Injurious mechanical ventilation affects neuronal activation in ventilated rats

Survivors of critical illness often have significant long-term brain dysfunction, and routine clinical procedures like mechanical ventilation (MV) may affect long-term brain outcome. We aimed to investigate the effect of the increase of tidal volume (Vt) on brain activation in a rat model. Male Sprague Dawley rats were randomized to three groups: 1) Basal: anesthetized unventilated animals, 2) low Vt (LVt): MV for three hours with Vt 8 ml/kg and zero positive end-expiratory pressure (ZEEP), and 3) high Vt (HVt) MV for three hours with Vt 30 ml/kg and ZEEP. We measured lung mechanics, mean arterial pressure (MAP), arterial blood gases, and plasma and lung levels of cytokines. We used immunohistochemistry to examine c-fos as a marker of neuronal activation. An additional group of spontaneously breathing rats was added to discriminate the effect of surgical procedure and anesthesia in the brain. After three hours on LVt, PaOdecreased and PaCOincreased significantly. MAP and compliance remained stable in MV groups. Systemic and pulmonary inflammation was higher in MV rats than in unventilated rats. Plasma TNFα was significantly higher in HVt than in LVt. Immunopositive cells to c-fos in the retrosplenial cortex and thalamus increased significantly in HVt rats but not in LVt or unventilated rats. MV promoted brain activation. The intensity of the response was higher in HVt animals, suggesting an iatrogenic effect of MV on the brain. These findings suggest that this novel cross-talking mechanism between the lung and the brain should be explored in patients undergoing MV

Activation of the Wnt/β-Catenin Signaling Pathway by Mechanical Ventilation Is Associated with Ventilator-Induced Pulmonary Fibrosis in Healthy Lungs

BACKGROUND: Mechanical ventilation (MV) with high tidal volumes (V(T)) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI. METHODOLOGY/PRINCIPAL FINDINGS: Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (V(T)) (6 mL/kg) or high V(T) (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-V(T) MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-V(T) MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI

Usefulness of Housekeeping Genes for the Diagnosis of Helicobacter pylori Infection, Strain Discrimination and Detection of Multiple Infection

Background: Helicobacter pylori infects human stomachs of over half the world's population, evades the immune response and establishes a chronic infection. Although most people remains asymptomatic, duodenal and gastric ulcers, MALT lymphoma and progression to gastric cancer could be developed. Several virulence factors such as flagella, lipopolysaccharide, adhesins and especially the vacuolating cytotoxin VacA and the oncoprotein CagA have been described for H. pylori. Despite the extensive published data on H. pylori, more research is needed to determine new virulence markers, the exact mode of transmission or the role of multiple infection. Materials and Methods: Amplification and sequencing of six housekeeping genes (amiA, cgt, cpn60, cpn70, dnaJ, and luxS) related to H. pylori pathogenesis have been performed in order to evaluate their usefulness for the specific detection of H. pylori, the genetic discrimination at strain level and the detection of multiple infection. A total of 52 H. pylori clones, isolated from 14 gastric biopsies from 11 patients, were analyzed for this purpose. Results: All genes were specifically amplified for H. pylori and all clones isolated from different patients were discriminated, with gene distances ranged from 0.9 to 7.8%. Although most clones isolated from the same patient showed identical gene sequences, an event of multiple infection was detected in all the genes and microevolution events were showed for amiA and cpn60 genes. Conclusions: These results suggested that housekeeping genes could be useful for H. pylori detection and to elucidate the mode of transmission and the relevance of the multiple infection

Los ODS como instrumento de aprendizaje: una experiencia multidisciplinar en los estudios universitarios

The approval of the 2030 Agenda and the Sustainable Development Goals (SDG) represents an ambitious roadmap which try to respond to the global and existential challenges that humanity faces. Under the slogan: “Leaving no one behind”, its 17 Goals include transcendental issues ranging from poverty eradication to climate action, through access to affordable, reliable, sustainable and modern energy or sustained economic growth, inclusive and sustainable and ending with the reduction of inequalities between countries or the promotion of peaceful and inclusive societies. In this context, Universities, like the rest of the actors, are called to play a fundamental role due to their position as generators and transmitters of knowledge. This is precisely the purpose of this educational innovation project in which the SDGs are used as a learning tool. It is an innovative and multidisciplinary experience implemented during several academic years in four different degrees at the European University of Valencia. More than a hundred students have had the opportunity to participate in the project, obtaining highly satisfactory results and an evident improvement in their knowledge and skills. A project, in which different learning methodologies are combined, with the aim that students, as future leaders and managers, not only know and are able to respond to these important challenges, but also they acquire a series of competencies, the so-called soft skills, which are currently essential for a better quality education and more human.La aprobación de la Agenda 2030 y de los Objetivos de Desarrollo Sostenible (ODS) representa una ambiciosa hoja de ruta para intentar dar respuesta a los desafíos globales y existenciales a los que se enfrenta a la humanidad. Bajo el lema de “No dejar a nadie a atrás” sus 17 objetivos comprenden cuestiones trascendentales que van desde la erradicación de la pobreza a la acción climática, pasando por el acceso a energías asequibles, fiables, sostenibles y modernas o el crecimiento económico sostenido, inclusivo y sostenible y terminando con la reducción de las desigualdades entre países o la promoción de sociedades pacíficas e inclusivas. En este contexto las Universidades, como el resto de los actores, están llamadas a desempeñar un papel crucial debido a su importante función como generadores y transmisores de conocimiento. Precisamente esta es la finalidad del presente proyecto de innovación educativa en el que nuevas metodologías de aprendizaje se utilizan para contribuir a este propósito. Se trata de una experiencia innovadora y multidisciplinar implantada durante varios cursos académicos en cuatro grados diferentes en la Universidad Europea de Valencia. Más de un centenar de estudiantes han tenido la oportunidad de participar en el proyecto obteniendo unos resultados altamente satisfactorios y una mejora evidente de sus conocimientos y competencias. Un proyecto, basado en alianzas y que posibilita que los estudiantes, en su condición de futuros líderes y gestores, no sólo conozcan y sean capaces de dar respuesta a estos importantes retos, sino que también adquieran una serie de competencias, las denominadas soft skills, que en la actualidad resultan imprescindibles

Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Peer reviewe

Injurious mechanical ventilation affects neuronal activation in ventilated rats

Survivors of critical illness often have significant long-term brain dysfunction, and routine clinical procedures like mechanical ventilation (MV) may affect long-term brain outcome. We aimed to investigate the effect of the increase of tidal volume (Vt) on brain activation in a rat model. Male Sprague Dawley rats were randomized to three groups: 1) Basal: anesthetized unventilated animals, 2) low Vt (LVt): MV for three hours with Vt 8 ml/kg and zero positive end-expiratory pressure (ZEEP), and 3) high Vt (HVt) MV for three hours with Vt 30 ml/kg and ZEEP. We measured lung mechanics, mean arterial pressure (MAP), arterial blood gases, and plasma and lung levels of cytokines. We used immunohistochemistry to examine c-fos as a marker of neuronal activation. An additional group of spontaneously breathing rats was added to discriminate the effect of surgical procedure and anesthesia in the brain. After three hours on LVt, PaOdecreased and PaCOincreased significantly. MAP and compliance remained stable in MV groups. Systemic and pulmonary inflammation was higher in MV rats than in unventilated rats. Plasma TNFα was significantly higher in HVt than in LVt. Immunopositive cells to c-fos in the retrosplenial cortex and thalamus increased significantly in HVt rats but not in LVt or unventilated rats. MV promoted brain activation. The intensity of the response was higher in HVt animals, suggesting an iatrogenic effect of MV on the brain. These findings suggest that this novel cross-talking mechanism between the lung and the brain should be explored in patients undergoing MV

Moderate Peep After Tracheal Lipopolysaccharide Instillation Prevents Inflammation and Modifies the Pattern of Brain Neuronal Activation

ABSTRACT Background: Ventilatory strategy and specifically positive end-expiratory pressure (PEEP) can modulate the inflammatory response and pulmonary-to-systemic translocation of lipopolysaccharide (LPS). Both inflammation and ventilatory pattern may modify brain activation, possibly worsening the patient's outcome and resulting in cognitive sequelae. Methods: We prospectively studied Sprague–Dawley rats randomly assigned to undergo 3 h mechanical ventilation with 7 mL/kg tidal ventilation and either 2 cmH2O or 7 cmH2O PEEP after intratracheal instillation of LPS or saline. Healthy nonventilated rats served as baseline. We analyzed lung mechanics, gas exchange, lung and plasma cytokine levels, lung apoptotic cells, and lung neutrophil infiltration. To evaluate brain neuronal activation, we counted c-Fos immunopositive cells in the retrosplenial cortex (RS), thalamus, supraoptic nucleus (SON), nucleus of the solitary tract (NTS), paraventricular nucleus (PVN), and central amygdala (CeA). Results: LPS increased lung neutrophilic infiltration, lung and systemic MCP-1 levels, and neuronal activation in the CeA and NTS. LPS-instilled rats receiving 7 cmH2O PEEP had less lung and systemic inflammation and more c-Fos-immunopositive cells in the RS, SON, and thalamus than those receiving 2 cmH2O PEEP. Applying 7 cmH2O PEEP increased neuronal activation in the CeA and NTS in saline-instilled rats, but not in LPS-instilled rats. Conclusions: Moderate PEEP prevented lung and systemic inflammation secondary to intratracheal LPS instillation. PEEP also modified the neuronal activation pattern in the RS, SON, and thalamus. The relevance of these differential brain c-Fos expression patterns in neurocognitive outcomes should be explored