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array:22 [ "pii" => "S0025775319301265" "issn" => "00257753" "doi" => "10.1016/j.medcli.2019.01.031" "estado" => "S300" "fechaPublicacion" => "2019-11-15" "aid" => "4779" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2019" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2019;153:341-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4 "HTML" => 4 ] "itemSiguiente" => array:19 [ "pii" => "S0025775319301277" "issn" => "00257753" "doi" => "10.1016/j.medcli.2019.01.032" "estado" => "S300" "fechaPublicacion" => "2019-11-15" "aid" => "4780" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2019;153:347-50" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1423 "formatos" => array:2 [ "HTML" => 1391 "PDF" => 32 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original</span>" "titulo" => "Utilidad de una escala de riesgo basada en la procalcitonina sérica para la discriminación temprana entre fascitis necrosante y celulitis de las extremidades" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "347" "paginaFinal" => "350" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Usefulness of a risk scale based on procalcitonin for early discrimination between necrotising fasciitis and cellulitis of the extremities" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1206 "Ancho" => 1508 "Tamanyo" => 76988 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Curva COR de la capacidad de discriminación en el diagnóstico de FN según el riesgo calculado por el nivel de procalcitonina (ABC: 0,86; IC<span class="elsevierStyleHsp" style=""></span>95%: 0,72-1) versus por la escala LRINEC (ABC: 0,77; IC<span class="elsevierStyleHsp" style=""></span>95%: 0,59-0,95) como variables categóricas.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carlos Daniel Novoa-Parra, Jayant Wadhwani, Maria Amparo Puig-Conca, Alejandro Lizaur-Utrilla, Daniel Montaner-Alonso, José L. Rodrigo-Pérez, Maria Morales-Suárez-Varela" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Carlos Daniel" "apellidos" => "Novoa-Parra" ] 1 => array:2 [ "nombre" => "Jayant" "apellidos" => "Wadhwani" ] 2 => array:2 [ "nombre" => "Maria Amparo" "apellidos" => "Puig-Conca" ] 3 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Lizaur-Utrilla" ] 4 => array:2 [ "nombre" => "Daniel" "apellidos" => "Montaner-Alonso" ] 5 => array:2 [ "nombre" => "José L." "apellidos" => "Rodrigo-Pérez" ] 6 => array:2 [ "nombre" => "Maria" "apellidos" => "Morales-Suárez-Varela" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020619304346" "doi" => "10.1016/j.medcle.2019.01.037" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020619304346?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775319301277?idApp=UINPBA00004N" "url" => "/00257753/0000015300000009/v1_201910300628/S0025775319301277/v1_201910300628/es/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Effectiveness of umbilical cord mesenchymal stem cells in patients with critical limb ischemia" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "341" "paginaFinal" => "346" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Wen-Hui Gao, Hong-Ye Gao, Yue-Tong Li, Ping-Ping Huang" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Wen-Hui" "apellidos" => "Gao" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">◊</span>" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Hong-Ye" "apellidos" => "Gao" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">◊</span>" "identificador" => "fn0005" ] ] ] 2 => array:3 [ "nombre" => "Yue-Tong" "apellidos" => "Li" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:4 [ "nombre" => "Ping-Ping" "apellidos" => "Huang" "email" => array:1 [ 0 => "huangpp@ihcams.ac.cn" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Institute of Hematology, General Medical Center, Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Tianjin University of Traditional Chinese Medicine, Tianjin, China" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectividad de las células madre mesenquimales del cordón umbilical en pacientes con isquemia crítica de extremidades" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3465 "Ancho" => 1474 "Tamanyo" => 131697 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Changes in TNF-α, IL-6 and IL-10 serum levels was measured before UC-MSCs treatment (Pre), and 24<span class="elsevierStyleHsp" style=""></span>h, 1 month after BMI treatment. *<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 vs. Pre. Data are shown as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral arterial disease (PAD). Furthermore, up to one third of the patients with PAD who are ineligible for revascularization by percutaneous transluminal angioplasty or bypass, still require amputation.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Therefore, new approaches in treating these patients with CLI are developed, and therapeutic neovascularization may become a potential and significant way to salvage.</p><p id="par0010" class="elsevierStylePara elsevierViewall">CLI results from limb artery occlusion with subsequent drastic reduction in oxygen levels in the affected limb. Following the ischemia, invasion of inflammatory cells and T-lymphocytes contribute to secondary injury through production of inflammatory mediators including interleukins and tumor necrosis factor α (TNF-α).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Endothelial progenitor cells (EPCs) are isolated from peripheral blood and participate in forming new blood vessels after recruitment and migration into the ischemic tissue, playing a vital role in the regeneration of the endothelial lining of blood vessels and wound repair. Some important various signaling pathways are being revealed by experiments in vitro and in-vivo.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2,3</span></a> Recently, it was reported that patients with CLI have low levels of EPCs and high levels of inflammatory mediators such as interleukin 6 (IL-6).<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,5</span></a> Several studies have also reported that inflammation influences EPCs biology.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> Interestingly, among the inflammatory mediators, TNF-α and IL-6 may be responsible for the reduction in EPCs.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In many pathological circumstances such as diabetes, the hyper-inflammatory environment inhibits vasculogenesis until the inflammation is controlled to a normal level. MSCs (mesenchymal stem cells), given their immunomodulatory and angiogenic properties, have been shown to be therapeutically effective in patients with CLI.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Several studies reported that MSCs are immunosuppressive, which can suppress the activities of several T-lymphocyte and NK cells both in vitro and in vivo. MSCs modulate the inflammatory response by downregulating pro-inflammatory cytokines such as TNF-α.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> Recent evidence suggests that the inflammatory cytokines, TNF-α and IL-6 released at the injury site mobilize endogenous bone-marrow-derived cells which play an important role in the process of neointimal hyperplasia after vascular injury.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> These properties make MSCs therapy a good candidate for CLI patients. In addition, MSCs are multipotent and differentiate into alternate cell types such as bone, cartilages, fat, muscles, endothelial cells and vascular smooth muscle cells. They can be expanded readily to enough cells of clinical grade MSCs for cell therapy. A phase I/II trial of allogeneic bone marrow derived MSCs for CLI showed the improved ankle brachial pressure index (ABPI) after the treatment.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Yang et al.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> proved that human cord blood-derived MSCs transplantation improved ischemia in patients with arteriosclerosis obliterans/thromboangitis obliterans (ASO/TAO).</p><p id="par0025" class="elsevierStylePara elsevierViewall">However, the underlying mechanism of action of umbilical cord mesenchymal stem cells (UC-MSCs) mediating improvements in CLI patients, especially with respect to the immune-inflammatory aspects of this disease, has not been fully addressed. There is little known about the distribution of T-lymphocyte subpopulations and the changes of inflammatory mediators in CLI patients before and after UC-MSC-based treatment. In our current findings, we treated CLI patients with umbilical cord-derived MSCs by intramuscular administration. We hypothesize that such an approach may attenuate the inflammatory response, and it is striking to speculate the changes in T-lymphocyte subpopulations and inflammatory mediators (IL-6, IL-10 and TNF-α) in PBMCs from CLI patients after MSCs-based treatment. We also sought to determine the correlation between inflammatory mediators and EPCs.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0030" class="elsevierStylePara elsevierViewall">The 8 CLI patients had a mean age of 57.75 years (range 21–75) and comprised 7 males and 1 female. Patients presented with the following: 5 patients with diabetes foot, 2 patients with ASO and 1 patient with TAO. They treated with UC-MSCs transplantation for lower-limb ischemia in the Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows baseline demographics and clinical characteristics of the patients. Participants’ mean age was 57.75 years (range 21–75) and 7 of them were male. 5 (63%) of these patients underwent a previous endovascular and/or surgical intervention in the index limb. These 8 patients were selected to undergo UC-MSCs implantation, because they were unresponsive to medication, or surgical and endovascular procedures were deemed inappropriate. All patients received antiplatelet or anticoagulant drugs before transplantation. After approval by the ethical committee of the Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences& Peking Union of Medical College, we obtained written informed consent from all patients for the study of cytokine in serum. UC-MSCs provided by the National Stem Cell Engineering Research Center. In addition, sterility, mycoplasma and endotoxin testing were performed to confirm that the cells were devoid of any microbial contaminants and were sterile. Under general anesthesia, each diseased lower limb was intra-muscularly injected (40 sites, 3<span class="elsevierStyleHsp" style=""></span>cm×3<span class="elsevierStyleHsp" style=""></span>cm distance, 1–1.5<span class="elsevierStyleHsp" style=""></span>cm deep) into the thigh and leg, with 6.29×10<span class="elsevierStyleSup">7</span><span class="elsevierStyleHsp" style=""></span>UC-MSCs/m<span class="elsevierStyleSup">2</span>. In addition, clinical efficacy of UC-MSCs transplantation can be shown by the formation of new collateral vessels confirmed by CT angiography.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Blood sampling</span><p id="par0035" class="elsevierStylePara elsevierViewall">Venous blood samples were taken from drainage veins of the transplant-recipient limb before UC-MSCs treatment, and further samples were taken at 24<span class="elsevierStyleHsp" style=""></span>h and 1 month respectively after UC-MSCs treatment.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Measurement of inflammation meditators and lymphocyte subsets</span><p id="par0040" class="elsevierStylePara elsevierViewall">To investigate the effects of UC-MSCs treatment on the inflammatory response, we measured serum cytokine levels before treatment as well as at 24<span class="elsevierStyleHsp" style=""></span>h and 1month after treatment. TNF-α and IL-6 are pro-inflammatory cytokines that serve as important serum markers, reflecting the body's inflammatory state. We also examined IL-10 levels, an anti-inflammatory cytokine, which can reduce tissue inflammation after injury. Serum levels of human IL-6, IL-10 and TNF-α were measured by ELISA assay, using commercially available kits (BD™OptEIA; BD Biosciences, Rockville, MD) according to the manufacturer's instructions. The distributions of CD3+, CD3+CD4+ and CD3+CD8+ cells in human peripheral blood mononuclear cells (PBMCs) were detected by a FACSC alibur flow cytometer (Becton Dickinson, USA). Cells were labeled by monoclonal antibodies (FITC/PE/Percp/APC); The complete blood count was performed using a Sysmex XE-2100 blood cell analyzer (Sysmex, Japan).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Assessment of circulating EPCs levels</span><p id="par0045" class="elsevierStylePara elsevierViewall">Circulating EPCs are characterized by the expression of immature markers, such as CD34 and CD133, and endothelial markers, such as kinase domain receptor (KDR). To determine the number of EPCs, PBMCs were purified by standard Ficoll-Hypaque density centrifugation. EPCs were measured using CD34-FITC, CD133-PE and KDR-APC (Meltianyi Biotec, GRE). Between 5.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span> and 1.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> cells were acquired in each analysis. The flow data were collected with a BD FACSC alibur machine (Becton Dickinson, USA) and analyzed by FlowJo software (Tree Star Inc).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">All experiments were repeated at least three times and differences were determined using Student's <span class="elsevierStyleItalic">t</span>-test. The interaction between the number of EPCs and TNF-α, was examined by bivariate correlation. Results were expressed as the mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD, and a value of *<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05, **<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01 was significant.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Clinical efficacy and safety of HUC-MSCs transplantation</span><p id="par0055" class="elsevierStylePara elsevierViewall">After the treatment, the formation of new collateral vessels is confirmed by CT angiography; this change was more obvious for the micro-vascular network than that for the macro-vascular network (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In addition, no transplantation-related complication and lower limb amputation occurred in this study over a total of 6 months of follow-up.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Changes in IL-6, IL-10 and TNF-α serum levels after UC-MSC treatment</span><p id="par0060" class="elsevierStylePara elsevierViewall">TNF-α and IL-6 serum levels increased significantly at 24<span class="elsevierStyleHsp" style=""></span>h after treatment and then decreased at 1month compared with that before treatment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), while IL-10 increased slightly at 24<span class="elsevierStyleHsp" style=""></span>h after treatment and then declined to baseline level at 1month.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Redistribution of lymphocyte subsets in PBMCs after UC-MSCs treatment</span><p id="par0065" class="elsevierStylePara elsevierViewall">The percentage of CD3+ T-lymphocytes was increased in CLI patients (73.99<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.55%) at baseline compared to the healthy controls (71.28<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.47%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.05). The percentage of CD3+ CD4+ T lymphocytes increased (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.05), while the percentage of CD3+ CD8+T-lymphocytes (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.05) decreased in CLI patients at baseline compared to the healthy controls, resulting in a higher CD4/CD8 ratio. The percentage of CD3CD16/CD56+ natural killer (NK cells) increased significantly in CLI patients (12.75<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.23%) at baseline compared to the healthy controls (9.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.08%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05). After UC-MSCs treatment, the percentages of CD3+ T, CD3+ CD4+ lymphocytes and NK cells decreased significantly (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.002, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.029, respectively), whereas the percentage of CD3+ CD8+ lymphocytes increased (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.275) compared to those at baseline (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Correlation between pro-inflammatory mediators and EPCs</span><p id="par0070" class="elsevierStylePara elsevierViewall">EPCs are characterized by the co-expression of CD34, CD133 and endothelial marker proteins VEGF receptor 2 (KDR). The number of circulating EPCs at 24<span class="elsevierStyleHsp" style=""></span>h after UC-MSCs treatment was lower compared to those at baseline (0.0464<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.0435% vs. 0.1051<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.0729%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.05). However, at 1 month after UC-MSCs treatment, the number of circulating EPCs increased compared to the baseline (0.1233<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.0765% vs. 0.1051<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.0729%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Using bivariate analysis, TNF-α (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.602, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05) was shown to be inversely correlated with the number of circulating EPCs (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion/conclusion</span><p id="par0075" class="elsevierStylePara elsevierViewall">PAD is a restriction of blood supply to limb, caused by pathological changes in the vascular system, such as atherosclerosis and inflammation. PAD can cause a wide variety of symptoms including chronic wounds, ulcers, rest pain and tissue necrosis with gangrene. For critical limb ischemia, there is no effective pharmacological treatment. Amputation is inevitable in a third of the PAD cases to solve the unbearable symptoms.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">It has been reported that immune activation is important at several stages in the development of chronic wounds of CLI, which results from various underlying disorders, including diabetes, vasculitis and vascular insufficiency. The healing process can be disturbed by various factors, including infection, tissue hypoxia, necrosis and hyper-inflammatory cytokines. Tuttolomondo et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> reported that higher plasma levels of IL-6 linked diabetic foot ulcers pathogenesis to microvascular and inflammatory events. Dinh et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> demonstrated that the number of inflammatory cells around vessels in diabetic patients was higher than healthy control subjects through forearm-skin biopsy. IL-6, which is believed to be secreted from macrophages and lymphocytes, has been shown to play an important role in chronic inflammation disorders.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> It is reported that IL-6 is highly upregulated in rheumatoid arthritis, and it is an effective treatment for rheumatoid arthritis with an IL-6 receptor antagonist<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a>. However, in this study, although we find that IL-6 serum levels increased at 24<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.017, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.099) after treatment and then decreased at 1 month (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.031, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.072) compared with those before treatment, we fail to find the identical significant difference in a negative association between the IL-6 serum levels and the relative expression levels of EPCs (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.313, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.322).</p><p id="par0085" class="elsevierStylePara elsevierViewall">It was reported that TNF-α is another important pro-inflammatory cytokine, which is elevated in many inflammatory diseases.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> In this study, the average plasma levels of IL-6 and TNF-α in patients were above the normal range before UC-MSC treatment (11.27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.32<span class="elsevierStyleHsp" style=""></span>pg/ml vs.<5.9<span class="elsevierStyleHsp" style=""></span>pg/ml; 41.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>30.70<span class="elsevierStyleHsp" style=""></span>pg/ml vs. <8.1<span class="elsevierStyleHsp" style=""></span>pg/ml). Among all the patients (RutherfordBecker categories 4–6), 4 of 8 patients underwent bypass surgery. However, their ulcers and rest pain had not been eased. These findings suggest that CLI patient's chronic inflammation state, which impedes the improvement in symptoms.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The continuous inflammation phenotype in the wound creates a barrier to treatment in chronic wounds. The infiltration of neutrophils, macrophages, dendritic cells and Tcells not only contribute to chronic inflammation but also release the enzyme elastase, which is capable of destroying important healing factors such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β). Dinh et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> also showed that T-lymphocytes around blood vessels were higher in diabetic patients. In our study, the percentage of CD3+ T-lymphocytes increased in CLI patients at baseline compared to the healthy controls. In addition, CD4/CD8 ratio is higher compared with the healthy controls. It suggested that the imbalance of T-lymphocyte subsets played a vital role in non-healing wound of CLI.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In 1998, Folkman<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> promoted the conception of “therapeutic angiogenesis”. Accumulating evidences supported cell therapy as a new treatment option for CLI. MSCs are superior to other cells for low immunogenicity, immunomodulatory and angiogenic properties. One study reported that intramuscular administration of allogeneic MSCs attenuated the local oxidative stress and endothelial inflammation in a mouse model of hind-limb ischemia.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> In addition, Pinheiro<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> reported that in the dystrophin-deficient mice, intramuscular injection of adipose tissue-derived MSCs can reduce local inflammation. It was also reported that Prostaglandin E2 (PGE2) was produced by human MSCs at levels which are able to suppress IL-6 and TNF-α expression in activated macrophages. However, in our study, TNF-α and IL-6 serum levels significantly increased at 24<span class="elsevierStyleHsp" style=""></span>h after UC-MSC treatment and then decreased at 1 month compared with that before treatment. The results might be explained by the following reasons. Cell transplantation-induced early inflammatory was accountable for the higher levels of pro-inflammatory cytokines. It was regarded as a direct action by implanted cells. The serum levels of TNF-α and IL-6 decreased at 1 month after treatment, which was considered that implanted MSCs secreted anti-inflammatory cytokines, PEG2 and inhibit T/NK cells proliferation. It was acknowledged to be an indirect paracrine action and immunomodulatory induced by the implanted cells.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The immunomodulatory effects of MSCs, including inhibition of the proliferation of T-lymphocytes and NK cells.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> MSCs inhibit T cell proliferation by arresting at the G0/G1check point.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> Ren et al. demonstrated that MSCs inhibited T cell proliferation by upregulation of inducible nitric oxide synthase (iNOS), in which process the generated NO can result in such an effect.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Chatterjee et al. reported that UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors prostaglandin (PG)-E2.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> MSCs has also been found to inhibit NK via Indoleamine-2,3-dioxygenase expression<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a>. In this study, after UC-MSCs treatment, the percentage of CD3+ T, CD3+ CD4+T-lymphocytes and NK cells decreased significantly (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.002, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.029, respectively), whereas the percentage of CD3+ CD8+ T-lymphocytes increased (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.275) compared to those at baseline. These findings suggested that intramuscular administration of UC-MSCs could inhibit proliferation of T-lymphocytes and modulate the balance of T-lymphocytes subsets in CLI.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The correlation between pro-inflammatory mediators and EPCs was also investigated in our study. EPCs generated from bone marrow were believed to participate in endothelial repair and postnatal angiogenesis, either by differentiating into endothelial cells or by secreting factors that stimulate proliferation of resident endothelial cells.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> Some studies reported that EPCs are significantly affected by chronic inflammation.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4,26</span></a> The negative correlation between IL-6, TNF-α levels and EPCs were described in rheumatoid arthritis patients and healthy controls.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">27,28</span></a> In our study, TNF-α (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.602, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05) was shown to be inversely correlated with the number of circulating EPCs. The underlying mechanism might be proinflammatory-mediated bone marrow suppression or exhaustion, leading to attenuate the release of EPCs into the circulation and a shift toward the release of more immature and dysfunctional EPCs.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> In addition, MMP-9 and SDF-1<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> play an important role in mobilization of EPCs form the bone marrow. Teraa et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> showed that MMP-9 levels and activity are reduced in the BM, and alterations in the SDF-1a/CXCR4 interaction in CLI contribute to the defective neovascularization response in CLI.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The limitations of this study are the small sample size. Moreover, many factors associated with the efficacy of cell replacement therapy for ischemic diseases. Larger studies should be conducted to identify immunomodulatory effects of UC-MSCs in CLI. This hypothesis needs to be tested in an adequately clinical trial. Furthermore, the proportion of men and women is unbalanced, which should be improved in future study. It should be noted that this study had examined only pro-inflammatory mediators, but levels of angiogenic factors such as vascular endothelial growth factor(VEGF), basic fibroblast growth factor (BFGF) and Epidermal Growth Factor(EGF) were not detected.</p><p id="par0115" class="elsevierStylePara elsevierViewall">In conclusion, we have primarily showed that chronic hyperinflammation state and the imbalance of lymphocyte subsets play a key role in nonhealing wound of CLI. This report highlights that the intramuscular administration of UC-MSCs exerts immunomodulatory effects in CLI patients via decreasing the levels of proinflammatory cytokines, including IL-6 and TNF-α, and the reduction of CD3+CD4+Tlymphocyte and NK cells. The findings of our study showed that circulating CD34+CD133+KDR+ EPCs was closely correlated with the increased TNF-α. In addition, our findings suggested a role for UC-MSCs as a potential treatment for large segment of the patients with critical ischemic limbs, and imply that analysis of pro-inflammatory cytokines levels in serum might serve as an additional tool for observation of efficacy. It has confirmed the promising results in clinic and provided evidences for a new helpful therapeutic tool for CLI.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Statement of ethics</span><p id="par0120" class="elsevierStylePara elsevierViewall">All the subjects are given their written informed consents. All the study procedures were approved by the Institutional Animal Care and Use Committee of Harbin Medical University (Reference No. KY2016-180). This study was conducted in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Academy Press (National Institutes of Health, revised in 1996).</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Authors’ contributions</span><p id="par0125" class="elsevierStylePara elsevierViewall">WHG contributed to the experimental design, carried out the flow cytometry assay and molecular biology experiments. HYG collected the data and blood of patients and performed the statistical analysis and drafted the manuscript. YTL and PPH conceived of the study, and participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding sources</span><p id="par0130" class="elsevierStylePara elsevierViewall">This study was supported by grants from CAMS Innovation Fund for Medical Sciences (2017-I2M-1-016).</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1259887" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1166919" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1259886" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1166920" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Blood sampling" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Measurement of inflammation meditators and lymphocyte subsets" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Assessment of circulating EPCs levels" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Clinical efficacy and safety of HUC-MSCs transplantation" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Changes in IL-6, IL-10 and TNF-α serum levels after UC-MSC treatment" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Redistribution of lymphocyte subsets in PBMCs after UC-MSCs treatment" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Correlation between pro-inflammatory mediators and EPCs" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion/conclusion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Statement of ethics" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Authors’ contributions" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding sources" ] 11 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interests" ] 12 => array:2 [ "identificador" => "xack432155" "titulo" => "Acknowledgments" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-11-24" "fechaAceptado" => "2019-01-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1166919" "palabras" => array:5 [ 0 => "Critical limb ischemia" 1 => "Peripheral arterial disease" 2 => "Umbilical cord" 3 => "Mesenchymal stem cell" 4 => "Immunomodulatory" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1166920" "palabras" => array:5 [ 0 => "Isquemia crítica de extremidades" 1 => "Enfermedad arterial periférica" 2 => "Cordón umbilical" 3 => "Células madre mesenquimatosas" 4 => "Inmunomodulador" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) has been shown to be effective in treating critical limb ischemia (CLI). However, the mechanism of MSCs-mediated improvements, especially on the immune-inflammatory aspects of this disease, is still unknown. In this study, we investigated the changes in T-lymphocyte subpopulations and inflammatory mediators (such as IL-6, IL-10 and TNF-α) in PBMCs from CLI patients after UC-MSCs treatment and correlation between inflammatory mediators and EPCs.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">8 patients received UC-MSCs transplantation. Before the treatment, at 24<span class="elsevierStyleHsp" style=""></span>h and 1 month thereafter, peripheral blood samples were collected from 8 patients and 8 healthy volunteers. Patients were evaluated for changes in IL-6, IL-10, TNF-α and levels of circulating EPCs.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">TNF-α and IL-6 serum levels increased at 24<span class="elsevierStyleHsp" style=""></span>h (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.017, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.099) after treatment and then decreased at 1 month (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.031, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.072) compared with those before treatment. The percentages of CD3+T, CD3+CD4+T-lymphocytes and NK cells decreased significantly after UC-MSCs treatment (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.002, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.029, respectively). TNF-α (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.602, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.038) was shown to be inversely correlated with the number of circulating EPCs.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study demonstrates that UC-MSCs have anti-inflammatory and immunomodulation properties in CLI and suggests that UC-MSCs promote healing of non-healing wounds.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El trasplante de células madre mesenquimales del cordón umbilical (CMM-CU) ha demostrado eficacia en el tratamiento de la isquemia crítica de las extremidades (ICE). Sin embargo, se desconoce el mecanismo de las mejoras mediadas por las CMM, especialmente en los aspectos inmune-inflamatorios de esta enfermedad. Este estudio analiza los cambios en las subpoblaciones de linfocitos T y en los mediadores inflamatorios (como IL-6, IL-10 y TNF-α) en CMSP de pacientes con ICE después del tratamiento con CMM-CU y estudia la correlación entre mediadores inflamatorios y células progenitoras endoteliales (CPE).</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ocho pacientes recibieron trasplante de CMM-CU. Se recogieron muestras de sangre periférica de 8 pacientes y 8 voluntarios sanos, antes del tratamiento, a las 24<span class="elsevierStyleHsp" style=""></span>h y un mes después. Los pacientes fueron evaluados para detectar cambios en IL-6, IL-10, TNF-α y niveles de CPE circulantes.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los niveles séricos de TNF-α e IL-6 aumentaron 24<span class="elsevierStyleHsp" style=""></span>h después del tratamiento (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,017, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,099) y luego disminuyeron al mes (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,031, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,072) en comparación con los niveles antes del tratamiento. Los porcentajes de CD3+T, CD3+CD4+ linfocitos T y células NK disminuyeron significativamente después del tratamiento con CMM-CU (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,002, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,012 y p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,029, respectivamente). TNF-α (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0,602, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,038) demostró estar correlacionada inversamente con el número de CPE circulantes.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este estudio demuestra que las CMM-CU tienen propiedades antiinflamatorias e inmunomoduladoras en la ICE y sugieren que las CMM-CU promueven la curación de heridas que no cicatrizan.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "◊" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Co-first author.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 962 "Ancho" => 1305 "Tamanyo" => 132720 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The result of CT angiographs came from a patient before (A) and after (B) treatment. The arrows refer to the same vessel in each one.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3465 "Ancho" => 1474 "Tamanyo" => 131697 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Changes in TNF-α, IL-6 and IL-10 serum levels was measured before UC-MSCs treatment (Pre), and 24<span class="elsevierStyleHsp" style=""></span>h, 1 month after BMI treatment. *<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 vs. Pre. Data are shown as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 948 "Ancho" => 1437 "Tamanyo" => 46294 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">It shows the time course of circulating EPCs in CLI patients. Abbreviations: CLI, Critical limb ischemia. EPCs: endothelial progenitor cells.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 957 "Ancho" => 1454 "Tamanyo" => 63245 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">There was a negative association between serum TNF-α levels and the relative expression levels of EPCs. Serum TNF-α levels were detected by ELISA, and EPCs was detected by flow cytometry.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ASO, Arteriosclerosis obliterans; DF, Diabetic Foot; TAO: thromboangitis obliterans. Rutherford-Becker categories: Cat. 0, asymptomatic; Cat. 1, mild claudication; Cat. 2, moderate claudication; Cat. 3 severe claudication; Cat. 4, rest pain; Cat. 5, minor tissue loss; Cat. 6,ulceration or gangrene.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gender \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rutherford-Becker \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk factors \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ASO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ASO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, diabetes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TAO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, diabetes, hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, diabetes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking, diabetes, hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2155012.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Patient characteristics.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">The data are presented as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SE. <span class="elsevierStyleItalic">Abbreviations</span>: CLI, Critical limb ischemia.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD3+T cells (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD3+CD4+T cells (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD3+CD8+T cells (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Ratio of CD4+/CD8+ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD3-CD16/CD56+NK cells (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CLI patients at baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.99<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.96<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22.49<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.16<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.75<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.23 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CLI after cells treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71.78<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41.66<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.69<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.96<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.78 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Healthy controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71.28<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.67<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.64<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.08 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2155011.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Distribution of T-lymphocyte subsets (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SE) in CLI patients.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inter-society consensus for the management of peripheral arterial disease (TASC II)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. 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