Individuals With SARS-CoV-2 Infection During the First and Second Waves in Catalonia, Spain: Retrospective Observational Study Using Daily Updated Data

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiologia; ComparacióCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiología; ComparaciónCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiology; ComparisonA description of individuals with SARS-CoV-2 infection comparing the first and second waves could help adapt health services to manage this highly transmissible infection.Objective: We aimed to describe the epidemiology of individuals with suspected SARS-CoV-2 infection, and the characteristics of patients with a positive test comparing the first and second waves in Catalonia, Spain. Methods: This study had 2 stages. First, we analyzed daily updated data on SARS-CoV-2 infection in individuals from Girona (Catalonia). Second, we compared 2 retrospective cohorts of patients with a positive reverse-transcription polymerase chain reaction or rapid antigen test for SARS-CoV-2. The severity of patients with a positive test was defined by their admission to hospital, admission to intermediate respiratory care, admission to the intensive care unit, or death. The first wave was from March 1, 2020, to June 24, 2020, and the second wave was from June 25, 2020, to December 8, 2020.Results: The numbers of tests and cases were lower in the first wave than in the second wave (26,096 tests and 3140 cases in the first wave versus 140,332 tests and 11,800 cases in the second wave), but the percentage of positive results was higher in the first wave than in the second wave (12.0% versus 8.4%). Among individuals with a positive diagnostic test, 818 needed hospitalization in the first wave and 680 in the second; however, the percentage of hospitalized individuals was higher in the first wave than in the second wave (26.1% versus 5.8%). The group that was not admitted to hospital included older people and those with a higher percentage of comorbidities in the first wave, whereas the characteristics of the groups admitted to hospital were more alike.This work was supported by grants from the European Union ERDF funds (Network for Prevention and Health Promotion in Primary Care, RedIAPP–CARDIOCAT; RD16/0007/0004) and from the Agency for Management of University and Research Grants (AGAUR; 2017-SGR 1146). We thank Eric Tornabell for his technical support. We also thank all health care professionals for their ceaseless work to care for COVID-19 patients in this pandemic

Interleukin-10 enhances the intestinal epithelial barrier in the presence of corticosteroids through p38 MAPK activity in Caco-2 monolayers : a possible mechanism for steroid responsiveness in ulcerative colitis

Altres ajuts: 2012 Spanish Gastroenterological Association i CIBER G0034Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis

Influencia de los ácidos grasos dietéticos y del ambiente en el desarrollo de colitis espontánea en ratones IL-10(-/ -)

Consultable des del TDXTítol obtingut de la portada digitalitzadaLa Enfermedad inflamatoria intestinal engloba una serie de enfermedades, siendo las más frecuentes la Colitis Ulcerosa y la Enfermedad de Crohn. Estas enfermedades de etiología desconocida y sin tratamiento curativo cursan crónicamente con periodos de remisión. Epidemiológicamente afectan a países industrializados lo que indica la influencia del factor ambiental siendo la dieta un factor clave. La evolución epidemiológica de esta enfermedad y de los hábitos alimenticios de las poblaciones con mayores índices de incidencia muestran una relación entre el aumento del consumo de grasas, especialmente de la familia n6. Los primeros datos genéticos quedaron patentes en estudios con gemelos y con familiares de enfermos. En la actualidad algunas alteraciones genéticas se asocian a distintos fenotipos de la enfermedad. Para el correcto funcionamiento del colon la mucosa intestinal compartimentaliza sus elementos de manera que se beneficia de los elementos positivos (nutrientes y flora comensal) a la vez que se protege de los posibles agentes tóxicos o patológicos del medio extraintestinal. En primera línea de interacción una monocapa epitelial constituye una barrera selectiva. Formada por células especializadas en la secreción de factores protectores y agentes antimicrobianos, y provistas de distintos receptores, el epitelio intestinal está implicado en la adquisición de la tolerancia frente a nutrientes y flora comensal mediante la información captada por estos receptores y que es transferida al compartimiento que se encuentra por debajo de esta monocapa epitelial, la lámina propia. En la lámina propia distintos tipos celulares inmunocompetentes instauran tolerancia frente a los nutrientes y a la flora comensal y estructuran una respuesta efectora frente a patógenos. La teoría más consolidada de las causas de la enfermedad inflamatoria intestinal es el reconocimiento anómalo de la flora comensal por parte del sistema inmune de la mucosa intestinal, provocando una inflamación descontrolada y crónica en individuos con predisposición genética. Aunque los factores causantes de la enfermedad inflamatoria intestinal no se conocen, los factores implicados están bien definidos: la dotación génica del individuo y la funcionalidad de los compartimientos de la mucosa cólica (epitelio y lámina propia) todo ello modulado por el ambiente. Frente a la complejidad del estudio de los factores implicados en la enfermedad inflamatoria intestinal los modelos experimentales suponen la posibilidad de recrear situaciones ambientales controladas, de testar distintos elementos nutricionales, farmacológicos, etc. y poder estudiar los efectos sobre el órgano afectado. El modelo de ratones deficientes para IL10 es un modelo que muestra alteraciones en la función barrera y que desarrolla un patrón inflamatorio Th1 similar al de la enfermedad de Crohn. Estos animales desarrollan enterocolitis espontáneamente con distinta gravedad en función de las condiciones de estabulación. Esta tesis ha tenido dos objetivos principales, valorar el desarrollo de enterocolitis en este modelo de colitis espontaneo estabulando los animales "wild type" (WT) y IL10 (-/-) en condiciones "specific pathogen free" y en condiciones convencionales. Y por otro evaluar el efecto terapéutico de triglicéridos de cadena media (MCT) en este mismo modelo substituyendo el 50% de la fracción lipidica de la dieta (ácidos grasos familia n6) por MCT (n6/MCT). El primer estudio muestra como en un ambiente controlado se consigue contener la inflamación sin que esta revierta sobre la lámina propia regulando mecanismos celulares (apoptosis) y moleculares (vía TLR/MyD88) mientras que en un ambiente complejo antigénicamente hablando la inflamación alcanza la lámina propia. El estudio terapéutico muestra resultados alentadores sobre la substitución de parte de la fracción lipídica de la dieta con MCT aunque son necesarios estudios con otros modelos de colitis.Inflammatory bowel disease (IBD) (Crohn's disease, ulcerative colitis and indeterminate colitis) is a chronic condition of unknown etiology with no curative treatment. It alternates periods of inflammatory activity with those of remission. This disease affects more frequently the developed countries, pointing out that there might be an environmental influence. One of the most important environmental factors that have been related to IBD is diet. There has been shown a relationship between a high fat intake (specially n6 fatty acids) with a greater IBD incidence. Another factor that is needed for this disease development is genetic susceptibility. The first associations between genetics and IBD were discovered when studies of twins and other close relatives of IBD patients were performed. Nowadays there is evidence of specific genetic alterations associated to different disease phenotypes. For a proper colonic physiology, the intestinal mucosa has developed an efficient background in order to obtain benefits from positive elements such as nutrients and commensal bacteria, and, at the same time, protecting itself from extraintestinal toxic and pathologic agents. The first line acts as a selective barrier and is constituted of an epithelial monolayer. Different specialized cells constitute the epithelial barrier. These cells secrete protective factors such as antimicrobial agents. This epithelial barrier works in tolerance acquisition to nutrients and commensal bacteria. The extraepitelial information is transferred to lamina propria situated under epithelial layer through epithelial receptors. Different immunological cells constitute the lamina propia. This compartment acts tolerating nutrients and comensal flora, and is implicated in the effector response to pathogens. Although disease causes are unknown, the implicated factors seem to be clear. The consolidated theory about causes of IBD is the abnormal recognition of commensal flora by the intestinal immunological system that causes an uncontrolled and unnecessary inflammation in genetic predisposed patients, all of these factors modulated by the patient environment. Experimental animal models represent a good tool in front of the complex pathway of factors involved in IBD. These models allow to recreate controlated environmental situations, to test different nutritional elements, drugs, etc., and to study the effect of this actions on the affected organ. IL10 deficient mice model shows barrier alterations and develop a Th1 answer similar to Crohn's disease. These animals develop spontaneous enterocolitis with different stages of severity when kept under different environmental conditions. This thesis had two major objectives, to evaluate the enterocolitis development in IL10 deficient mice, wild type and knockout, that were housed under specific pathogen free (SPF) or conventional conditions. The second objective was to evaluate the therapeutic effect of replacing 50% of fat fraction (n6) of the diet with medium chain triglycerides in IL10 deficient mice. The first study shows that in a monitored environment (SPF) inflammation is controlled without affecting lamina propria through regulating cellular (apoptosis) and molecular (TLR2 and MyD88) mechanisms, whereas a complex antigenic environment (conventional conditions) induces an inflammatory process in the lamina propria. The therapeutic study shows encouraging results in the replacement of part of the fat fraction of the diet with MCT although studies with other models are necessary

Interleukin-10 enhances the intestinal epithelial barrier in the presence of corticosteroids through p38 MAPK activity in Caco-2 monolayers : a possible mechanism for steroid responsiveness in ulcerative colitis

Altres ajuts: 2012 Spanish Gastroenterological Association i CIBER G0034Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis

IL-10 reverts the GC-mediated decrease in phosphorylated-p38 MAPK activity.

<p>Figure shows (median (IQR, limits)) the ratio for total p38 MAPK (Panel A) and phosphorylated p38 MAPK (Panel B) versus control group in TNF-treated Caco-2 cell monolayers. An example of Western blot bands obtained for these proteins and α-tubulin (as housekeeping protein) is provided in Panel C. *p≤ 0.026 <i>vs</i>. all other groups, ^#p = 0.028 <i>vs</i>. TNF_IL10 and TNF_GC_IL10;.</p

IL-10 and GC preserve p38 MAPK-dependent desmosome integrity and strength in Caco-2 monolayers.

<p>Representative transmission electron microscopy images of the paracellular junctions in Caco-2 cell monolayers treated with GC (Panel A), GC plus IL-10 (Panel B) or GC, IL-10 and SB203580 (Panel C) D: desmosomes; TJ: tight junctions. Magnification varies from 25,000 x to 100,000 x.</p

Steroid-sensitive UC patients show a greater DSG2 staining.

<p>Immunofluorescence staining score (mean±SEM) of DSG2 (Panel A) in colonic biopsies of steroid-sensitive and steroid-refractory UC patients, before and after treatment. Representative DSG2 staining intensity of steroid-sensitive (Panel B) and steroid-refractory (Panel C) patients are also provided. All images are 630 x. *p≤ 0.004 <i>vs</i> steroid-refractory patients, ^#p = 0.023 <i>vs</i> after GC treatment.</p

SB203580 reverses the synergistic action of IL-10 and GC on TEER in Caco-2 cell monolayers.

<p>Values are median (IQR, limits) of percent TEER changes in Caco-2 cell monolayers after 48h of incubation with different stimuli. *p≤ 0.042 <i>vs</i> control.</p