40;SEM 1&#46;0&#41; vs Paq T 4&#46;1 &#40;SEM 0&#46;7&#41;&#41;&#46;</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&#44;<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&#44; central nervous system and joint inflammation respectively following the use of prophylactic low and high doses of Paquinimod&#44; a compound that inhibits S100A9 but not S100A8&#44; binding to TLR4&#46; We have previously shown that serum S100A8&#47;A9 levels are elevated during NTN and that S100A9 deficiency significantly attenuates disease&#44; in part by inhibiting release of proinflammatory cytokines and chemokines&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> We found no effect of S100A9 deficiency on glomerular neutrophil recruitment&#44; but noted a significant reduction in glomerular macrophage infiltration&#46; In this report&#44; we show that using the same NTN model&#44; different doses of Paquinimod administered at the time of&#44; or following&#44; disease induction were not efficacious in attenuating disease&#46; We found a non-significant trend of increased glomerular calprotectin expression in those animals given the highest dose of Paquinimod&#44; and a similar trend in the number of glomerular macrophages&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Denoric et al&#46;&#44;<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&#44; but not neutrophils in the omentum or at subcutaneous sites of inflammation&#46; While&#44; in alum-induced inflammation&#44; in which neutrophils were the predominant cell population&#44; Paquinimod failed to reduce the accumulation of inflammatory cells&#46; Therefore our NTN model&#44; which relies on early transient neutrophil recruitment followed by monocyte&#47;macrophage infiltration into the kidney by day 3&#44; may not be easily attenuated by Paquinimod&#46; Another possible explanation for our observations may relate to the findings of Vandal et al&#46;&#44;<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&#46; They found that LPS led to S100A8&#44; S100A9 and S100A8&#47;A9 in the pouch exudates that preceded the neutrophil accumulation&#46; Blocking S100A8 inhibited neutrophil migration 3<span class="elsevierStyleHsp" style=""></span>h after LPS injection&#44; but blocking S100A9 had no significant effect&#46; 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&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition&#44; Paquinimod appears to induce a transient increase in levels of inflammatory markers&#44; such as C-reactive protein &#40;CRP&#41; and erythrocyte sedimentation rate&#44; reported in Paquinimod-treated SLE patients&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> These changes were more evident with higher dosages of Paquinimod &#40;4&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day and 6&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;day compared to 3&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46; Similar increases in inflammatory markers&#44; were also reported in the first weeks of treatment from clinical trials with Laquinimod&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;9</span></a> The mechanisms that cause these changes remain unclear and are being investigated&#44; but if replicated in our NTN model could explain the lack of efficacy observed in a short term animal model&#46; It is noteworthy that the efficacy of Paquinimod in other experimental models have utilised more prolonged time courses compared to ours&#46; Our NTN model may evolve too rapidly to dissect out any transient increase and subsequent reduction in inflammation that may occur with this compound&#44; in contrast to genetic deficiency of S100A9&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; we could not show a benefit from Paquinimod in prevention or treatment of a murine NTN model&#44; despite having previously shown a benefit from complete S100A9 deficiency using the same model&#46; However&#44; due to the transient proinflammatory action of this compound&#44; a murine glomerulonephritis model of longer duration may be necessary to fully test the efficacy of this drug&#44; 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&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors&#8217; 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&#58; performed animal work&#44; participated in the design of the study&#44; performed the statistical analysis and drafted the manuscript&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">RP&#58; performed animal work&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">AS&#58; performed animal work&#44; conceived of the study&#44; and participated in its design and coordination&#46;</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&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">All authors read and approved the final manuscript&#46;</p></span></span>"
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              "titulo" => "High-dose prevention and treatment Paquinimod therapy"
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          ]
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          "identificador" => "sec0065"
          "titulo" => "Discussion"
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        9 => array:2 [
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          "titulo" => "Conclusions"
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          "identificador" => "sec0075"
          "titulo" => "Authors&#8217; contribution"
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          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2015-11-26"
    "fechaAceptado" => "2016-03-16"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:4 [
            0 => "Glomerulonephritis"
            1 => "Animal model"
            2 => "Calprotectin"
            3 => "Paquinimod"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec763368"
          "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">&#8722;&#47;&#8722;</span>"
            11 => "TLR4<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>"
            12 => "NTS"
            13 => "CFA"
            14 => "LPS"
            15 => "PaqP"
            16 => "PaqT"
            17 => "PAS"
            18 => "CPR"
          ]
        ]
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Glomerulonefritis"
            1 => "Modelo animal"
            2 => "Calprotectina"
            3 => "Paquinimod"
          ]
        ]
      ]
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    "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&#44; such as paquinimod&#44; which targets the protein S100A9&#44; have demonstrated efficacy in treating autoimmune diseases&#46; S100A9&#44; in association with S100A8&#44; forms the heterodimer S100A8&#47;S100A9&#44; known as calprotectin&#59; that has been shown to be upregulated in numerous inflammatory disorders&#46; We had previously demonstrated protection from glomerular disease in S100A9-deficient mice&#46; The aim of this study was to assess the efficacy of paquinimod in the prevention and treatment of experimental glomerulonephritis&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Nephrotoxic nephritis &#40;NTN&#41; was induced in C57BL&#47;6 mice according to our standard protocol&#46; Mice were treated with different doses of paquinimod either at disease induction &#40;prevention group&#41; or two days following induction &#40;therapeutic group&#41; and sacrificed 8 days following induction&#46; Disease was assessed histologically &#40;number of glomerular crescents&#44; degree of glomerular thrombosis&#44; number of infiltrating leucocytes and calprotectin expression&#41; and biochemically &#40;serum creatinine and urea levels&#44; and urinary levels of protein&#41;&#46;</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 &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; or high &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; doses of paquinimod&#44; given preventatively or therapeutically&#44; led to disease attenuation&#44; as assessed by biochemical or histological parameters&#46; Additionally&#44; we found trends for an increase in renal glomerular calprotectin expression in the high dose groups&#44; suggesting a possible feedback regulation of calprotectin expression&#46;</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&#46; Other models of immune-mediated glomerulonephritis need to be tested to investigate the therapeutic potential of this compound in renal disease&#46;</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"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los compuestos relacionados con la 3-carboxamina-quinolina han demostrado eficacia en el tratamiento de enfermedades autoinmunes&#46; Uno de estos compuestos&#44; el paquinimod&#44; ejerce su funci&#243;n a trav&#233;s del targeting de la prote&#237;na S100A9&#46; La prote&#237;na S100A9&#44; en asociaci&#243;n con S100A8&#44; forma el heterod&#237;mero S100A8&#47;S100A9&#44; conocido como calprotectina&#44; que se ha demostrado que est&#225; elevada en variadas enfermedades inflamatorias&#46; Hab&#237;amos demostrado anteriormente la protecci&#243;n contra la enfermedad glomerular en ratones deficientes de S100A9&#46; El objetivo de este estudio fue evaluar la eficacia de paquinimod en la prevenci&#243;n y el tratamiento de la glomerulonefritis experimental&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La nefritis nefrot&#243;xica &#40;NTN&#41; se indujo en ratones C57BL&#47;6 de acuerdo con el protocolo est&#225;ndar&#46; Los ratones fueron tratados con diferentes dosis de paquinimod en el momento de la inducci&#243;n de la enfermedad &#40;grupo de prevenci&#243;n&#41; o 2 d&#237;as despu&#233;s de la inducci&#243;n &#40;grupo terap&#233;utico&#41;y se sacrificaron 8 d&#237;as despu&#233;s de la inducci&#243;n&#46; La enfermedad se evalu&#243; histol&#243;gicamente &#40;n&#250;mero de semilunas glomerulares&#44; el grado de trombosis glomerular&#44; n&#250;mero de leucocitos infiltrantes y de expresi&#243;n de calprotectina&#41; y bioqu&#237;mico &#40;niveles s&#233;ricos de creatinina y urea&#44; y los niveles urinarios de prote&#237;nas&#41;&#46;</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 &#40;0&#44;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; o altas &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; dosis de paquinimod&#44; administrados preventiva o terap&#233;uticamente&#44; resultaron en la atenuaci&#243;n de la enfermedad&#44;seg&#250;n los par&#225;metros bioqu&#237;micos o histol&#243;gicos&#46; Adem&#225;s&#44; encontramos una tendencia al aumento en la expresi&#243;n renal de la calprotectina glomerular en los grupos con dosis altas&#44; lo que indica una posible regulaci&#243;n de la retroalimentaci&#243;n de la expresi&#243;n de calprotectina&#46;</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 &#233;xito la NTN en los ratones&#46; Otros modelos de glomerulonefritis inmunomediadas necesitan ser testados para investigar el potencial terap&#233;utico de este compuesto en la enfermedad renal&#46;</p></span>"
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            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by &#40;a&#41; serum creatinine and &#40;b&#41; urea and &#40;c&#41; urinary protein excretion in control and Paquinimod-treated animals&#59; Renal histology assessed by &#40;d&#41; percentage glomerular crescents and &#40;e&#41; glomerular thrombosis score in control and Paquinimod-treated animals&#46; Medians shown&#46; Paquinimod was administered at a dosage of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Renal function assessed by &#40;a&#41; serum creatinine and &#40;b&#41; urea and &#40;c&#41; urinary protein excretion in controls and animals treated with Paquinimod prophylactically &#40;Paq-P&#41;or therapeutically &#40;Paq-T&#41;&#59; Renal histology assessed by &#40;d&#41; percentage glomerular crescents and &#40;e&#41; glomerular thrombosis score in control and Paquinimod-treated animals&#46; Medians shown&#46; Paquinimod was administered at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day&#46;</p>"
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                      "titulo" => "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis&#58; a multicentre&#44; randomised&#44; double-blind&#44; placebo-controlled phase IIb study"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Comi"
                            1 => "A&#46; Pulizzi"
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                        0 => array:2 [
                          "etal" => true
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                            0 => "C&#46; Polman"
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                      ]
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                  ]
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