95 research outputs found

    Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

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    Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (T 1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring T 17 and T 2 responses for clearance (bacterial and helminth infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use

    Feasibility and short-term outcomes in liver-first approach: a Spanish snapshot study (the RENACI Project)

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    (1) Background: The liver-first approach may be indicated for colorectal cancer patients with synchronous liver metastases to whom preoperative chemotherapy opens a potential window in which liver resection may be undertaken. This study aims to present the data of feasibility and short-term outcomes in the liver-first approach. (2) Methods: A prospective observational study was performed in Spanish hospitals that had a medium/high-volume of HPB surgeries from 1 June 2019 to 31 August 2020. (3) Results: In total, 40 hospitals participated, including a total of 2288 hepatectomies, 1350 for colorectal liver metastases, 150 of them (11.1%) using the liver-first approach, 63 (42.0%) in hospitals performing <50 hepatectomies/year. The proportion of patients as ASA III was significantly higher in centers performing ≥50 hepatectomies/year (difference: 18.9%; p = 0.0213). In 81.1% of the cases, the primary tumor was in the rectum or sigmoid colon. In total, 40% of the patients underwent major hepatectomies. The surgical approach was open surgery in 87 (58.0%) patients. Resection margins were R0 in 78.5% of the patients. In total, 40 (26.7%) patients had complications after the liver resection and 36 (27.3%) had complications after the primary resection. One-hundred and thirty-two (89.3%) patients completed the therapeutic regime. (4) Conclusions: There were no differences in the surgical outcomes between the centers performing <50 and ≥50 hepatectomies/year. Further analysis evaluating factors associated with clinical outcomes and determining the best candidates for this approach will be subsequently conducted

    Synchronization of Optomechanical Nanobeams by Mechanical Interaction

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    The synchronization of coupled oscillators is a phenomenon found throughout nature. Mechanical oscillators are paradigmatic examples, but synchronizing their nanoscaled versions is challenging. We report synchronization of the mechanical dynamics of a pair of optomechanical crystal cavities that, in contrast to previous works performed in similar objects, are intercoupled with a mechanical link and support independent optical modes. In this regime they oscillate in antiphase, which is in agreement with the predictions of our numerical model that considers reactive coupling. We also show how to temporarily disable synchronization of the coupled system by actuating one of the cavities with a heating laser, so that both cavities oscillate independently. Our results can be upscaled to more than two cavities and pave the way towards realizing integrated networks of synchronized mechanical oscillators

    Synchronization of Optomechanical Nanobeams by Mechanical Interaction

    Get PDF
    The synchronization of coupled oscillators is a phenomenon found throughout nature. Mechanical oscillators are paradigmatic examples, but synchronizing their nanoscaled versions is challenging. We report synchronization of the mechanical dynamics of a pair of optomechanical crystal cavities that, in contrast to previous works performed in similar objects, are intercoupled with a mechanical link and support independent optical modes. In this regime they oscillate in antiphase, which is in agreement with the predictions of our numerical model that considers reactive coupling. We also show how to temporarily disable synchronization of the coupled system by actuating one of the cavities with a heating laser, so that both cavities oscillate independently. Our results can be upscaled to more than two cavities and pave the way towards realizing integrated networks of synchronized mechanical oscillators

    Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model

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    The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer

    Nature and consequences of interactions between Salmonella enterica serovar Dublin and host cells in cattle

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    International audienceAbstractSalmonella enterica is a veterinary and zoonotic pathogen of global importance. While murine and cell-based models of infection have provided considerable knowledge about the molecular basis of virulence of Salmonella, relatively little is known about salmonellosis in naturally-affected large animal hosts such as cattle, which are a reservoir of human salmonellosis. As in humans, Salmonella causes bovine disease ranging from self-limiting enteritis to systemic typhoid-like disease and exerts significant economic and welfare costs. Understanding the nature and consequences of Salmonella interactions with bovine cells will inform the design of effective vaccines and interventions to control animal and zoonotic infections. In calves challenged orally with S. Dublin expressing green fluorescent protein (GFP) we observed that the bacteria were predominantly extracellular in the distal ileal mucosa and within gut-associated lymph nodes 48 h post-infection. Intracellular bacteria, identified by flow cytometry using the GFP signal, were predominantly within MHCII+ macrophage-like cells. In contrast to observations from murine models, these S. Dublin-infected cells had elevated levels of MHCII and CD40 compared to both uninfected cells from the same tissue and cells from the cognate tissue of uninfected animals. Moreover, no gross changes of the architecture of infected lymph nodes were observed as was described previously in a mouse model. In order to further investigate Salmonella-macrophage interactions, net replication of S. enterica serovars that differ in virulence in cattle was measured in bovine blood-derived macrophages by enumeration of gentamicin-protected bacteria and fluorescence dilution, but did not correlate with host-specificity

    Reflexiones desde el Aula de Clases en Arquitectura

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    Las líneas que siguen a continuación son el resultado de un ejercicio académico de estudiantes de noveno semestre del Programa de Arquitectura de la Universidad de la Costa, en el marco de la asignatura Electiva en Proyecto de Investigación II dirigida por el profesor Samuel Padilla-Llano, donde se aborda la investigación como un proceso de coproducción del conocimiento a través de metodologías y estrategias pedagógicas en el aula que permiten al estudiante deconstruir conceptos y elaborar colectivamente posturas y argumentación que aporten a la elaboración de ejercicios investigativos que decantan en productos de investigación y que reflejan en aprendizaje y el dominio de las competencias genéricas y específicas que consolidan su formación académica y profesional. La metodología de este ejercicio rápido de escritura está basada en las lecturas previas de fuentes primarias y bibliografía estructurada en las temáticas desarrolladas en la asignatura las cuales tienen un enfoque en la relación existente entre la arquitectura y los saberes relacionados con la salud y la medicina. Durante una sesión de clases de 3 horas se realiza un debate para socializar y puesta en común de las ideas. Posteriormente cada estudiante dedica un tiempo de la misma sesión a la elaboración del escrito bajo los parámetros indicados (ser reflexiones inéditas, usar citas bibliográficas a partir de las lecturas, tener control del sistema de citación APA). Luego se socializa el resultado y se organiza en documento colectivo y se prepara la publicación conjunta como resultado del trabajo reflexivo. Esta serie de lecturas realizadas durante el curso plantea la lectura semanal de dos artículos. Estos artículos que referencian trabajos locales, nacionales e internacionales, abordan elementos que ponen en discusión las formas de habitar del ser humano y la calidad de vida en los espacios donde trascurre el habitar. Preguntarnos sobre la calidad del hábitat humano y los aspectos que la definen, también es un acto que los arquitectos desde una disciplina concentrada en el hacer espacios para habitar (la casa, la calle, el barrio, la ciudad, etc.), debemos asumir con vocación y conciencia del efecto y la importancia que tiene sobre la vida del ser (o seres) que habitan el espacio. Y desde esa conciencia, el hacer la arquitectura es el arte de pensar, proyectar y configurar formas de habitar en el mudo

    Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

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    PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

    Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

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    PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks
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