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This document lays out some potential pathways for the future development and sustainability of the InGRID research infrastructure. It is a summary and compilation of key documents prepared under the InGRID-2 project and its work plan, including three strategic notes on data, methods and policy.

This: This Dutch Mesenteric Ischemia Study group consists of: Ron Balm, Academic Medical Center, Amsterdam Gert Jan de Borst, University Medical Center Utrecht, Utrecht Juliette T Blauw, Medisch Spectrum Twente, Enschede Marco J Bruno, Erasmus MC University Medical Center, Rotterdam Olaf J Bakker, St Antonius Hospital, Nieuwegein Louisa JD van Dijk, Erasmus MC University Medical Center, Rotterdam Hessel CJL Buscher, Gelre Hospitals, Apeldoorn Bram Fioole, Maasstad Hospital, Rotterdam Robert H Geelkerken, Medisch Spectrum Twente, Enschede Jaap F Hamming, Leiden University Medical Center, Leiden Jihan Harki, Erasmus MC University Medical Center, Rotterdam Daniel AF van den Heuvel, St Antonius Hospital, Nieuwegein Eline S van Hattum, University Medical Center Utrecht, Utrecht Jan Willem Hinnen, Jeroen Bosch Hospital, ‘s-Hertogenbosch Jeroen J Kolkman, Medisch Spectrum Twente, Enschede Maarten J van der Laan, University Medical Center Groningen, Groningen Kaatje Lenaerts, Maastricht University Medical Center, Maastricht Adriaan Moelker, Erasmus MC University Medical Center, Rotterdam Desirée van Noord, Franciscus Gasthuis & Vlietland, Rotterdam Maikel P Peppelenbosch, Erasmus MC University Medical Center, Rotterdam André S van Petersen, Bernhoven Hospital, Uden Pepijn Rijnja, Medisch Spectrum Twente, Enschede Peter J van der Schaar, St Antonius Hospital, Nieuwegein Luke G Terlouw, Erasmus MC University Medical Center, Rotterdam Hence JM Verhagen, Erasmus MC University Medical Center, Rotterdam Jean Paul PM de Vries, University Medical Center Groningen, Groningen Dammis Vroegindeweij, Maasstad Hospital, Rotterdam review provides an overview on the clinical management of chronic mesenteric ischemia (CMI). CMI is defined as insufficient blood supply to the gastrointestinal tract, most often caused by atherosclerotic stenosis of one or more mesenteric arteries. Patients classically present with postprandial abdominal pain and weight loss. However, patients may present with, atypically, symptoms such as abdominal discomfort, nausea, vomiting, diarrhea or constipation. Early consideration and diagnosis of CMI is important to timely treat, to improve quality of life and to prevent acute-on-chronic mesenteric ischemia. The diagnosis of CMI is based on the triad of clinical symptoms, radiological evaluation of the mesenteric vasculature and if available, functional assessment of mucosal ischemia. Multidisciplinary consensus on the diagnosis of CMI is of paramount importance to adequately select patients for treatment. Patients with a consensus diagnosis of single-vessel or multi-vessel atherosclerotic CMI are preferably treated with endovascular revascularization.

Background and objective: The objective of this article is to externally validate and update a recently published score chart for chronic mesenteric ischemia (CMI). Methods: A multicenter prospective cohort analysis was conducted of 666 CMI-suspected patients referred to two Dutch specialized CMI centers. Multidisciplinary consultation resulted in expert-based consensus diagnosis after which CMI consensus patients were treated. A definitive diagnosis of CMI was established if successful treatment resulted in durable symptom relief. The absolute CMI risk was calculated and discriminative ability of the original chart was assessed by the c-statistic in the validation cohort. Thereafter the original score chart was updated based on the performance in the combined original and validation cohort with inclusion of celiac artery (CA) stenosis cause. Results: In 8% of low-risk patients, 39% of intermediate-risk patients and 94% of high-risk patients of the validation cohort, CMI was diagnosed. Discriminative ability of the original model was acceptable (c-statistic 0.79). The total score of the updated chart ranged from 0 to 28 points (low risk 19% absolute CMI risk, intermediate risk 45%, and high risk 92%). The discriminative ability of the updated chart was slightly better (c-statistic 0.80). Conclusion: The CMI prediction model performs and discriminates well in the validation cohort. The updated score chart has excellent discriminative ability and is useful in clinical decision making.

The identification of new and emerging occupations has proven to be a challenging task, in which real-time information on labour market developments is key. At present, the most commonly used data sources do not provide up-to-date information, are narrow in scope or limited in size. In this light, online job portals have been suggested as an interesting data source for real-time labour market analysis. This report aims to contribute to the identification of new and emerging occupations by presenting an updated version of the methodology underpinning the Occupations Observatory developed by Beblavý et al. (2016). We use data extracted from online job boards using web scraping techniques, compare newly identified occupations with existing occupational classifications, and present examples of the tasks and skills required. With this update, we set out to further fine-tune the data collection, processing and analysis steps, but also to make the methodology and outputs more user-friendly, while providing more information at the same time. The proposed revised methodology consists of seven stages, and has been tested for the case of Ireland.

BACKGROUND: Short-chain fatty acids (SCFAs), fermentation products of undigested fibers, are considered beneficial for colonic health. High plasma concentrations are potentially harmful; therefore, information about systemic SCFA clearance is needed before therapeutic use of prebiotics or colonic SCFA administration. OBJECTIVE: The aim of this study was to investigate the effect of rectal butyrate administration on SCFA interorgan exchange. METHODS: Twelve patients (7 men; age: 66.4 +/- 2.0 y; BMI 24.5 +/- 1.4 kg/m(2)) undergoing upper abdominal surgery participated in this randomized placebo-controlled trial. During surgery, 1 group received a butyrate enema (100 mmol sodium butyrate/L; 60 mL; n = 7), and the other group a placebo (140 mmol 0.9% NaCl/L; 60 mL; n = 5). Before and 5, 15, and 30 min after administration, blood samples were taken from the radial artery, hepatic vein, and portal vein. Plasma SCFA concentrations were analyzed, and fluxes from portal-drained viscera, liver, and splanchnic area were calculated and used for the calculation of the incremental area under the curve (iAUC) over a 30-min period. RESULTS: Rectal butyrate administration led to higher portal butyrate concentrations at 5 min compared with placebo (92.2 +/- 27.0 mumol/L vs. 14.3 +/- 3.4 mumol/L, respectively; P < 0.01). In the butyrate-treated group, iAUCs of gut release (282.8 +/- 133.8 mumol/kg BW . 0.5 h) and liver uptake (-293.7 +/- 136.0 mumol/kg BW . 0.5 h) of butyrate were greater than in the placebo group [-16.6 +/- 13.4 mumol/kg BW . 0.5 h (gut release) and 16.0 +/- 13.8 mumol/kg BW . 0.5 h (liver uptake); P = 0.01 and P < 0.05, respectively]. As a result, splanchnic butyrate release did not differ between groups. CONCLUSION: After colonic butyrate administration, splanchnic butyrate release was prevented in patients undergoing upper abdominal surgery. These observations imply that therapeutic colonic SCFA administration at this dose is safe. The trial was registered at clinicaltrials.gov as NCT02271802.

BACKGROUND: COPD is accepted to be a multicomponent disease with various comorbidities. The contribution of the gastrointestinal tract to the systemic manifestation of COPD has never been investigated. This metabolically active organ may experience recurring local oxygen deficits during daily life, leading to disturbed intestinal integrity in COPD patients. METHOD: 18 patients with moderate COPD (mean FEV1: 55+/-3%predicted) and 14 matched healthy controls were tested on two occasions, a baseline measurement at rest and, at another day, during the performance of activities of daily living (ADLs). To assess enterocyte damage, plasma intestinal fatty acid binding protein (IFABP) levels were determined, whereas urinary excretion of orally ingested sugar probes was measured using liquid chromatography and mass spectrometry to assess gastrointestinal permeability. RESULTS: Plasma IFABP concentrations were not different between COPD patients and healthy controls at rest. In contrast, 0-3h urinary lactulose/rhamnose and sucralose/erythritol ratios and 5-24h urinary sucralose/erythritol ratios were significantly higher in COPD patients compared to controls, indicating increased permeability of the small intestine and colon. Furthermore, the performance of ADLs led to significantly increased plasma IFABP concentrations in COPD patients but not in control subjects. In line, the intestinal permeability difference between COPD patients and controls was intensified. CONCLUSION: Besides an altered intestinal permeability in COPD patients at rest, performing ADLs led to enterocyte damage in addition to intestinal hyperpermeability in COPD patients but not in controls, indicating functional alteration in the gastrointestinal tract. Hence, intestinal compromise should be considered as a new component of the multisystem disorder COPD. CLINICAL TRIAL REGISTRATION: ISRCTN33686980.

Cet article concerne la notion de consommateur moyen en droit des marques, critère d’appréciation-clé en droit des marques comme en droit de la consommation. Le « consommateur moyen » est un être abstrait, une fiction juridique, imaginé par la Cour de Justice de l’Union européenne, dont la jurisprudence n’est pas toujours ni très convaincante, ni très cohérente, comme le montre la présente contribution., info:eu-repo/semantics/published

The use of total parenteral nutrition (TPN) in the treatment of critically ill patients has been the subject of debate because it has been associated with disturbances in intestinal homeostasis. Important factors in maintaining the intestinal homeostasis are the intestinal microbiota and Paneth cells, which exist in a mutually amendable relationship. We hypothesized that the disturbed intestinal homeostasis in TPN-fed individuals results from an interplay between a shift in microbiota composition and alterations in Paneth cells. We studied the microbiota composition and expression of Paneth cell antimicrobial proteins in rats receiving TPN or a control diet for 3, 7, or 14 d. qPCR analysis of DNA extracts from small intestinal luminal contents of TPN-fed rats showed a shift in Firmicutes:Bacteroidetes ratio in favor of Bacteroidetes after 14 d (P < 0.05) compared with the control group. This finding coincided with greater staining intensity for lysozyme and significantly greater mRNA expression of Paneth cell antimicrobial proteins lysozyme (P < 0.05), rat alpha-defensin 5 (P < 0.01), and rat alpha-defensin 8 (P < 0.01). Finally, 14 d of TPN resulted in greater circulating ileal lipid-binding protein concentrations (P < 0.05) and greater leakage of horseradish peroxidase (P < 0.01), which is indicative of enterocyte damage and a breached intestinal barrier. Our findings show a shift in intestinal microbiota in TPN-fed rats that correlated with changes in Paneth cell lysozyme expression (r(s) = -0.75, P < 0.01). Further studies that include interventions with microbiota or nutrients that modulate them may yield information on the involvement of microbiota and Paneth cells in TPN-associated intestinal compromise.

The intestinal microbiota is increasingly acknowledged to play a crucial role in the development of obesity. A shift in intestinal microbiota composition favouring the presence of Firmicutes over Bacteroidetes has been observed in obese subjects. A similar shift has been reported in mice with deficiency of active Paneth cell alpha-defensins. We aimed at investigating changes in Paneth cell antimicrobial levels in the gut of obese subjects. Next, we studied activation of the unfolded protein response (UPR) as a possible mechanism involved in altered Paneth cell function. Paneth cell numbers were counted in jejunal sections of 15 severely obese (BMI > 35) and 15 normal weight subjects. Expression of Paneth cell antimicrobials human alpha-defensin 5 (HD5) and lysozyme were investigated using immunohistochemistry, qPCR, and western blot. Activation of the UPR was assessed with western blot. Severely obese subjects showed decreased protein levels of both HD5 and lysozyme, while Paneth cell numbers were unchanged. Lysozyme protein levels correlated inversely with BMI. Increased expression of HD5 (DEFA5) and lysozyme (LYZ) transcripts in the intestine of obese subjects prompted us to investigate a possible translational block caused by UPR activation. Binding protein (BiP) and activating transcription factor 4 (ATF4) levels were increased, confirming activation of the UPR in the gut of obese subjects. Furthermore, levels of both proteins correlated with BMI. Involvement of the UPR in the lowered antimicrobial protein levels in obese subjects was strongly suggested by a negative correlation between BiP levels and lysozyme levels. Additionally, indications of ER stress were apparent in Paneth cells of obese subjects. Our findings provide the first evidence for altered Paneth cell function in obesity, which may have important implications for the obesity-associated shift in microbiota composition. In addition, we show activation of the UPR in the intestine of obese subjects, which may underlie the observed Paneth cell compromise. Copyright (c) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Human intestinal ischemia-reperfusion (IR) is a frequent phenomenon carrying high morbidity and mortality. Although intestinal IR-induced inflammation has been studied extensively in animal models, human intestinal IR induced inflammatory responses remain to be characterized. Using a newly developed human intestinal IR model, we show that human small intestinal ischemia results in massive leakage of intracellular components from ischemically damaged cells, as indicated by increased arteriovenous concentration differences of intestinal fatty acid binding protein and soluble cytokeratin 18. IR-induced intestinal barrier integrity loss resulted in free exposure of the gut basal membrane (collagen IV staining) to intraluminal contents, which was accompanied by increased arteriovenous concentration differences of endotoxin. Western blot for complement activation product C3c and immunohistochemistry for activated C3 revealed complement activation after IR. In addition, intestinal IR resulted in enhanced tissue mRNA expression of IL-6, IL-8, and TNF-alpha, which was accompanied by IL-6 and IL-8 release into the circulation. Expression of intercellular adhesion molecule-1 was markedly increased during reperfusion, facilitating influx of neutrophils into IR-damaged villus tips. In conclusion, this study for the first time shows the sequelae of human intestinal IR-induced inflammation, which is characterized by complement activation, production and release of cytokines into the circulation, endothelial activation, and neutrophil influx into IR-damaged tissue.

Glutamine is an essential amino acid for enterocytes, especially in states of critical illness and injury. In several studies it has been speculated that the beneficial effects of glutamine are dependent on the route of supply (luminal or systemic). The aim of this study was to investigate the relevance of both routes of glutamine delivery to in vitro intestinal cells and to explore the molecular basis for proposed beneficial glutamine effects: (a) by determining the relative uptake of radiolabelled glutamine in Caco-2 cells; (b) by assessing the effect of glutamine on the proteome of Caco-2 cells using a 2D gel electrophoresis approach; and (c) by examining glutamine incorporation into cellular proteins using a new mass spectrometry-based method with stable isotope labelled glutamine. Results of this study show that exogenous glutamine is taken up by Caco-2 cells from both the apical and the basolateral side. Basolateral uptake consistently exceeds apical uptake and this phenomenon is more pronounced in 5-day-differentiated cells than in 15-day-differentiated cells. No effect of exogenous glutamine supply on the proteome was detected. However, we demonstrated that exogenous glutamine is incorporated into newly synthesized proteins and this occurred at a faster rate from basolateral glutamine, which is in line with the uptake rates. Interestingly, a large number of rapidly labelled proteins is involved in establishing cell-cell interactions. In this respect, our data may point to a molecular basis for observed beneficial effects of glutamine on intestinal cells and support results from studies with critically ill patients where parenteral glutamine supplementation is preferred over luminal supplementation.