El asilo eclesiástico

El asilo eclesiástico o “santuario” consiste en apoyar, aconsejar y ofrecer refugio a los refugiados que viven bajo la amenaza de ser deportados a un lugar donde se exponen a vivir en condiciones inhumanas, a la tortura o incluso a la muerte. Su práctica puede estar a medio camino entre la benevolencia y la política

Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo

Objective: Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of anti-adhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. Design: We explored integrin expression in IBD patients by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanized mouse model in DSS-treated immunodeficient mice. Results: High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. TCR stimulation and TGF-β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from IBD patients under vedolizumab therapy. Conclusion: AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD

El legado de la política hidráulica de Epitácio Pessoa: llevando el agua a su molino

Epitácio Pessoa, el único presidente oriundo del Nordeste durante la Primera República, elevó la ‘lucha contra la sequía’ a absoluta prioridad nacional, ganándose los elogios de sus paisanos contemporáneos e incluso de historiadores posteriores, lo que sorprende dado el grado de instrumentalización política de la sequía por parte del oligarca Pessoa. Casi cien años más tarde, con Luiz Inácio Lula da Silva, otro presidente de origen nordestino inicia obras de grandes dimensiones en la zona de la sequía y es comparado con Pessoa, en un sentido positivo, alabado por su extraordinario compromiso con el Nordeste. Por un lado, la comparación entre Epitácio Pessoa y Lula da Silva tiene que limitarse a ciertos aspectos de la política hidráulica, ya que tanto los dos presidentes en sí como sus circunstancias y retos sociales son muy distintos. Por otro lado, indagar en el historial de Epitácio Pessoa y en la historia de su política hidráulica nos permite plantear algunas cuestiones generales vinculadas a ambos períodos de intervención estatal en el Nordeste, como por ejemplo: ¿cuáles son las conveniencias e inconveniencias de los megaproyectos centralizadores, sobre todo en relación al concepto social y ecológico de la ‘convivencia con la sequía’? Siguiendo esta línea, ¿han cumplido los dos presidentes nordestinos con las expectativas

El legado de la política hidráulica de Epitácio Pessoa: llevando el agua a su molino

Epitácio Pessoa, el único presidente oriundo del Nordeste durante la Primera República, elevó la ‘lucha contra la sequía’ a absoluta prioridad nacional, ganándose los elogios de sus paisanos contemporáneos e incluso de historiadores posteriores, lo que sorprende dado el grado de instrumentalización política de la sequía por parte del oligarca Pessoa. Casi cien años más tarde, con Luiz Inácio Lula da Silva, otro presidente de origen nordestino inicia obras de grandes dimensiones en la zona de la sequía y es comparado con Pessoa, en un sentido positivo, alabado por su extraordinario compromiso con el Nordeste. Por un lado, la comparación entre Epitácio Pessoa y Lula da Silva tiene que limitarse a ciertos aspectos de la política hidráulica, ya que tanto los dos presidentes en sí como sus circunstancias y retos sociales son muy distintos. Por otro lado, indagar en el historial de Epitácio Pessoa y en la historia de su política hidráulica nos permite plantear algunas cuestiones generales vinculadas a ambos períodos de intervención estatal en el Nordeste, como por ejemplo: ¿cuáles son las conveniencias e inconveniencias de los megaproyectos centralizadores, sobre todo en relación al concepto social y ecológico de la ‘convivencia con la sequía’? Siguiendo esta línea, ¿han cumplido los dos presidentes nordestinos con las expectativas

The α4β1 homing pathway is essential for ileal homing of Crohn's disease effector T cells in vivo

The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn’s disease (CD) are still unclear and clinical outcome data from inflammatory bowel disease (IBD) patients treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis (UC) and CD. Methods: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. Results: Despite in vitro blockade of CD Teff adhesion to MAdCAM-1 and in contrast to previous oberservations in UC, anti-α4β7 treatment did not result in reduced Teff cell homing to the gut in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from CD patients compared with controls, while its expression in the peripheral blood declined and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to VCAM-1 was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the inflamed ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. Conclusions: Our findings suggest that Teff cell homing to the ileum via the axis α4β1 – VCAM-1 is an essential and non-redundant pathway in CD in vivo possibly affecting efficacy of clinical treatment with anti-adhesion compounds

Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion

Rectal washout in rectal cancer surgery

BackgroundRectal washout (RW) is performed to eliminate intraluminal cancer cells and thereby reducing the risk of local recurrence (LR). The overall aim of this thesis was to investigate the importance of RW in rectal cancer surgery.MethodPaper I: Survey of the current practice of RW among Swedish colorectal units.Paper II: The association between RW and 30-day postoperative complications after anterior resection (AR) for rectal cancer was analysed using data from the Swedish Colorectal Cancer Registry (SCRCR).Paper III: The impact of RW on the 5-year oncological outcome after abdominoperineal resection (APR) for rectal cancer was analysed using data from the SCRCR.Paper IV: The impact of RW on the 3- and 5-year oncological outcome after AR for rectal cancer was analysed using data from the SCRCR.Paper V: Patients undergoing transanal total mesorectal excision (taTME) for rectal cancer were assessed for the presence of intraluminal cancer cells during RW.ResultsPaper I: RW was reported to be routinely performed in open and minimally invasive rectal cancer surgery, most often using sterile water or an alcohol-based solution with a minimum volume of 100-Paper II: The RW group had fewer overall and surgical complications. RW was not a risk factor for overall complications (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.60-0.90, p=0.002) or for surgical complications (OR 0.62, 95% CI 0.50-0.78, pPaper III: There were no differences between the RW and no RW group in rates of LR (10/265 (3.8%) vs. 87/2160 (4.0%), p=0.839), distant metastasis (51/265 (19.2%) vs. 476/2160 (22.0%), p=0.293) and overall recurrence (53/265 (20.0%) vs. 505/2160 (23.4%), p=0.213) at 5-year follow up.Paper IV: RW in AR did not impact the 3-year oncological outcome. A decreased 5-year risk of LR was observed after RW in multivariable analysis (hazard ratio 0.53, 95% CI 0.31-0.90, p=0.018).Paper V: Only three of 21 patients had washout samples positive for cancer cells and all samples were negative after 500 ml of RW.ConclusionThis thesis contributes to increased knowledge about RW and investigates the importance of RW in rectal cancer surgery. Swedish practice of RW is described. RW in AR for rectal cancer seems to be a safe technique with no evidence of increased 30-day postoperative complications. Routine RW in APR for rectal cancer to improve the 5- year oncological outcome is not supported. RW in AR for rectal cancer does not appear to impact the 3-year oncological outcome. However, RW was associated with decreased 5-year risk of LR, justifying continued practice of RW in AR for rectal cancer. Even if intraluminal cancer cells were rare during RW in taTME for rectal cancer, 500 ml of RW is probably needed to ensure elimination of intraluminal cancer cells

El legado de la política hidráulica de Epitácio Pessoa: llevando el agua a su molino

Epitácio Pessoa, el único presidente oriundo del Nordeste durante la Primera República, elevó la ‘lucha contra la sequía’ a absoluta prioridad nacional, ganándose los elogios de sus paisanos contemporáneos e incluso de historiadores posteriores, lo que sorprende dado el grado de instrumentalización política de la sequía por parte del oligarca Pessoa. Casi cien años más tarde, con Luiz Inácio Lula da Silva, otro presidente de origen nordestino inicia obras de grandes dimensiones en la zona de la sequía y es comparado con Pessoa, en un sentido positivo, alabado por su extraordinario compromiso con el Nordeste. Por un lado, la comparación entre Epitácio Pessoa y Lula da Silva tiene que limitarse a ciertos aspectos de la política hidráulica, ya que tanto los dos presidentes en sí como sus circunstancias y retos sociales son muy distintos. Por otro lado, indagar en el historial de Epitácio Pessoa y en la historia de su política hidráulica nos permite plantear algunas cuestiones generales vinculadas a ambos períodos de intervención estatal en el Nordeste, como por ejemplo: ¿cuáles son las conveniencias e inconveniencias de los megaproyectos centralizadores, sobre todo en relación al concepto social y ecológico de la ‘convivencia con la sequía’? Siguiendo esta línea, ¿han cumplido los dos presidentes nordestinos con las expectativas

IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity

Validation of a simplified micromodel for analysis of infilled RC frames exposed to cyclic lateral loads

An RC frame structure with masonry infill walls (‘‘framed-masonry’’) exposed to lateral loads acts as a composite structure. Numerical simulation of framed-masonry is difficult and generally unreliable due to many difficulties and uncertainties in its modelling. In this paper, we reviewed the usability of an advanced non-linear FEM computer program to accurately predict the behaviour of framed-masonry elements when exposed to cyclic lateral loading. Numerical results are validated against the test results of framedmasonry specimens, with and without openings. Initial simplified micromodels were calibrated by adjustment of the input parameters within the physically justifiable borders, in order to obtain the best correlation between the experimental and numerical results. It has been shown that the use of simplified micromodels for the investigation of composite masonry-infilled RC frames requires in-depth knowledge and engineering judgement in order to be used with confidence. Modelling problems were identified and explained in detail, which in turn offer an insight to practising engineers on how to deal with them