Transient Mesenteric Ischemia Leads to Remodeling of Rat Mesenteric Resistance Arteries

Mesenteric ischemia/reperfusion (I/R) is associated with high rates of morbidity and mortality. We studied the effect of mesenteric I/R on structural and mechanical properties of rat mesenteric resistance artery (MRA) that, once disrupted, might impact the outcome of this devastating clinical condition. Superior mesenteric artery from Wistar–Kyoto rats was occluded (90 min) and reperfused (24 h). The effect of tezosentan, a dual endothelin (ET)-receptor antagonist, was studied in ischemic (IO) and sham-operated (SO) animals. MRA structure and mechanics were assessed by pressure myography. Nuclei distribution, elastin content and organization, collagen I/III and ET-1 expression, ET-1 plasma levels, superoxide anion (O2⋅−) production, and mRNA levels of NAD(P)H-oxidase subunits were measured. To assess ET-1 effects on O2⋅− production, MRA from non-operated rats were incubated in culture medium with ET-1. Mesenteric I/R increased MRA wall thickness (P < 0.05) and cross-sectional area (P < 0.05) but decreased wall stiffness (P < 0.05). Arterial remodeling was paralleled by enhancement of: (i) collagen I/III expression (P < 0.01), ET-1 expression (P < 0.05), and O2⋅− formation (P < 0.01) in the vessel wall; (ii) number of internal elastic lamina (IEL) fenestrae (P < 0.05); and (iii) plasma levels of ET-1 (P < 0.05). Moreover, ET-1 increased O2⋅− (P < 0.05) production in cultured MRA. Tezosentan prevented hypertrophic remodeling and collagen I/III deposition, and enhanced O2⋅− production, but it did not affect the decreased wall stiffness after mesenteric I/R. These results indicate that 90 min occlusion/24 h reperfusion induces hypertrophic remodeling of MRA linked to ET-1-mediated increase of collagen and O2⋅−. Decreased stiffness may be associated with increased number of IEL fenestrae. The resulting MRA remodeling, initially adaptive, might become maladaptive contributing to the pathology and poor outcome of mesenteric I/R, and might be a valuable treatment target for mesenteric I/R

Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase –NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase –PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.This study was supported by Ministerio de Economía y Competitividad (SAF2012-38530), CiberCV (CB16/11/00286 and CB16/11/00264), and Fondo Europeo de Desarrollo Regional (FEDER) a way to build Europe, Comunidad de Madrid (B2017/BMD-3676

La motivación en los diferentes contextos educativos en alumnado de Educación Secundaria Obligatoria

En el presente artículo realiza una revisión teórica sobre la importancia que ejerce la motivación en el aprendizaje de los alumnos de Educación Secundaria Obligatoria. En primer lugar, se realizará un breve análisis sobre los cambios, tanto físicos como psicológicos, que influyen en los adolescentes y en su motivación para aprender los contenidos teóricos y prácticos durante su estancia en el instituto. Posteriormente, se realizará un análisis sobre los factores que más influyen en esta motivación, tales como el profesor, los iguales y el contenido que se pretende enseñarles. Las conclusiones extraídas indican que las últimas reformas educativas se han centrado en potenciar la motivación académica y las calificaciones escolares de los estudiantes, sin profundizar en el conocimiento de la influencia que pueden tener los factores sociales o contextuales sobre la motivación en el ámbito escolar.Proyecto de Innovación Docente ReiDoCrea. Departamento de Psicología Social. Universidad de Granada

Hepatic encephalopathy-associated cerebral vasculopathy in acute-on-chronic liver failure: Alterations on endothelial factor release and influence on cerebrovascular function

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F releases were increased, whereas thromboxane (TX) B was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI synthase, and TXA S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE. 1α 2 2 2This research was funded by the Ministerio de Economía y Competitividad (SAF2016-80305-P), CiberCV (Grant number: CB16/11/00286), the European Regional Development Grant (FEDER) (Comunidad de Madrid, grant number B2017/BMD- 3676), and R C D projects for young researchers, Universidad Autónoma de Madrid-Comunidad de Madrid (SI1-PJI-2019- 00321). RR-D received a fellowship from Juan de la Cierva Program (IJCI-2017-31399)

Myoinvasive pattern as a prognostic marker in low-grade, early-stage endometrioid endometrial carcinoma

Low-grade and early Federation for Gynecology and Obstetrics (FIGO) stage endometrioid endometrial carcinomas (EEC) have an excellent prognosis. However, approximately 10% of patients develop recurrence, which cannot be correctly predicted at diagnosis. We evaluated myoinvasive patterns as a prognostic factor of relapse in low-grade, early-stage EEC. Two-hundred and fifty-eight cases were selected according to the following inclusion criteria: (i) endometrioid endometrial carcinomas, (ii) grade 1 or 2 with (iii) FIGO stage I or II, and (iv) clinical follow-up. Slides were reviewed to annotate the myoinvasive pattern present in each case (infiltrative glands, microcystic, elongated and fragmented –MELF-, broad front, adenomyosis-like and adenoma malignum). Microsatellite instability was studied by immunoexpression of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). There were 29 recurrences (11.2%) among the 258 cases analysed. A predominant broad front myoinvasive pattern was significantly associated with tumour relapse (p = 0.003). The presence of a pattern of infiltrative glands (p = 0.001) and microsatellite instability (p = 0.004) were associated with lower disease-free survival, without having an impact on overall survival. Our observations suggest the potential value of the pattern of myoinvasion as a prognostic factor in low-grade, early-stage endometrioid endometrial carcinomaThis research was funded by the Instituto de Salud Carlos III (ISCIII) (PI17/01723), co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (FEDER)

Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma

Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumoursThis research was funded by the Instituto de Salud Carlos III (ISCIII) (PI17/01723), co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (FEDER

Proposta didáctica para o desenvolvimento da capacidade aeróbica através da Educação Física no terceiro ciclo do Ensino Básico

Introducción: La realización de una actividad física regular predice mantener una buena salud presente y futura. Asimismo, un factor relacionado con la actividad física es la condición física, la cual suele evaluarse en la población escolar a través de la capacidad aeróbica con el uso del test de Course Navette. Revisiones de la literatura recientes concluyen que resulta necesario mejorar los niveles de capacidad aeróbica en los escolares ya que se considera un factor importante para el mantenimiento y optimización de la salud. En consecuencia, el objetivo del presente escrito es realizar una propuesta didáctica para el desarrollo de la capacidad aeróbica desde la Educación Física en tercer ciclo de Educación Primaria. Desarrollo: La propuesta se basa en una sesión prototipo con la que se podría iniciar el trabajo de la capacidad aeróbica en clase de una manera lúdica. Está diseñada según la instrucción 12/2022 de 23 de junio, para 5º de Educación Primaria con un total de 26 estudiantes. Se basa en la temática “La vida en la selva” a partir de una historia que explica el contenido de cada actividad. La sesión consta de calentamiento, parte principal con 5 juegos y vuelta a la calma. Conclusión: Desde la comunidad educativa se debe prestar atención a la comunidad científica, con el fin de observar desde una base científica “qué está pasando” entre nuestros y nuestras escolares, detectar una cuestión con necesidad de solventar y poner una solución.Introduction: Regular physical activity is predictive of good current and future health. Also, a factor related to physical activity is physical fitness, which is often assessed in the school population through aerobic capacity using the Course Navette test. Recent literature reviews conclude that there is a need to improve aerobic capacity levels as it is considered an important factor for the maintenance and optimisation of health. Consequently, the aim of this paper is to make a didactic proposal to aerobic capacity development in physical education in third-year primary school student. Development: The proposal is based on a prototype session which could be used to start working on aerobic capacity in class in a playful way. It is designed according to instruction 12/2022 of 23 June, for 5th year of primary school with a total of 26 students. It is based on the topic "Life in the jungle" with a story that explains the content of each activity. This session consists of a warm-up, a main part with 5 games and a cool-down. Conclusion: The educational community should pay attention to the scientific community, in order to observe on a scientific basis "what is happening" among our students, to detect an issue that needs to be solved and to find a solution.Introdução: A actividade física regular é um indicador de boa saúde actual e futura. Além disso, um factor relacionado com a actividade física é a aptidão física, que é frequentemente avaliada na população escolar através da capacidade aeróbica utilizando o teste Course Navette. Revisões recentes da literatura concluem que é necessário melhorar os níveis de capacidade aeróbica em crianças em idade escolar, uma vez que esta é considerada um factor importante para a manutenção e optimização da saúde. Assim, o objectivo deste trabalho é desenvolver uma proposta didáctica para o desenvolvimento da capacidade aeróbia a partir da Educação Física no terceiro ciclo do Ensino Básico. Desenvolvimento: A proposta baseia-se numa sessão protótipo que pode ser utilizada para começar a trabalhar a capacidade aeróbica nas aulas de uma forma lúdica. Foi concebida de acordo com a instrução 12/2022 de 23 de Junho, para o 5º ano do Ensino Básico com um total de 26 alunos. Baseia-se no tema "A vida na selva" com uma história que explica o conteúdo de cada atividade. A sessão é composta por um aquecimento, uma parte principal com 5 jogos e um regresso à calma. Conclusão: A comunidade educativa deve prestar atenção à comunidade científica, a fim de observar numa base científica "o que está a acontecer" entre os nossos alunos, para detetar um problema que precisa de ser resolvido e encontrar uma solução

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation.Peer reviewe

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation.Peer reviewe

Proteomic analysis of low-grade, early-stage endometrial carcinoma reveals new dysregulated pathways associated with cell death and cell signaling

Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumorsThis research was funded by the Instituto de Salud Carlos III (ISCIII) (PI17/01723), cofinanced by the European Development Regional Fund “A way to achieve Europe” (FEDER