Background: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). Methods: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. Results: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. Conclusions: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

Abstract Background Evaluation of disease severity (DS) in the Inflammatory Bowel Diseases (IBD) requires comprehensive consideration of disease course and health status of individual patients. It is not clear how well physician assessment covers disease impact as perceived by patients. We compared patient and physician global assessment of disease severity in relation to standardized assessment using a clinical disease severity score (DSI, Siegel 2018). Methods Patients with ulcerative colitis (UC) and Crohn’s disease (CD) were prospectively recruited from the national patient organization (DCCV) and by participating physicians. Physicians (IBD experts) were approached via the DCCV advisory board and other professional contacts. Both groups graded disease severity for a random selection of written standard short cases (1 page, maximum 5 CD, 3 UC) on a simple visual analogue scale (VAS) (online survey). For analysis, VAS were transferred to a 0 (minimal severity) to 100 (maximal severity) scale, in analogy to the range of the DSI. We present graphs of mean scores by rater group with 95% CI. Differences between mean patient and physician assessments were calculated per case. In addition, we examined the difference from the DSI. Results We included 824 ratings from 319 patients (168 CD, 151 UC), and 143 ratings from 34 physicians (20 ISS, 14 external)(recruitment ongoing). UC cases received on average 124 patient ratings (range 122–125), and 21 physician ratings (range 17–26). Means from both rater groups discriminated well between disease severity as scored by the DSI. Mean physician ratings were consistently and substantially lower than patient ratings for all three UC cases. Differences between means ranged from 8.5 (95% CI 0.5 to 16.5) for mild disease to 10.1 (95% CI 1.3 to 18.9) for moderate disease (p < 0.001) (Figure 1). In contrast, deviations from the DSI did not show a clear pattern. CD cases were rated by a mean of 91 patients (77–125) and 16 physicians (13–21). Mean physician and mean patient ratings were very close, in particular in those with medium DSI (Figure 2). Conclusion Physicians agreed, on average, very well with patient grading on disease severity grading of exemplary cases of CD. Lower scores were given for UC cases, and mild CD, but the overall trend remained intact. In contrast, correlation with DSI scores was poor and will need further analysis.

Background: Colorectal cancer is the main leading cause of cancer-related deaths worldwide. Present data suggest that plant-derived anthocyanins have anti-inflammatory and chemopreventive properties. This study was aimed at evaluating the effect of an anthocyanin-rich extract from bilberries on colorectal tumour development and growth in the administration of azoxymethan (AOM)/dextran sodium sulfate (DSS) mouse model. Methods: Colonic carcinogenesis was induced by AOM and DSS 3 or 5%, respectively, in 50 female Balb/c mice. Mice received either normal food (controls) or a diet containing either 10 or 1% anthocyanin-rich bilberry extract. Colonoscopy took place at week 4 and 9 after initiation of carcinogenesis. After termination at week 9, colon samples were analysed macroscopically and microscopically. Results: Mice receiving 10% anthocyanins showed significantly (p < 0.004) less reduced colon length (12.1 cm [8.5-14.4 cm]) as compared to controls (11.2 cm [9.8-12.3]) indicating less inflammation. Mice fed with 10% anthocyanin-rich extract revealed significantly less mean tumour numbers (n = 1.2) compared to control (n = 14) and anthocyanin 1% treated mice (n = 10.6, p < 0.001). Conclusion: Anthocyanins prevented the formation and growth of colorectal cancer in AOM/DSS-treated Balb/c mice. Further studies should investigate the mechanisms of how anthocyanins influence the development of colorectal cancer.

Non-destructive inspection records have to be characterized before evaluation of acceptance if they are evaluated as material or fabrication flaws. When multiple flaws are detected by volumetric examination, the question of interacting flaws arises if they are close to each other: can the conventional approach based on individual flaw be applied?Alternative flaw characterization requirements may be applied in lieu of using current codes by considering recent fracture mechanics research. In order to relax the conservatism of current interaction criteria, specific work was performed to describe interaction rules for flaws located in different planes. The proximity criteria are valid for linear elastic or limited elastic plastic material behavior : this is generally the case in large components.This paper presents the technical basis including validation of the proximity criteria based on a specific component with several flaws and considering 3D numerical modeling using elastic-plastic material behavior in order to check if the plastic material behavior affects the selected proximity criteria. The component is submitted to uniform (pressure) and non-uniform loading (like thermal shock).

Hintergrund: Gastroösophagealer Reflux zeigt mit bis zu 15% eine hohe Prävalenz in den westlichen Industrieländern. Obwohl die medikamentöse Therapie mit Protonenpumpenhemmern (PPI) meist effektiv ist, ist die Langzeit-Einnahme gerade bei noch jungen Patienten mit relevanten Nebenwirkungen verbunden. Offene und laparoskopische Chirurgie weisen gleichfalls gewisse Risiken und ästhetische Beeinträchtigungen auf. Seit kurzem steht mit der endoskopischen Stapler-Technik mittels MUSETM-System (Medigus Ultrasonic Surgical Endostapler) nun ein experimentelles, neues Verfahren ohne Notwendigkeit eines Hautschnittes zur Verfügung. In Deutschland liegen bisher nur Fallberichte vor.

According to the pertinent regulations, the integrity of a reactor pressure vessel (RPV) of a nuclear power plant is to be assessed by fracture mechanics for postulated flaws under most severe loading conditions. In such an analysis usually loss of coolant accidents are assumed to cause highest possible loading of the structural material of the RPV. This is due to the fact that such a pressurized thermal shock (PTS) event during which cold emergency coolant is injected into the primary system generates additional thermal stresses in the RPV wall. Based on the applicable regulation, the initiation of postulated flaws is to be excluded by the comparison of the calculated crack tip loading and the fracture toughness of the particular material. This kind of assessment was motivation of various research projects in the last decades addressing both evaluation approaches and experimental testing. A crucial result in this context is the existence of the so-called warm pre-stress effect (WPS) on the resulting fracture toughness. Generally, it is known as the increase of the apparent fracture toughness of a flaw in a specimen or structure after loading at high temperatures, generally in the upper shelf region, followed by a reloading at a lower temperature. This represents the typical loading scenario postulated for the assessment of a RPV during a PTS event. Experiments were performed to quantify this effect in the case of the irradiated reactor pressure vessel base material of the nuclear power plant Beznau unit 1. This paper presents the results of the Master Curve tests to determine the reference temperature (according to ASTM E 1921) and the design and testing of the warm pre-stress experiments using irradiated 10×10 mm reconstituted single edge notch bend (SE(B)) specimens. The design of these warm pre-stress tests was based on the loading transients for postulated surface and sub-surface flaws investigated within the scope of the assessment of the Beznau unit 1 reactor pressure vessel against brittle failure. Finite element simulations were performed to transfer the loading conditions at the crack tip of the RPV determined during the brittle fracture safety assessment onto the SE(B) specimen. The simulation results were used to control the loading conditions as a function of time and temperature during the experimental tests. The fracture toughness values of the warm pre-stress specimens were finally compared with the original fracture toughness values determined in the absence of a warm pre-stress effect to demonstrate the increase of the safety margin when the warm pre-stress effect is taken into account.

Background: We recently identified galectin-3 (gal-3) as a new and strong fibroblast activator produced by colonic epithelial cells. Very little is known about the influence of gal-3 in inflammatory bowel disease. We, therefore, investigated the impact of gal-3 on dextran sodium sulfate (DSS)-induced colitis in a mouse model. Methods: Colonic lamina propria fibroblasts of healthy controls were used for co-incubation studies of gal-3 with gal-1, TGF-β1, IFNγ, IL-4 and IL-10. Acute and chronic DSS colitis was induced by 3% DSS in drinking water in female Balb/c mice weighing 20-22 g. Recombinant gal-3 was expressed by the pET vector system and used for a 5-day treatment in different concentrations intraperitoneally. The distal third of the colon was used for histologic analysis. Colonic cytokine expression was determined by quantitative RT-PCR. Results: In vitro, gal-3 induced IL-8 secretion was significantly reduced by co-incubation with IL-10 (5 ng/ml) and IL-4 (10 ng/ml). Acute DSS-induced colitis was ameliorated by gal-3 treatment as indicated by increased colonic length and reduced weight loss compared to that of controls. In acute and chronic colitis, gal-3 treatment resulted in a significant suppression of colonic IL-6. Conclusion: Gal-3 significantly reduces inflammation in acute and chronic DSS colitis in mice indicating a potential role in intestinal inflammation.

Hintergrund/Einleitung: Probiotische Mikroorganismen wurden erfolgreich in der Behandlung chronisch entzündlicher Darmerkrankungen eingesetzt. EcN erwies sich als Alternative zu Mesalazin in der Remissionserhaltung der Colitis ulcerosa. Es gibt Hinweise auf eine Wirkungsvermittlung durch Beeinflussung der intestinalen Darmflora und Effekte auf das Immunsystem.

Hintergrund/Einleitung: Eine Reihe von Monozytenantigenen für die Rezeption und Transmission von entzündlichen Signalen werden bei der Differenzierung von Makrophagen der intestinalen Mukosa herabreguliert. Eine verminderte funktionelle Aktivität unterstützt das Konzept der „Desensibilisierung“ intestinaler Makrophagen. Mithilfe einer subtraktiven Hybridisierung von Makrophagen mRNA von Patienten mit Morbus Crohn versus Makrophagen mRNA von Kontrollmukosa wurden Unterschiede in der RNA Expression beider Makrophagenpopulationen untersucht.

Hintergrund/Einleitung: Das Hämoxygenasesystem besteht aus drei Proteinen, der Hämoxygenase-1 (HO-1), -2 (HO-2) und -3 (HO-3). HO-1 und HO-2 sind in der Lage, Häm enzymatisch in Biliverdin, freies Eisen und Kohlenmonoxid zu katabolisieren. HO-1 ist normalerweise gering oder nicht nachweisbar und wird durch verschiedene Zytokine (IL-1, IL-6, TNF) oder bakterielles Lipopolysaccharid rasch hochreguliert. Es konnte gezeigt werden, dass HO-1 anti-inflammatorische, anti-apoptotische und anti-proliferative Eigenschaften hat. Bisher liegen keine Daten zur Expression und einer möglichen protektiven Wirkung der HO-1 bei chronisch entzündlichen Darmerkrankungen (CED) vor.

Einleitung: Immunstimulatorische DNA-Sequenzen bakterieller DNA (CpG) sind als potente Stimulatoren des Immunsystems bekannt. Wie kürzlich gezeigt werden konnte, entwicklen Tiere nach Applikation von CpG-DNA vor Induktion einer murinen Colitis überraschenderweise eine deutlich geringer ausgeprägte intestinale Entzündung, wobei die genauen Mechanismen dieses protektiven Effektes bakterieller DNA bislang nicht bekannt sind.

Hintergrund/Einleitung: Neben der Regulation des Kalziumhaushaltes besitzt Vitamin D3 immunmodulatorische Wirkungen. Es induziert die Differenzierung regulatorischerT-Lymphozyten und hat protektive Effekte in experimentellen Modellen chronisch entzündlicher Erkrankungen. Die therapeutische Anwendung ist jedoch durch die Induktion einer Hyperkalzämie limitiert.

Spontaneous amelioration of inflammation (often accompanied by fibrosis) is a well-known, but poorly understood, outcome of many chronic inflammatory processes. We studied this phenomenon in a chronic trinitrobenzene sulfonic acid–induced colitis model, an experimental colitis in mice that we showed to ultimately undergo spontaneous resolution, despite continued trinitrobenzene sulfonic acid stimulation. Analysis of the mechanism of this resolution revealed that it was critically dependent on IL-13 activation of STAT6, followed by phosphorylation (inactivation) of glycogen synthase kinase-3β, at least in part via STAT6 induction of p38 MAPK. Such glycogen synthase kinase-3β inactivation causes changes in CREB and p65 DNA-binding activity that favors decreased proinflammatory IL-17 production and increased anti-inflammatory IL-10 production. Thus, in this case, IL-13 acts as a molecular switch that leads to resolution of inflammation.

With the introduction of anti-TNF therapies in the treatment of IBD, the therapeutic strategies have changed to an accelerated step-up care to avoid long-term complications. Little is known about the implementation of these strategies into daily care. We aimed to evaluate this question and to identify factors associated with the early use of immunosuppressants or anti-TNF therapies in a population-based IBD cohort.

BACKGROUND:Markers that predict the occurrence of a complicated disease behavior in patients with Crohn's disease (CD) can permit a more aggressive therapeutic regimen for patients at risk. The aim of this cohort study was to test the blood levels of hemoglobin (Hgb) and hematocrit (Hct) for the prediction of complicated CD behavior and CD related surgery in an adult patient population. METHODS:Blood samples of 62 CD patients of the German Inflammatory Bowel Disease-network "Kompetenznetz CED" were tested for the levels of Hgb and Hct prior to the occurrence of complicated disease behavior or CD related surgery. The relation of these markers and clinical events was studied using Kaplan-Meier survival analysis and adjusted COX-proportional hazard regression models. RESULTS:The median follow-up time was 55.8 months. Of the 62 CD patients without any previous complication or surgery 34% developed a complication and/or underwent CD related surgery. Low Hgb or Hct levels were independent predictors of a shorter time to occurrence of the first complication or CD related surgery. This was true for early as well as late occurring complications. Stable low Hgb or Hct during serial follow-up measurements had a higher frequency of complications compared to patients with a stable normal Hgb or Hct, respectively. CONCLUSIONS:Determination of Hgb or Hct in complication and surgery naïve CD patients might serve as an additional tool for the prediction of complicated disease behavior.

Comprehensive crack initiation and crack arrest tests were performed, up to neutron fluences far beyond the end of life range, on irradiated original reactor pressure vessel (RPV) steel specimens from German pressurized water reactors (PWR). The neutron fluences applied to the specimen materials under light water reactor conditions were between 5.44 x 10(18) n/cm(2) and 7.67 x 10(19) n/cm(2) (E > 1 MeV) with a neutron flux from 2.64 x 10(10) n/cm(2)s to 2.55 x 10(12) n/cm(2)s. The objective was to extend the already existing experimental database to reach a final comparative assessment of both the RTNDT and the RTT0 (Master Curve) concepts for proof of sufficient margin against RPV brittle fracture and to assess the impact of important factors such as neutron flux, manufacturing effects and specific irradiation effects such as late blooming effects. The test data show that most of the measured fracture toughness data are enveloped by the "lower bound" ASME KIc-curve for crack initiation and that the RTTO concept compared to the RTNDT concept leads to lower reference temperatures for the base materials. However, for the weld materials, the general trend of RTNDT> RTTO is less or not at all pronounced. It was also found that the measured Delta T-41 and Delta T-O data show a good correlation and that the RTTO of heat affected zone ( HAZ) materials is lower compared to the base materials. Finally, the applicability of both the RTNDT and the Master curve concepts for crack arrest was confirmed, except the alternative use of RTTO for indexing of the KIa fracture toughness curve could not be confirmed by the measured data. The application of a socalled duplex specimen geometry for crack arrest testing led to essential improvements; however, further optimizations of the specimens' fabrication process are still recommended. Finally, the complete database is assessed with respect to benefits for future RPV safety analyses.

Background:Cytosine-guanosine dinucleotide (CpG) motifs are immunostimulatory components of bacterial DNA and activators of innate immunity through Toll-like receptor 9 (TLR9). Administration of CpG oligodeoxynucleotides before the onset of experimental colitis prevents intestinal inflammation by enforcement of regulatory mechanisms. It was investigated whether physiologic CpG/TLR9 interactions are critical for the homeostasis of the intestinal immune system. Methods:Mesenteric lymph node cell and lamina propria mononuclear cell (LPMC) populations from BALB/c wild-type (wt) or TLR9−/− mice were assessed by flow cytometry and proteome profiling. Cytokine secretion was determined and nuclear extracts were analyzed for nuclear factor kappa B (NF-&kgr;B) and cAMP response-element binding protein activity. To assess the colitogenic potential of intestinal T cells, CD4+-enriched cells from LPMC of wt or TLR9−/− donor mice were injected intraperitoneally in recipient CB-17 SCID mice. Results:TLR9 deficiency was accompanied by slight changes in cellular composition and phosphorylation of signaling proteins of mesenteric lymph node cell and LPMC. LPMC from TLR9−/− mice displayed an increased proinflammatory phenotype compared with wt LPMC. NF-&kgr;B activity in cells from TLR9−/− mice was enhanced, whereas cAMP response-element binding activity was reduced compared with wt. Transfer of lamina propria CD4+-enriched T cells from TLR9−/− mice induced severe colitis, whereas wt lamina propria CD4+-enriched T cells displayed an attenuated phenotype. Conclusions:Lack of physiologic CpG/TLR9 interaction impairs the function of the intestinal immune system indicated by enhanced proinflammatory properties. Thus, physiologic CpG/TLR interaction is essential for homeostasis of the intestinal immune system as it is required for the induction of counterregulating anti-inflammatory mechanisms.

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels.

In the CARISMA [1] and CARINA [2] projects comprehensive tensile, Charpy-impact and fracture toughness tests were performed for unirradiated and irradiated original reactor pressure vessel (RPV) steel specimens from German pressurized water reactors (PWR) up to neutron fluences in the range of 60 operational years and beyond.In addition, crack arrest fracture toughness tests were performed to demonstrate the crack arrest behavior of the materials. To determine the crack arrest properties of ferritic steels, the designated test method according to ASTM E1221 [3] was used. However, in particular for irradiated reactor pressure vessel materials with higher irradiation embrittlement, the prescribed standard test specimen does not always provide adequate test results. During starter notch preparation annealing effects occurred in the heat affected zone (HAZ) of the brittle weld of the starter notch causing crack arrest in the HAZ after unstable crack initiation. Therefore a modified test method to perform crack arrest tests with so called duplex specimens was investigated.In this paper this modified method and the test results of five base and four weld metals with a fluence up to 4,69E+19 cm(-2) (E >1 MeV) are discussed.The available test results show that the duplex specimen is an appropriate alternative to the standard compact crack arrest (CCA) specimen. The measured K-ia fracture toughness data are enveloped by the "lower bound" of the ASME K-Ta-curve indexed with RTNDTj or T-Kla but not all data are enveloped by indexing the "lower bound" curve with RT10 like described in the ASME Code Case N-629 [4]. Furthermore correlations of the crack arrest test results with Charpy-impact and fracture toughness test results will be shown.

AIM:To demonstrate a high prevalence of extraintestinal manifestations (EIMs) in a prospective population-based cohort of inflammatory bowel disease (IBD) patients at first diagnosis as well as during the early course of the disease.METHODS:EIMs are common in patients with IBD. Data on the frequency of EIMs have mostly been assessed in patients from tertiary centers; however, data about the prevalence of EIMs at first diagnosis as well as factors influencing their incidence during the early course of disease from prospective population-based cohorts are scarce. We present data of patients of our population-based "Oberpfalz cohort" (Bavaria, Germany) from first diagnosis (up to 3 mo after first diagnosis) as well as during the early course of the disease. Possible risk factors were assessed by calculating the relative risk (RR) as well as using logistic regression analysis.RESULTS:In total, data of 257 newly diagnosed patients with IBD were evaluated [161 Crohn's disease (CD), 96 ulcerative colitis (UC)]. Median duration of follow-up was 50 mo after first diagnosis. In 63.4% of all patients (n = 163), an EIM was diagnosed at any point during the observation period. At first diagnosis, patients with CD had a significantly increased risk of an EIM [n = 69 (42.9%)] compared with UC patients [n = 21 (21.9%); P < 0.001; RR = 1.96; 95%CI: 1.30-2.98]. Active smoking increased the risk of CD patients developing an EIM during the early course of the disease, but notably not of UC patients (P = 0.046; RR = 1.96; 95%CI: 1.01-3.79). In addition, using logistic regression analysis, the need for IBD-related surgery and a young age at first diagnosis were identified as risk factors for the development of an EIM in CD patients. No association with EIMs was found for the factors sex, localization of the disease and positive family history of IBD. In contrast, no key factors which increased the risk of development of an EIM could be identified in UC patients.CONCLUSION:We found a high prevalence of EIM in this cohort at first diagnosis and during the early course of the disease. In patients with CD, smoking, need for surgery and younger age at first diagnosis were risk factors for the development of an EIM.