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Toll-like receptor signaling pathway involved in pathogenesis of thromboangiitis obliterans through activating of NF-κB
Facai Guoa, Yan Bib, Jiangyan Yinc, Yi Guod,
Corresponding author
guoyi429@163.com

Corresponding author.
a Department of Vascular Surgery, Lanzhou University Second Hospital, Gansu, China
b Department of Laboratory Medicine Center, Lanzhou University Second Hospital, Gansu, China
c Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
d Department of General Surgery, Chongqing University Central Hospital (Chongqing Emergency Medical Center), Chongqing, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Background</span><p id="para0009" class="elsevierStylePara elsevierViewall">Thromboangiitis obliterans &#40;TAO&#41;&#44; also known as Buerger&#39;s disease&#44; was first described in 1908 by Buerger&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> It is a non-atherosclerotic inflammatory disorder of unknown etiology and can affect small and medium-sized arteries and veins in the upper and lower extremities&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Although the inflammatory reactions of vasal intima have been shown in patients with TAO&#44; the pathogenesis of TAO is still not explained exactly&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Additionally&#44; it is generally accepted that autoimmune inflammation is an ultimate pathogenic factor of TAO&#44;<a class="elsevierStyleCrossRefs" href="#bib0001"><span class="elsevierStyleSup">1&#8211;3</span></a> but the action mechanism of autoimmune inflammation in patients with TAO remains unknown&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">Toll-like receptor signaling pathways &#40;TLRs&#41; are one of the most deeply researched signaling pathways related to inflammatory diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0004"><span class="elsevierStyleSup">4&#8211;6</span></a> TLRs are one kind of protein molecule involved in nonspecific immunity and it is also a bridge between nonspecific immunity and specific immunity&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> As public data described&#44; TLRs can be triggered via two signaling pathways&#44; named Myeloid Differentiation factor 88 &#40;MyD88&#41; dependent signaling pathway and MyD88 independent signaling pathway &#40;also known as TRIF signaling pathway&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Interestingly&#44; both two signaling pathways may work by activating the downstream NF-&#954;B signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> However&#44; whether TLRs&#47;MyD88&#40;TRIF&#41;&#47;NF-&#954;B signaling pathways are involved in the pathogenesis of TAO is still elusive&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">In the present study&#44; the authors ascertained the protein levels of MyD88&#44; TRIF and NF-&#954;B in the vascular walls of TAO patients and determined the subcellular localization of MyD88&#44; TRIF and NF-&#954;B in the vascular walls of TAO patients&#46; These findings preliminarily uncovered that TLRs&#47;MyD88&#40;TRIF&#41;&#47;NF-&#954;B signaling pathways are involved in the pathogenesis of TAO&#44; which may provide more therapeutic targets for TAO patients&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and method</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Patients and sample collection</span><p id="para0012" class="elsevierStylePara elsevierViewall">From January 2015 to December 2019&#44; a total of 46 patients with TAO were admitted to the first affiliated hospital of Chongqing Medical University and affiliated central hospital of Chongqing University&#46; TAO was diagnosed via color Doppler flow imaging instrument&#44; manifesting as peripheral arterial ischemia to varying degrees&#46; The inclusion criteria of TAO patients were&#58; i&#41; History of smoking&#59; ii&#41; Age less than 50-years old&#59; iii&#41; Occlusion on infrapopliteal&#47;upper extremity artery and&#47;or wandering phlebitis engagement&#46; Patients with hepatorenal dysfunction&#44; proximal limb arterial embolism&#44; atherosclerosis&#44; hematological system diseases and other autoimmune diseases were excluded&#46; Additionally&#44; 32 individuals served as the controls&#46; Patients with hypertension&#44; hyperlipidemia and other cardiovascular and cerebrovascular organic diseases were excluded&#46; The clinical characteristics of the patients are reported in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46; The vascular tissues were obtained via surgery and stored at -80&#176;C for succeeding experiments&#46; The study protocols were approved by the research ethics and scientific committee of the first affiliated hospital of Chongqing Medical University and the affiliated central hospital of Chongqing University&#44; and all subjects gave informed consent&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Western blot assays</span><p id="para0013" class="elsevierStylePara elsevierViewall">Vascular tissues were lysed in RIPA buffer containing 50 mM Tris&#8211;HCl&#44; 150 mM NaCl&#44; 1&#37; NP-40&#44; 0&#46;1&#37; SDS&#44; 0&#46;5&#37; sodium deoxycholate&#44; 2 Mm sodium fluoride&#44; 2 mM Na<span class="elsevierStyleInf">3</span>VO4<span class="elsevierStyleInf">2</span>&#44; 1 mM EDTA&#44; and 1 mM EGTA&#44; and then analyzed by western blotting as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> In brief&#44; samples &#40;20 &#181;g of total protein or 1 mg of total cell proteins&#41; were loaded onto SDS-PAGE gels &#40;Invitrogen&#41; and separated by size using electrophoresis&#46; Proteins were then transferred to PVDF membranes for 1h&#46; The membranes were then blocked for 1h with 5&#37; non-fat milk&#46; Membranes were incubated with primary antibodies against MyD88 &#40;Abcam biotechnology&#44; inc&#44; USA&#59; 1&#58;500 dilution&#41;&#44; TRIF &#40;Abcam&#59; 1&#58;500 dilution&#41; and NF-&#954;B &#40;Abcam&#59; 1&#58;500 dilution&#41; at 4&#176;C overnight&#46; After incubation with horseradish peroxidase-conjugated secondary antibody &#40;1&#58;1000 dilution&#41; for 3h at 37&#176;C&#46; Proteins were detected by ECL chemiluminescence and analyzed by densitometry with image software&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Immunofluorescent assay</span><p id="para0014" class="elsevierStylePara elsevierViewall">Frozen tissues were fixed with 4&#37; paraformaldehyde for 24h and then cut into 20-&#956;m-thick sections&#46; Sections were incubated by mouse anti-MyD88&#47;TRIF&#47;NF-&#954;B &#40;Abcam&#59; 1&#58;100 dilution&#41;&#44; mouse anti-&#945;-SMA &#40;a vascular smooth muscle cell marker&#59; Abcam&#59; 1&#58;250 dilution&#41; and mouse anti-CD31 &#40;a vascular endothelial cell marker&#59; Abcam&#59; 1&#58;250 dilution&#41; primary antibodies at 4&#176;C overnight&#46; Then&#44; the slices were incubated with an anti-mouse secondary antibody &#40;1&#58;100 dilution&#41; at 25&#176;C for 60 min&#44; followed by adding freshly prepared 0&#46;02&#37; diaminobenzidine for 5 min&#46; Tissue sections were observed and photographed under a laser confocal microscope&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Statistical analysis</span><p id="para0015" class="elsevierStylePara elsevierViewall">Statistical Package for the Social Science software &#40;version 19&#46;0&#59; SPSS Concepts&#41; was used for the data analysis&#46; Measurement data were expressed as mean &#177; SD and statistically evaluated by independent-samples t-test&#59; <span class="elsevierStyleItalic">p</span> &#60; 0&#46;05 was considered to indicate a statistically significant difference&#46;</p></span></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Result</span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Protein expressions of MyD88&#44; TRIF and NF-&#954;B in vascular tissues of two groups</span><p id="para0016" class="elsevierStylePara elsevierViewall">The authors found that the protein levels of MyD88 &#40;0&#46;763 &#177; 0&#46;041&#41;&#44; TRIF &#40;0&#46;806 &#177; 0&#46;015&#41; and NF-&#954;B &#40;0&#46;785 &#177; 0&#46;032&#41; in TAO group were dramatically elevated compared to those in the control group &#40;MyD88 &#91;0&#46;188 &#177; 0&#46;021&#93;&#44; TRIF &#91;0&#46;162 &#177; 0&#46;017&#93; and NF-&#922;b &#91;0&#46;175 &#177; 0&#46;011&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41; &#40;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Subcellular localization of MyD88 and TRIF in vascular tissues of TAO group</span><p id="para0017" class="elsevierStylePara elsevierViewall">The subcellular localization of MyD88 and TRIF in vascular tissues of TAO patients were then ascertained&#46; The authors found that MyD88 was mainly located in vascular endothelial cells &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41; and vascular smooth muscle cells &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>&#41;&#46; Meanwhile&#44; TRIF was observed to be located in vascular smooth muscle cells &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia><elsevierMultimedia ident="fig0003"></elsevierMultimedia><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Subcellular localization of NF-&#954;B in vascular tissues of TAO group</span><p id="para0018" class="elsevierStylePara elsevierViewall">For further detection of the subcellular localization of NF-&#954;B in vascular tissues of TAO group&#44; the immunofluorescent assay was used&#46; The results showed that NF-&#954;B protein &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>-b&#44; green&#41; and vascular endothelial cell marker CD31 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>-c&#44; red&#41; were co-expressed evidently &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>-d&#44; yellow&#41;&#46; Also&#44; the results showed that NF-&#954;B protein &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>-b&#44; green&#41; and vascular smooth muscle marker SMA &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>-c&#44; red&#41; were co-expressed evidently &#40;<a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>-d&#44; yellow&#41;&#46; These results implied that NF-&#954;B was also located in vascular endothelial cells and vascular smooth muscle cells&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Discussion</span><p id="para0019" class="elsevierStylePara elsevierViewall">More than 100 years have passed as the first description of TAO&#44; but the pathogenesis of TAO is still unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> Previous studies have indicated that tobacco-induced autoimmune inflammation is closely related to the pathogenesis of TAO <a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a>&#44; but the mechanisms of occurrence and development of autoimmune inflammation are still ambiguous&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> It is acknowledged that autoimmune inflammation is a complex molecular biological process involving multiple inflammatory pathways&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">15&#8211;17</span></a> Interestingly&#44; public data showed that the TLRs signaling pathway&#44; acting as a widespread innate immune pathway&#44; can activate signaling pathways that result in immune responses and autoimmune inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> However&#44; whether TLRs is involved in the onset and progression of TAO is still not determined&#46; In the current study&#44; the authors preliminarily detected the expression and subcellular localization of TLRs-related signaling pathways in vascular tissues of patients with TAO patients&#44; namely MyD88&#44; TRIF and NF-&#954;B&#46;</p><p id="para0020" class="elsevierStylePara elsevierViewall">As illustrated in many research&#44; stimulation of TLRs triggers the activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent &#40;TRIF-dependent&#41; signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> Both of these two pathways are strongly related to innate and adaptive immune responses that are the potential predisposing factors for autoimmune inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> It is generally accepted that TLRs play an important role in many autoimmune inflammation diseases&#44; such as systemic lupus erythematosus&#44; rheumatoid arthritis&#44; systemic sclerosis&#44; and Sjogren&#39;s syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0024"><span class="elsevierStyleSup">24&#8211;26</span></a> TAO is an autoimmune inflammation disease with an unexplained mechanism&#44; the authors speculated it may be also associated with TLRs&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> In this study&#44; the authors found that the expression of MyD88 and TRIF was much higher in patients with TAO&#46; Meanwhile&#44; the results of subcellular localization showed that MyD88 was mainly located in vascular endothelial cells and vascular smooth muscle cells&#44; while TRIF was observed to be located in vascular smooth muscle cells&#46; According to the dates&#44; the authors found that the main inflammatory injuries of TAO were located at vascular endothelial cells and vascular smooth muscle cells&#46; Also&#44; higher expressions of MyD88 and TRIF in those cells indicated that activation of TLRs signaling pathway might participate in the pathogenesis and progression of TAO&#46;</p><p id="para0021" class="elsevierStylePara elsevierViewall">For further determination of the relationships between TLRs and TAO&#44; the expression of NF-&#954;B&#44; an important downstream transcription factor of TLRs was detected&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> NF-&#954;B signaling pathway as a primary inflammatory pathway has been widely confirmed to participate in many autoimmune inflammation diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> including TAO&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Many inflammatory processes can be initiated by NF-&#954;B signaling pathways such as angiospasm&#44; inflammatory cell infiltration&#44; and thrombosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0032"><span class="elsevierStyleSup">32&#8211;34</span></a> Interestingly&#44; all of those inflammatory processes were considered important pathophysiological changes to be involved in the progression of TAO&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a><a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> In the present study&#44; the authors found that the expression of NF-&#954;B was much higher in patients with TAO compared to that of control individuals&#46; At the same time&#44; NF-&#954;B was mainly located in the nucleus and cytoplasm of vascular endothelial cells and vascular smooth muscle cells&#46; The results evidenced that the activation of NF-&#954;B signaling pathway may have participated in the pathogenesis of TAO&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">Some limitations have also existed in this study&#46; First&#44; the NF-&#954;B signaling pathway can promote inflammatory cell infiltration by activation of intercellular adhesion molecule-1&#44; vascular cell adhesion molecule-1&#44; and inflammatory factors&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a><a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> Second&#44; NF-&#954;B signaling pathway may also promote thrombosis and vascular inflammation by accelerating the production of anti-neutrophil cytoplasmic antibodies&#44; anticardiolipin antibodies&#44; and other immune-related antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> The authors will elucidate these issues in the future&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Conclusion</span><p id="para0023" class="elsevierStylePara elsevierViewall">In a word&#44; the current study uncovers the high expression of MyD88&#44; TRIF and NF-&#954;B in the vascular wall of patients with TAO&#44; indicating that the activation of TLRs&#47;MyD88&#47;NF-&#954;B and TLRs&#47;TRIF&#47;NF-&#954;B signaling pathways may promote the progression of TAO by induction of vascular inflammation&#46; These findings preliminarily evidenced that targeted therapy for the TLRs signaling pathway may be a potential therapeutic target for TAO&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "titulo" => "Background"
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        4 => array:3 [
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          "titulo" => "Materials and method"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "Patients and sample collection"
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            1 => array:2 [
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              "titulo" => "Western blot assays"
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              "titulo" => "Immunofluorescent assay"
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          "titulo" => "Result"
          "secciones" => array:3 [
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              "identificador" => "sec0008"
              "titulo" => "Protein expressions of MyD88&#44; TRIF and NF-&#954;B in vascular tissues of two groups"
            ]
            1 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Subcellular localization of MyD88 and TRIF in vascular tissues of TAO group"
            ]
            2 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Subcellular localization of NF-&#954;B in vascular tissues of TAO group"
            ]
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        6 => array:2 [
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          "titulo" => "Discussion"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2023-05-08"
    "fechaAceptado" => "2024-04-01"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1903307"
          "palabras" => array:6 [
            0 => "Thromboangiitis obliterans"
            1 => "TLR signaling pathway"
            2 => "MyD88"
            3 => "TRIF"
            4 => "NF-&#954;B"
            5 => "Pathogenic mechanism"
          ]
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">The pathogenic mechanisms of Thromboangiitis Obliterans &#40;TAO&#41; are not entirely known and autoimmune inflammation plays a vital role in the initiation and continuance of TAO activity&#46; The authors investigated in this study the role of the TLR signaling pathway in the pathogenesis of TAO&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">First&#44; the authors detected the expressions of MyD88&#44; TRIF and NF-&#954;B in vascular walls of 46 patients with TAO and 32 patients with trauma and osteosarcoma by western blot assay&#46; Second&#44; the authors detected the cellular localization of MyD88&#44; TRIF and NF-&#954;B in vascular walls of patients with TAO by immunofluorescent assay&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">The protein expressions of MyD88&#44; TRIF and NF-&#954;B were much higher in vascular walls of TAO patients &#40;<span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#41;&#46; Higher expressions of MyD88 and NF-&#954;B were detected both on vascular endothelial and vascular smooth muscle cells of TAO patients&#46; However&#44; higher expression of TRIF was just detected on vascular smooth muscle cells of TAO patients&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusions</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">These dates suggest that the TLR signaling pathway might play an important role in the pathogenesis of TAO&#44; it might induce vasospasm&#44; vasculitis and thrombogenesis to lead to the pathogenesis and progression of TAO&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col">TAO group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col">Control group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0007"></a><td class="td-with-role" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35&#46;2 &#177;7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38&#46;1 &#177; 16&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Gender &#40;M&#47;F&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46&#47;0 100&#47;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">18&#47;14 56&#46;3&#47;43&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;267 &#177; 0&#46;143&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;023 &#177; 1&#46;045&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Previous smoking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15 46&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0019"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">History of intermittent claudication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Pain at rest &#40;narcotic requirement&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Ischemic nonhealing ulcer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38 82&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0028"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Thrombophlebitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">36 78&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Raynaud&#39;s phenomenon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35 76&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Previous treatments with drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Aspirin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">44 95&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2 6&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Warfarin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3 6&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Iloprost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0046"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Previous amputation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Major&#47;minor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#47;7 6&#46;5&#47;15&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#47;0 0&#47;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Distal bypass graft&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Below knee&#47;crural arteries&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&#47;0 17&#46;4&#47;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#47;0 0&#47;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0058"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Sympathectomy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">31 67&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Immunosuppression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0064"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Malnutrition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10 21&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2 6&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><a name="en0067"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">MyD88&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">TRIF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">NF-&#954;B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0072"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Control group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;188 &#177; 0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;162 &#177; 0&#46;017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;175 &#177; 0&#46;011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0077"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TAO group<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;763 &#177; 0&#46;041&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;806 &#177; 0&#46;015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;785 &#177; 0&#46;032&nbsp;\t\t\t\t\t\t\n
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
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          "identificador" => "cebibsec1"
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              "identificador" => "bib0001"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thromboangiitis obliterans &#40;Buerger&#39;s Disease&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                      "doi" => "10.1056/NEJM200009213431207"
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                        "tituloSerie" => "New Engl J Med"
                        "fecha" => "2000"
                        "volumen" => "343"
                        "numero" => "12"
                        "paginaInicial" => "864"
                        "paginaFinal" => "869"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10995867"
                            "web" => "Medline"
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              "identificador" => "bib0002"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thromboangiitis obliterans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G Piazza"
                            1 => "MA&#46; Creager"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.110.942383"
                      "Revista" => array:8 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2010"
                        "volumen" => "121"
                        "numero" => "16"
                        "paginaInicial" => "1858"
                        "paginaFinal" => "1861"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20421527"
                            "web" => "Medline"
                          ]
                        ]
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                          "pii" => "S0167527319335739"
                          "estado" => "S300"
                          "issn" => "01675273"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thromboangiitis obliterans &#40;Buerger&#39;s disease&#41;"
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Article information
ISSN: 18075932
Original language: English
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2024 May 45 26 71
2024 April 38 30 68

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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos