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(A: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.691 [95%CI: 0.565–0.817], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.008; AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.706 [95%CI: 0.543–0.868] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.038; C: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.713 [95%CI: 0.540–0.887] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.046).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.Á. Muñoz-Sánchez, A. Rodríguez-Rodríguez, J.J. Egea-Guerrero, E. Gordillo-Escobar, Á. Vilches-Arenas, A. 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The serum concentration of TAFI had a strong negative correlation with the serum levels of IL-1β, IL-6, TNF-α, PCT and CRP.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "H. Pang, C. Zhang, F. Liu, X. Gong, X. Jin, C. Su" "autores" => array:6 [ 0 => array:2 [ "nombre" => "H." "apellidos" => "Pang" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Zhang" ] 2 => array:2 [ "nombre" => "F." "apellidos" => "Liu" ] 3 => array:2 [ "nombre" => "X." "apellidos" => "Gong" ] 4 => array:2 [ "nombre" => "X." "apellidos" => "Jin" ] 5 => array:2 [ "nombre" => "C." 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Muñoz-Sánchez, A. Rodríguez-Rodríguez, J.J. Egea-Guerrero, E. Gordillo-Escobar, Á. Vilches-Arenas, A. Carrillo-Vico, J.M. Guerrero, F. Murillo-Cabezas" "autores" => array:8 [ 0 => array:3 [ "nombre" => "M.Á." "apellidos" => "Muñoz-Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "A." "apellidos" => "Rodríguez-Rodríguez" "email" => array:2 [ 0 => "rodriguezana13m@gmail.com" 1 => "swroder_an@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "J.J." "apellidos" => "Egea-Guerrero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "E." "apellidos" => "Gordillo-Escobar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Á." "apellidos" => "Vilches-Arenas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "A." "apellidos" => "Carrillo-Vico" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 6 => array:3 [ "nombre" => "J.M." "apellidos" => "Guerrero" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 7 => array:3 [ "nombre" => "F." "apellidos" => "Murillo-Cabezas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Urgencias, Hospital Universitario Virgen del Rocío, IBIS/CSIC/Universidad de Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Cuidados Críticos, Hospital Universitario Virgen del Rocío, IBIS/CSIC/Universidad de Sevilla, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Medicina Preventiva y Salud Pública, Hospital Virgen Macarena, Universidad de Sevilla, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Bioquimica Médica, Biología molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El sistema urotensinérgico en un modelo experimental de hemorragia subaracnoidea" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1136 "Ancho" => 3404 "Tamanyo" => 196104 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ROC analysis comparing sensitivity to 1-specificity of serum U-II on fifth day (A), URP mRNA (B) and UT mRNA (C) to discriminate SAH rats. (A: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.691 [95%CI: 0.565–0.817], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.008; AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.706 [95%CI: 0.543–0.868] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.038; C: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.713 [95%CI: 0.540–0.887] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.046).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Spontaneous subarachnoid hemorrhage (SAH) has an annual incidence rate of 4–28 cases per 100,000 people.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1,2</span></a> SAH accounts for about 80% of all nontraumatic extravasated bleeding into the subarachnoid space, 5% of stroke deaths and over a quarter of potential life years lost due to stroke.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1,3,4</span></a> Approximately 15% of SAH patients die after aneurysmal rupture. Another 25–50% die within a month of the bleeding. Of those who survive, 40% present disabling sequelae.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5,6</span></a> It is estimated that cerebral vasospasm (CVS) is responsible for neurological deterioration, and even death, in 15–20% of patients with SAH.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5,7</span></a> CVS is characterized by diffuse and long-lasting arterial constriction. Several vasoconstrictor proteins have been shown to contribute to this narrowing process.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">8–11</span></a> However, Urotensin-II (U-II), defined as the most potent vasoconstrictor peptide in mammals according to Ames et al. research study, is not among these biomarkers.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">U-II is an 11-amino-acid peptide with a cysteine disulfide bond, derived from the polypeptide precursor known as prepro-urotensin-II (preproU-II).<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a> Proteolytic cleavage of the C-terminal fragment from this precursor is required for biological activity. The result of this proteolysis is an undecapeptide with a cyclic hexapeptide sequence, fundamental for this hormonal action.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">14</span></a> Once the active form of the peptide is generated, U-II mediates its biological action by interacting with a specific plasma membrane G-protein coupled receptor identified as GRP14, or UT.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> This receptor binds different U-II sequences, including the U-II fragment (4–11) and U-II (5–11), as well as the urotensin-related peptide (URP), which derives from a different precursor.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">15</span></a> URP is shorter (octapeptide), but exhibits the cyclic hexapeptide core sequence. U-II expression has been found throughout the heart, kidney, urogenital system and nervous system.<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">16–18</span></a> Tian et al. described its expression, as well as UT expression, in the cytoplasm of neurons and in vascular endothelial cells from rats.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a> Our research group recently found that high doses of U-II (10<span class="elsevierStyleHsp" style=""></span>μM) in intact rat cerebral arteries evoke arterial contraction. However, in depolarized vascular smooth muscle, lower U-II concentrations (0.1 and 1<span class="elsevierStyleHsp" style=""></span>μM) cause dose-dependent arterial contraction.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">20</span></a> This effect could facilitate arterial CVS in vascular pathophysiological processes such as SAH, where sustained depolarization is present.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">21</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The objective of the present study was to determine the normal range for U-II serum levels and analyze U-II serum and mRNA expression values for the urotensinergic system genes (U-II, URP and UT) in an experimental murine model of SAH; with the purpose of using these molecules as biomarkers of arterial vasoconstriction in SAH.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Materials and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">Procedures were performed in the experimental operating room of the Biomedicine Institute of Seville (Instituto de Biomedicina de Sevilla [IBiS]/CSIC University of Seville), at the Virgen del Rocío University Hospital, Seville, Spain. This research project was overseen and approved by our hospital's Animal Experimentation Committee. It met all the legal requirements and ethical standards for research established by current legislation (Directive 2010/63/EU).</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Animals and samples</span><p id="par0025" class="elsevierStylePara elsevierViewall">Wistar rats weighing 300–350<span class="elsevierStyleHsp" style=""></span>g were used. The procedure was performed on males, to eliminate the cyclic cardioprotective effects of the estrous cycle. After the procedure, the animals were housed in independent cages, in a dry area away from infectious sources and surgical areas, and kept on a 12:12<span class="elsevierStyleHsp" style=""></span>h light/dark cycle. A stable room temperature was set between 23<span class="elsevierStyleHsp" style=""></span>°C and 27<span class="elsevierStyleHsp" style=""></span>°C. Food and water was provided without restrictions, before and after surgery.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Animals were anesthetized by intraperitoneal injection of the following preparation: 50<span class="elsevierStyleHsp" style=""></span>mg ketamine hydrochloride (Ketolar<span class="elsevierStyleSup">©</span>, Pfizer; 50<span class="elsevierStyleHsp" style=""></span>mg/mL), 2<span class="elsevierStyleHsp" style=""></span>mL Xylazine (Rompun<span class="elsevierStyleSup">©</span> 2%, Bayer; 20<span class="elsevierStyleHsp" style=""></span>mg/mL) and 1<span class="elsevierStyleHsp" style=""></span>mg atropine (Atropina Bayer<span class="elsevierStyleSup">©</span>, 1<span class="elsevierStyleHsp" style=""></span>mg/mL). The optimal dose for analgesia and sedation was established at 0.025<span class="elsevierStyleHsp" style=""></span>mL per gram of body weight.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">20,22</span></a> Adequate depth of anesthesia in the spontaneously breathing rats was ensured by the absence of corneal reflex and withdrawal reflex after pressure on the hind legs. Cardiac and respiratory rates were measured during the procedure.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Procedures for the two animal models</span><p id="par0035" class="elsevierStylePara elsevierViewall">SAH group: The SAH model was executed as previously described by our research group.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a> The animals were put in prone position with their heads fixed to a stereotaxic frame (Stoelting<span class="elsevierStyleSup">©</span>). A non-heparinized syringe was used to obtain 100<span class="elsevierStyleHsp" style=""></span>μL of autologous blood from the proximal part of the tail (1<span class="elsevierStyleHsp" style=""></span>mL BD Plastipak<span class="elsevierStyleSup">©</span>). This was injected into the intracisternal space via cisterna magna, after extraction of the same volume of CSF.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Sham group: Identical procedures were executed with one exception: 100<span class="elsevierStyleHsp" style=""></span>μL of isotonic saline was administered in place of blood after CSF extraction.</p><p id="par0045" class="elsevierStylePara elsevierViewall">On day 5 post-surgery, the animals were sacrificed with a lethal dose of ketamine hydrochloride (0.01<span class="elsevierStyleHsp" style=""></span>mL/kg) (Ketolar<span class="elsevierStyleSup">©</span>, Pfizer, 50<span class="elsevierStyleHsp" style=""></span>mg/mL) injected into the intraperitoneal cavity.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">20,22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Blood draws were performed on day 1 prior to the execution of the animal model and on day 5, prior to the sacrifice. Animals were placed in a supine position for blood sample collection. Using binocular lens, an inguinal incision was made, freeing up layers of the abdominal wall, to expose the femoral vein. For serum isolation, 0.8<span class="elsevierStyleHsp" style=""></span>mL of venous blood was collected in a VACUETTE<span class="elsevierStyleSup">®</span> serum separator tube containing aprotinin (0.6<span class="elsevierStyleHsp" style=""></span>TIU/mL of blood). An additional extraction was performed on day 5, after the lethal injection of ketamine. Each animal's entire blood volume was extracted by cardiac puncture and collected in a VACUTAINER<span class="elsevierStyleSup">®</span> CPT™ tube (Cell Preparation Tube) (BD, Franklin Lakes, NJ), for mononuclear cell isolation. Brains were removed and examined macroscopically to analyze the presence or absence of pathological findings.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The VACUETTE<span class="elsevierStyleSup">®</span> tubes were centrifuged at 1600<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 10<span class="elsevierStyleHsp" style=""></span>min at room temperature. The separated sera were frozen in aliquots at −80<span class="elsevierStyleHsp" style=""></span>°C prior to their analysis. VACUTAINER<span class="elsevierStyleSup">®</span> CPT™ tubes were centrifuged at 1900<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 20<span class="elsevierStyleHsp" style=""></span>min at room temperature. Mononuclear cells were collected from the processed CPT by gently inverting the collection tube several times, and drawing off the mononuclear cells containing plasma with a pipette into a tube containing 10<span class="elsevierStyleHsp" style=""></span>mL of saline. Following the manufacturer's instructions, this tube was centrifuged at 300<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 5<span class="elsevierStyleHsp" style=""></span>min at 4<span class="elsevierStyleHsp" style=""></span>°C. Mononuclear cells were washed twice with saline as described in the previous step and finally pelleted by centrifugation at 16,000<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 5<span class="elsevierStyleHsp" style=""></span>min at 4<span class="elsevierStyleHsp" style=""></span>°C in a sterile Eppendorf tube.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Measurement of Urotensin-II serum levels</span><p id="par0060" class="elsevierStylePara elsevierViewall">U-II serum levels were measured by fluorescent enzyme immunoassay (EIA) produced by Phoenix Pharmaceuticals, Inc. For peptide extraction, serum samples were previously loaded into a SEP-COLUMN containing 200<span class="elsevierStyleHsp" style=""></span>mg of C18 (Cat. No. RK-SEPCOL-1) following the manufacturer's indications. Data on cross-reactivity was provided by the manufacturer: 100% with rat UT-II and 11% with URP. No cross-reactivity was found with rat endothelin-I, C-type natriuretic peptide-22, calcitonin gene-related peptide, adrenomedullin, atrial natriuretic peptide, bradykinin, angiotensin II or brain natriuretic peptide.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Nucleic acid extraction</span><p id="par0065" class="elsevierStylePara elsevierViewall">The pelleted mononuclear cells were lysed by repetitive pipetting with 750<span class="elsevierStyleHsp" style=""></span>μL of TRIsure™ Isolation Reagent (Bioline). The samples were incubated for 5<span class="elsevierStyleHsp" style=""></span>min at room temperature to ensure the complete dissociation of nucleoprotein complexes. We then added 300<span class="elsevierStyleHsp" style=""></span>μL of chloroform and vigorously shook the Eppendorf for 15<span class="elsevierStyleHsp" style=""></span>s. This step was followed by 2–15<span class="elsevierStyleHsp" style=""></span>min of incubation on ice, and 15<span class="elsevierStyleHsp" style=""></span>min of centrifugation at 12,000<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span>, to separate the solution into three phases. The upper colorless phase contained the RNA fraction—it was carefully removed and drawn into an Eppendorf containing 500<span class="elsevierStyleHsp" style=""></span>μL of isopropanol. After 5–10<span class="elsevierStyleHsp" style=""></span>min of incubation, samples of this new mixture were incubated for 2<span class="elsevierStyleHsp" style=""></span>h at −20<span class="elsevierStyleHsp" style=""></span>°C and then centrifuged at 12,000<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 10<span class="elsevierStyleHsp" style=""></span>min at 4<span class="elsevierStyleHsp" style=""></span>°C to form an RNA pellet. This pellet was isolated and washed twice with 1<span class="elsevierStyleHsp" style=""></span>mL of ethanol. Finally, the pellet was resuspended in 30<span class="elsevierStyleHsp" style=""></span>μL of RNAs-free water.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Prior to cDNA synthesis, extracted RNA concentration and purity (OD<span class="elsevierStyleInf">260</span>/OD<span class="elsevierStyleInf">280</span>) were quantified by spectrophotometry at 260–280<span class="elsevierStyleHsp" style=""></span>nm (NanoDrop, PeqLab Technology, Erlangen, Germany). An OD<span class="elsevierStyleInf">260</span>/OD<span class="elsevierStyleInf">280</span> ratio between 1.7 and 2.0 indicates reasonable RNA purity. Samples above or below this purity range were discarded.</p><p id="par0075" class="elsevierStylePara elsevierViewall">One μg of RNA from each sample was retrotranscripted into cDNA with the QuantiTect Reverse Transcription Kit (Qiagen), following the manufacturer's protocol. This protocol includes treating the samples with gDNA wipeout buffer, to eliminate genomic DNA contamination.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Real-time PCR</span><p id="par0080" class="elsevierStylePara elsevierViewall">To conduct a polymerase chain reaction (PCR), half of the lymphocyte samples were selected from both animal groups by applying block randomization. This procedure also ensured that the two subgroups were of equal size. The remaining samples were used for other analyses (unpublished).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Commercially available Real-Time ready assays for the target genes (U-II, URP and UT), and the 18 ribosomal RNA housekeeping genes, were obtained lyophilized in 384-well PCR plates, with forward and reverse primers (400<span class="elsevierStyleHsp" style=""></span>nM) and fluorescently labeled hydrolysis probes (200<span class="elsevierStyleHsp" style=""></span>nM), from Universal Probe Library (Roche Applied Science). Gene expression analysis was performed using real-time PCR with final reaction volumes of 10<span class="elsevierStyleHsp" style=""></span>μL (5<span class="elsevierStyleHsp" style=""></span>μL LightCycler<span class="elsevierStyleSup">®</span> 480 Probes Master, 2<span class="elsevierStyleHsp" style=""></span>μL water [PCR Grade], 0.5<span class="elsevierStyleHsp" style=""></span>μL RealTime ready Assay and 2.5<span class="elsevierStyleHsp" style=""></span>μL cDNA sample). Thermal cycling on the LightCycler<span class="elsevierStyleSup">®</span> 480 used the following program: one cycle at 95<span class="elsevierStyleHsp" style=""></span>°C for 10<span class="elsevierStyleHsp" style=""></span>min for enzyme activation and denaturation, followed by 45 cycles of 95<span class="elsevierStyleHsp" style=""></span>°C for 10<span class="elsevierStyleHsp" style=""></span>s, 60<span class="elsevierStyleHsp" style=""></span>°C for 30<span class="elsevierStyleHsp" style=""></span>s and signal detection at 72<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>s, with detection and cooling at 40<span class="elsevierStyleHsp" style=""></span>°C for 30<span class="elsevierStyleHsp" style=""></span>s. The samples subjected to the 45 cycles were assayed in duplicate.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Gene expression levels were evaluated using the threshold cycle (Ct) method. This data was normalized to the 18 ribosomal RNA reference gene and analyzed according to the 2<span class="elsevierStyleSup">−ΔCt</span> method.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Statistical analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Quantitative variables were presented as medians (interquartile range [IQR]: P25-P75), since they followed a non-normal distribution. We executed the non-parametric Wilcoxon test to analyze within-group differences, and the Mann Whitney <span class="elsevierStyleItalic">U</span> test to verify between-group differences. If significant differences were obtained, 95% confidence intervals (CI) were calculated. Spearman's rank correlation was used to test the association between biomarkers analyzed in this study. Receiver Operator Characteristic (ROC) curve analysis was performed on U-II serum values and on U-II, URP and UT 2<span class="elsevierStyleSup">−ΔCt</span> values to allocate rats in the Sham or SAH groups. The resulting area under the curve (AUC) was used to establish a cut-off point for animal classification, choosing the point which reached the greatest sum of sensitivity plus specificity. Statistical significance was defined as <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05. Statistical analyses were performed using SPSS software (Version 20.0, Chicago, IL, USA).</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">A total of 96 animals underwent surgery. They were classified as follows: 22 Sham and 74 SAH. Four animals (including one Sham animal) died within 5 days of the surgical intervention.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The macroscopic evaluation of the brains showed that one SAH rat presented an intercisural hematoma.</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Urotensin-II serum levels</span><p id="par0110" class="elsevierStylePara elsevierViewall">When analyzing U-II serum levels, we observed the following results: the SAH rats suffered an increase on U-II serum values from day 1 (0.62<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.36–1.8]) to day 5 (0.74<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.39–1.43]) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.04). In the Sham group, no significant differences in U-II serum levels were found between day 1 (0.56<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.06–0.83]) and day 5 (0.37<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.23–0.62]) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.959).</p><p id="par0115" class="elsevierStylePara elsevierViewall">Between-group differences in U-II serum levels were found on day 5 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.008) but not on day 1 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.174).</p><p id="par0120" class="elsevierStylePara elsevierViewall">Based on U-II serum levels on day 1 in the Sham group, we were able to define the normal median basal serum level for U-II in rats: 0.56<span class="elsevierStyleHsp" style=""></span>pg/mL (IQR 0.06–0.83).</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">U-II, URP and UT mRNA expression</span><p id="par0125" class="elsevierStylePara elsevierViewall">For conducting PCR, half lymphocyte samples were randomly selected from both animal groups. The remaining samples were stored for possible future analysis. Thus, we selected 37 SAH samples and 11 Sham samples. Three of the SAH group samples did not have sufficient RNA for inclusion in the analysis.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The results showed that the SAH rats had higher expression levels for URP and UT genes: URP 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7.07<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−6</span> (IQR 7.48<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>–6.40<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−3</span>) SAH vs. URP 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8.38<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span> (IQR 4.37<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>–11.58<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>) Sham, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.037; UT 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.97<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−6</span> (IQR 2.26<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>–4.49<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−5</span>) SAH vs. UT 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.22<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span> (IQR 1.37<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>–4.50<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span>) Sham, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.046 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). U-II expression levels did not reach statistical significance: U-II 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.28<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span> (IQR 2.84<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−8</span>–2.04<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−6</span>) SAH vs. U-II 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4.02<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−8</span> (IQR 2.55<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−8</span>–9.64<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−8</span>) Sham, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.175.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In the correlation analysis, in the SAH group, all the quantified gene expressions correlated positively with each other: U-II vs. URP <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.786, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; U-II vs. UT <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.727, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; URP vs. UT <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.906, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001. Additionally, URP mRNA showed a positive correlation with U-II serum levels on day 1 (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.490; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.024) and with U-II serum levels on day 5 (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.409; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.038). In the Sham group, just correlation between U-II 2<span class="elsevierStyleSup">−ΔCt</span> and UT 2<span class="elsevierStyleSup">−ΔCt</span> was found (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.767; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.016).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Receiver operating characteristics curves</span><p id="par0140" class="elsevierStylePara elsevierViewall">ROC curves were calculated for U-II serum levels and for U-II, URP and UT mRNA expression. The analysis showed that day 5<span class="elsevierStyleHsp" style=""></span>U-II serum levels, URP mRNA and UT mRNA could discriminate between Sham and SAH rats. The AUC for these variables were: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.691; 95%CI: 0.565–0.817; for day 5<span class="elsevierStyleHsp" style=""></span>U-II serum levels; AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.706; 95%CI: 0.543–0.868; for URP; and, AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.713; 95%CI: 0.540–0.887; for UT (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">When examining the coordinates of the ROC curve for day 5 U-II serum levels, we observed that the best cut-off, chosen as the one which reached the greatest sum of sensitivity plus specificity, was the value previously defined as the normal median basal serum level for U-II in rats: 0.56<span class="elsevierStyleHsp" style=""></span>pg/mL, with 66.2% sensitivity and 76.2% specificity, 2.15 positive likelihood ratio (LR+), 0.42 negative likelihood ratio (LR−). In our series, the best cut-offs for gene expression were 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3.77<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−7</span> for URP, and 2<span class="elsevierStyleSup">−ΔCt</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.62<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">−6</span> for UT. These cut-offs were applied in our model to determine the accuracy of the variables. URP mRNA displayed 61.3% sensitivity and 83.3% specificity, 3.67 LR+, 0.46 LR−; and UT mRNA showed 60% sensitivity and 80% specificity, 3 LR+, 0.5 LR−.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">This is the first study carried out in an experimental murine model to demonstrate that U-II serum levels are significantly elevated on fifth day after SAH, date that coincides with the usual CVS period in both rats<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a> and humans.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">25</span></a> Moreover, we found that the three urotensinergic system genes were up-regulated after in vivo brain exposure to blood injected into the subarachnoid space. We were also able to define the normal range for U-II serum levels in rats.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The fact that U-II is widely recognized as a peptide with vasoactive properties,<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">26,27</span></a> yet no research exists on its role in SAH and its complications, led us to investigate urotensinergic genes in this pathology. In doing so, we detected changes not only in U-II serum level, but in the expression of URP and UT genes as well. We also uncovered the ability of these three genes to discriminate SAH rats. Although no research studies have examined the role of the urotensinergic system in SAH, a recent paper suggested its implication in arterial vasospasm development, based on U-II contraction activity in both intact and depolarized arteries.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">20</span></a> In the present study, the fact that rats with SAH suffer a delayed increase in their gene expression and protein production levels compared to baseline and Sham animals, points to urotensinergic activation in SAH. The increase in plasmatic U-II, limited to the SAH group and confined to the usual CVS period in both rats<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a> and humans,<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">25</span></a> opens the door to a wide range of possibilities for the study of U-II as a biomarker for cerebral arterial vasoconstriction and even the possibility of constituting a new therapeutic target.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The results concerning the correlation between quantified gene expression levels coincides with Yoshimoto et al., who pointed out U-II's function as an autocrine/paracrine.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a> Based on our observations, we could highlight this peptide's autocrine activity (correlation between three gene expressions of the urotensinergic system, within the lymphocyte) and its possible paracrine activity (correlation between lymphocyte gene expression, specifically URP, and protein serum levels). Nevertheless, we should note that although there are other sources of U-II release throughout the organism, we only measured mRNA production in the lymphocyte.</p><p id="par0165" class="elsevierStylePara elsevierViewall">U-II has been proposed as a biomarker for various diseases in humans, since its concentration results in a variety of clinical and experimental pathologies, including renal and heart failure, essential and portal hypertension, diabetes, and liver cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">29</span></a> But before using U-II quantification to assess disease onset or progression, we must first establish a normal range for its physiological serum concentration. Several authors have attempted this, and while most agree that U-II serum concentration is found in the picomolar range in species that have been studied, the reports do not agree on the protein's exact concentration range.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">30–33</span></a> On the other hand, some authors suggest that the physiological concentration of U-II is under detectable limits.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">34</span></a> This lack of consensus stems from the absence of interchangeability between the analytical assays employed for U-II quantification.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">35</span></a> These methods include radioimmunoassay, radioreceptor assays, enzyme immunoassays and ELISA.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> The main obstacle is that these methods use antibodies for, but not limited to, U-II (e.g. U-II metabolites). In nonhuman U-II plasma quantification, there is an additional problem: despite the high conservation of this protein throughout the species, the exact sequence varies between them.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> As a result, specific antibodies must be designed for each species. In this study, we solved this problem by using specific biochemical reagents for <span class="elsevierStyleItalic">Rattus norvegicus</span>, in both ELISA and PCR execution. As a result, we were able to define the normal range for U-II serum levels in rats measured by fluorescent enzyme immunoassay (EIA, Phoenix Pharmaceuticals, Inc.). This range of normal values is a significant finding, given that it could serve as a reference for assessing U-II serum levels not only in SAH but in other pathologies as well.</p><p id="par0170" class="elsevierStylePara elsevierViewall">The major strengths of this study rest in the utilization of specific biochemical reagents for the species analysis. Additionally, we performed a very easy and reproducible murine model, which would allow other researchers to reproduce our experiments and continue with this line of investigation. Finally, this animal model of SAH allowed us to study biomarker variation in vivo, and thereby study the progression of the disease in real time.</p><p id="par0175" class="elsevierStylePara elsevierViewall">There were some limitations to the present study. The main limitation was the lack of human analysis. We consider that experimental analysis is important prior to human studies, but we recognize that once demonstrated the up-regulation of the urotensinergic system genes in a SAH model, it is necessary to analyze the same biomarkers in SAH human pathology. We analyzed two blood samples, at baseline and on day 5 after surgery, but did not analyze biomarker evolution throughout the development of the disease. By analyzing more blood samples prior to sacrifice, we could define the kinetics of metabolite production. This research could also benefit from the analysis of other tissues, such as brain tissue, which would provide information on tissue status and their potential gene production.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conclusion</span><p id="par0180" class="elsevierStylePara elsevierViewall">Ours is the first study carried out in an experimental murine model to demonstrate that U-II protein serum levels, as well as U-II, URP and UT mRNA expression levels are up-regulated on the fifth day after a percutaneous SAH, usual CVS period in both rats<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a> and humans.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">25</span></a> Furthermore, the three genes showed a high discriminative ability to identify SAH rats. These findings suggest that measurements of gene expression or production, depending on the gene, could serve as biomarkers for SAH onset and progression. Additional studies on SAH patients would be necessary to ascertain the U-II correlation with CVS development, and subsequently determine if this tendency is also observed in humans. These noninvasive analyses could offer physicians early and accurate information on a patient's condition. Furthermore, these results open a new research line for the design of new therapeutic targets for the treatment of the SAH pathology.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Funding</span><p id="par0200" class="elsevierStylePara elsevierViewall">This study was funded by a grant from the Instituto de Salud Carlos III (Spanish National Health System) (10/02044), Consejería de Igualdad, Salud y Políticas Sociales de Andalucía, Spain (PI-0136-2012) and Consejería de Igualdad, Salud y Políticas Sociales de Andalucía, Spain (PI-0002-2013).</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Authors contribution</span><p id="par0205" class="elsevierStylePara elsevierViewall">The manuscript has been read and approved by all of the authors and each author believes that the manuscript represents honest work.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Conflict of interest</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare no conflicting interest in this work.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres933234" "titulo" => "Abstract" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Setting" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Participants" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Interventions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Main variables of interest" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec907592" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres933235" "titulo" => "Resumen" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Ámbito" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Participantes" ] 4 => array:2 [ "identificador" => "abst0065" "titulo" => "Intervenciones" ] 5 => array:2 [ "identificador" => "abst0070" "titulo" => "Principales variables de interés" ] 6 => array:2 [ "identificador" => "abst0075" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "abst0080" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec907593" "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" => "Animals and samples" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Procedures for the two animal models" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Measurement of Urotensin-II serum levels" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Nucleic acid extraction" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Real-time PCR" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] 7 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Urotensin-II serum levels" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "U-II, URP and UT mRNA expression" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Receiver operating characteristics curves" ] ] ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0095" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0100" "titulo" => "Authors contribution" ] 12 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 13 => array:2 [ "identificador" => "xack315026" "titulo" => "Acknowledgments" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-17" "fechaAceptado" => "2016-10-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec907592" "palabras" => array:5 [ 0 => "Subarachnoid hemorrhage" 1 => "Experimental model" 2 => "Biomarkers" 3 => "Urotensin" 4 => "Urotensinergic system" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec907593" "palabras" => array:5 [ 0 => "Hemorragia subaracnoidea" 1 => "Modelo experimental" 2 => "Biomarcadores" 3 => "Urotensina" 4 => "Sistema urotensinérgico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cerebral vasospasm, one of the main complications of subarachnoid hemorrhage (SAH), is characterized by arterial constriction and mainly occurs from day 4 until the second week after the event. Urotensin-II (U-II) has been described as the most potent vasoconstrictor peptide in mammals. An analysis is made of the serum U-II concentrations and mRNA expression levels of U-II, urotensin related peptide (URP) and urotensin receptor (UT) genes in an experimental murine model of SAH.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Design</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">An experimental study was carried out.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Setting</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Experimental operating room of the Biomedicine Institute of Seville (IBiS), Virgen del Rocío University Hospital (Seville, Spain).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Participants</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">96 Wistar rats: 74 SAH and 22 sham intervention animals.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Interventions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Day 1: blood sampling, followed by the percutaneous injection of 100<span class="elsevierStyleHsp" style=""></span>μl saline (sham) or blood (SAH) into the subarachnoid space. Day 5: blood sampling, followed by sacrifice of the animals.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Main variables of interest</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Weight, early mortality, serum U-II levels, mRNA values for U-II, URP and UT.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Serum U-II levels increased in the SAH group from day 1 (0.62<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.36–1.08]) to day 5 (0.74<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.39–1.43]) (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05), though not in the sham group (0.56<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.06–0.83] day 1; 0.37<span class="elsevierStyleHsp" style=""></span>pg/mL [IQR 0.23–0.62] day 5; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.959). Between-group differences were found on day 5 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05). The ROC analysis showed that the day 5 serum U-II levels (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.691), URP mRNA (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.706) and UT mRNA (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.713) could discriminate between sham and SAH rats. The normal serum U-II concentration range in rats was 0.56<span class="elsevierStyleHsp" style=""></span>pg/mL (IQR 0.06–0.83).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The urotensinergic system is upregulated on day 5 in an experimental model of SAH.</p></span>" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Setting" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Participants" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Interventions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Main variables of interest" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El vasoespasmo cerebral, una de las principales complicaciones secundarias a hemorragia subaracnoidea (HSA), se caracteriza por una constricción arterial que tiene lugar principalmente entre el día 4 y la segunda semana. La urotensina-II (U-II) ha sido definida como el péptido con mayor capacidad vasoconstrictora en mamíferos. Quisimos analizar los niveles séricos de U-II, así como los niveles de expresión de los genes de U-II, péptido relacionado con urotensina y receptor de urotensina, en un modelo murino experimental de HSA.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diseño</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Estudio experimental.</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ámbito</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Quirófano experimental del Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío.</p></span> <span id="abst0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Participantes</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Noventa y seis ratas Wistar: 74 con inyección percutánea de sangre (HSA), 22 con inyección percutánea de 100<span class="elsevierStyleHsp" style=""></span>μL de salino (Sham).</p></span> <span id="abst0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Intervenciones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Día 1: extracción de muestras de sangre. Posteriormente, inyección percutánea de 100<span class="elsevierStyleHsp" style=""></span>μL de salino (Sham) o de sangre (HSA) en el espacio subaracnoideo. Día 5: extracción de muestras de sangre y sacrificio del animal.</p></span> <span id="abst0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Principales variables de interés</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Peso, mortalidad precoz, niveles séricos de U-II, valores de ARNm de U-II, péptido relacionado con urotensina y receptor de urotensina.</p></span> <span id="abst0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Resultados</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Observamos un incremento en los niveles de U-II sérica en el grupo HSA desde el día 1 (0,62<span class="elsevierStyleHsp" style=""></span>pg/mL [RI 0,36-1,08]) al día 5 (0,74<span class="elsevierStyleHsp" style=""></span>pg/mL [RI 0,39-1,43]) (p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,05); pero no observamos tal diferencia en el grupo Sham (0,56<span class="elsevierStyleHsp" style=""></span>pg/mL [RI 0,06-0,83] día 1; 0,37<span class="elsevierStyleHsp" style=""></span>pg/mL [RI 0,23-0,62] día 5) (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,959). Se encontraron diferencias en los niveles de U-II entre ambos grupos al quinto día (p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,05). El análisis de curvas ROC demostró que la U-II sérica al quinto día (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,691), ARNm de péptido relacionado con urotensina (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,706) y ARNm de receptor de urotensina (AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,713) podían discriminar entre ratas Sham y HSA. Además, definimos un rango de normalidad para los niveles de U-II séricos en ratas: 0,56<span class="elsevierStyleHsp" style=""></span>pg/mL (RI 0,06-0,83).</p></span> <span id="abst0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusión</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Este estudio demuestra por primera vez que el sistema urotensinérgico ve incrementada su expresión en el quinto día en un modelo de HSA.</p></span>" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Ámbito" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Participantes" ] 4 => array:2 [ "identificador" => "abst0065" "titulo" => "Intervenciones" ] 5 => array:2 [ "identificador" => "abst0070" "titulo" => "Principales variables de interés" ] 6 => array:2 [ "identificador" => "abst0075" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "abst0080" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 642 "Ancho" => 3316 "Tamanyo" => 144834 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Expression of U-II (A), URP (B) and UT (C) by quantitative RT-PCR assay on the fifth day after brain exposure to blood (SAH) compared to saline injection (Sham). (U-II: <span class="elsevierStyleItalic">p</span> = 0.175; URP: <span class="elsevierStyleItalic">p</span> = 0.037; UT: <span class="elsevierStyleItalic">p</span> = 0.046 relative to Sham).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1136 "Ancho" => 3404 "Tamanyo" => 196104 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ROC analysis comparing sensitivity to 1-specificity of serum U-II on fifth day (A), URP mRNA (B) and UT mRNA (C) to discriminate SAH rats. (A: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.691 [95%CI: 0.565–0.817], <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.008; AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.706 [95%CI: 0.543–0.868] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.038; C: AUC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.713 [95%CI: 0.540–0.887] <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.046).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0185" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology and clinical presentation of aneurysmal subarachnoid hemorrhage" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K.J. 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Year/Month | Html | Total | |
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2024 November | 1 | 5 | 6 |
2024 October | 38 | 49 | 87 |
2024 September | 38 | 29 | 67 |
2024 August | 39 | 37 | 76 |
2024 July | 65 | 21 | 86 |
2024 June | 32 | 36 | 68 |
2024 May | 37 | 26 | 63 |
2024 April | 38 | 38 | 76 |
2024 March | 36 | 24 | 60 |
2024 February | 32 | 38 | 70 |
2024 January | 29 | 34 | 63 |
2023 December | 33 | 39 | 72 |
2023 November | 44 | 36 | 80 |
2023 October | 23 | 30 | 53 |
2023 September | 48 | 35 | 83 |
2023 August | 32 | 23 | 55 |
2023 July | 34 | 24 | 58 |
2023 June | 22 | 15 | 37 |
2023 May | 47 | 37 | 84 |
2023 April | 36 | 21 | 57 |
2023 March | 86 | 31 | 117 |
2023 February | 50 | 43 | 93 |
2023 January | 23 | 17 | 40 |
2022 December | 59 | 49 | 108 |
2022 November | 78 | 32 | 110 |
2022 October | 65 | 54 | 119 |
2022 September | 63 | 28 | 91 |
2022 August | 61 | 42 | 103 |
2022 July | 68 | 43 | 111 |
2022 June | 68 | 35 | 103 |
2022 May | 85 | 34 | 119 |
2022 April | 48 | 46 | 94 |
2022 March | 53 | 57 | 110 |
2022 February | 23 | 30 | 53 |
2022 January | 35 | 34 | 69 |
2021 December | 68 | 50 | 118 |
2021 November | 35 | 45 | 80 |
2021 October | 45 | 70 | 115 |
2021 September | 31 | 33 | 64 |
2021 August | 29 | 38 | 67 |
2021 July | 40 | 33 | 73 |
2021 June | 23 | 22 | 45 |
2021 May | 36 | 40 | 76 |
2021 April | 85 | 63 | 148 |
2021 March | 54 | 30 | 84 |
2021 February | 52 | 39 | 91 |
2021 January | 38 | 28 | 66 |
2020 December | 35 | 16 | 51 |
2020 November | 27 | 22 | 49 |
2020 October | 32 | 29 | 61 |
2020 September | 32 | 19 | 51 |
2020 August | 18 | 20 | 38 |
2020 July | 23 | 19 | 42 |
2020 June | 37 | 18 | 55 |
2020 May | 29 | 11 | 40 |
2020 April | 20 | 9 | 29 |
2020 March | 19 | 7 | 26 |
2020 February | 79 | 28 | 107 |
2020 January | 33 | 28 | 61 |
2019 December | 33 | 18 | 51 |
2019 November | 32 | 27 | 59 |
2019 October | 28 | 13 | 41 |
2019 September | 34 | 26 | 60 |
2019 August | 28 | 18 | 46 |
2019 July | 25 | 24 | 49 |
2019 June | 13 | 13 | 26 |
2019 May | 39 | 34 | 73 |
2019 April | 22 | 23 | 45 |
2019 March | 12 | 20 | 32 |
2019 February | 17 | 21 | 38 |
2019 January | 25 | 36 | 61 |
2018 December | 50 | 27 | 77 |
2018 November | 84 | 60 | 144 |
2018 October | 155 | 28 | 183 |
2018 September | 20 | 12 | 32 |
2018 August | 17 | 8 | 25 |
2018 July | 25 | 10 | 35 |
2018 June | 31 | 14 | 45 |
2018 May | 14 | 10 | 24 |
2018 April | 21 | 12 | 33 |
2018 March | 20 | 3 | 23 |