Glucocorticoid receptor intestinal epithelial knockout mice show attenuated colonic inflammatory response but unaffected permeability in early experimental sepsis

Introduction: Sepsis is defined as an organic dysfunction that threatens the life of patients due to an abnormally regulated response to infection [1]. The initial phase of sepsis is dominated by an increased production of proinflammatory cytokines, which leads to augmented capillary permeability, extravasation, hypercoagulability and myelopoiesis. One of the main sources of infection in sepsis is believed to be the intestinal microbiota via traslocation through the mucosa to the bloodstream. Systemic inflammation weakens intestinal barrier function (IBF) in animal models, resulting in increased bacterial traslocation [2]. Even if the management of sepsis has advanced in the last decades, mortality is still high and there are blanks in terms of pathological systems and long-term consequences. Thus, the search for effective treatments is clearly justified. Glucocorticoids (GC) are part of the drugs used in sepsis, but they have only shown a moderate therapeutic effect. This fact may be caused by harmful effects of GCs on IBF, whose compromise may limit GC clinical benefit by facilitating luminal translocation of microorganisms. Besides, GC treatment impairs epithelial healing in experimental colitis in mice [3]. Previous results of our research group have shown that mice with induced deletion of the GC receptor (GR) in intestinal epithelial cells (i.e. NR3C1ΔIEC mice) are protected against dextran sulphate sodium (DSS)-induced colitis [4]. In turn, gene deletion results in a short lived inflammatory response in the colon [5]. Objective: Understanding the role of the intestinal epithelial GR and its involvement in IBF regulation in experimental sepsis, with the ultimate goal of improving the management of sepsis with GCs. Matherial and methods: The cecal ligation and puncture (CLP) model of sepsis was applied to WT C57BL/6J and NR3C1ΔIEC mice. Ceacum-exposed mice were used as control (Sham). Mice were sacrificed 24 hours after surgery. Four hours before sacrifice, mice were administered 4 kD FITC-dextran, a fluorescent marker of permeability. Colon, jejunum, adrenes, kidney and liver RT-qPCRs were performed as well as determination of plasma FITC-dextran and corticosterone plasma levels. Results: After 24 h, CLP mice exhibited elevated corticosterone plasma levels with hypoglycemia and splenomegaly. Intestinal barrier function was weakened, as indicated by increased FITC-dextran plasma levels. A modest increase in inflammatory markers (S100a8, Cxcl1) was noted in the colon and jejunum. The expression of Tjp1, involved in barrier function, was downregulated in CLP mice. Similarly, the colonic expression of Cyp11a1 and Lrh1, involved in local steroidogenesis, was lower in CLP mice, regardless of genotype. Markers of inflammation were also augmented in the lung and kidney. CLP mice exhibited hypercorticosteronemia, which was associated to increased Cyp11a1 in the adrenes. Of note, both parameters were less pronounced in KO mice. The latter also exhibited dampened inflammatory response in the colon but not the jejunum. FITC-dextran plasma levels were similarly increased in WT and KO mice. Conclusions: In the early stages of the CLP model of sepsis the colon and jejunum are inflamed, and epithelial deletion of the glucocorticoid receptor appears to modulate inflammation in the former, with no change in barrier function. Further studies will characterize the microbiota composition and phenotype in later stages and in the response to glucocorticoid treatment

Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet

Funding: This research was funded by the Ministry of Economy and Competitivity of Spain, partly with Fondo Europeo de Desarrollo Regional FEDER funds [BFU2014-57736-P, AGL2014-58883-R, SAF2017-88457-R, AGL2017-85270-R] and by Junta de Andalucía [CTS235, CTS164]. MTG, RGB and CHC were supported by fellowships from the Ministry of Education. CIBERehd is funded by Instituto de Salud Carlos III. Institutional Review Board Statement: The study was conducted according to the guidelines of the Guide for the Care and Use of Laboratory Animals, and approved by the Animal Welfare Committee of the University of Granada (registry number: CEEA 01/03/2017–029). Informed Consent Statement: Not applicable for studies not involving humans. Acknowledgments: We gratefully acknowledge the assistance of Mercedes González and the rest of the group.The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP+/− haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP+/− and WT mice fed the MCD diet. In turn, TNAP+/− mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP+/− mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet.Ministry of Economy and Competitivity of SpainEuropean Commission BFU2014-57736-P AGL2014-58883-R SAF2017-88457-R AGL2017-85270-RJunta de Andalucia CTS235 CTS164Ministry of EducationInstituto de Salud Carlos III European Commissio

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Ventilación natural y sensación térmica en las aulas de los Centros de Educación Básica Estatal, Sector 9 - Nuevo Chimbote 2019” – “Centro de Educación Básica Estatal

En Perú se está promoviendo un crecimiento intensivo en la construcción de diversas edificaciones, los cuales emplean sistemas de ventilación artificiales, buscando el confort del usuario, de igual manera sucede en las aulas de los centros educativos, generando malestar térmico en los alumnos, ocasionando bajo rendimiento debido al cansancio, sofocación, distracción e incluso trasmisión de enfermedades. Lo mismo ocurre en las 8 II.EE. básicas estatales del Sector 9 de Nuevo Chimbote, es por ello, que la presente investigación tuvo como objetivo determinar la influencia de la ventilación natural en la sensación térmica de los alumnos dentro de sus aulas en los centros objeto de estudio. El tipo de investigación fue de enfoque Cualitativo – Descriptivo, porque permite comparar nuevos resultados obtenidos con investigaciones previas e implica observar y describir los criterios que se tomaron en cuenta para su desarrollo. La población tomada en cuenta son los alumnos de primaria y secundaria, donde se aplicó la formula finita y obtuvo una muestra de 370 alumnos. Se usó como instrumentos: cuadernillos de observación, fichas de análisis documental, entrevista a expertos y a los alumnos. Los instrumentos arrojaron como resultados que los alumnos en temporada de verano sienten calor, cansancio, etc. dentro de sus aulas porque los sistemas de ventilación natural empleados no se les dan mantenimiento y no se aprovechan por la mala orientación en relación con la incidencia del viento, además los alumnos no tienen una vestimenta reglamentaria adecuada para la temporada. En base a los resultados se concluyó que la ventilación natural influye positivamente en la sensación térmica en las aulas; de igual forma, se recomienda que los centros de educación básica estatal deben alinearse con respecto a las características de su entorno; así como en las aulas, se recomienda, tener presente las relaciones espaciales, la antropometría y los aspectos tecnológicos para generar el confort en los alumnos