Genetische, lipidomische und radiologische Merkmale der Nicht-alkoholischen Fettlebererkrankung im Kindes- und Jugendalter

Die nicht-alkoholische Fettlebererkrankung (NAFLD) ist die häufigste chronische Lebererkrankung im Kindes- und Jugendalter und ätiologisch mit der Adipositas und der einhergehenden metabolischen Dysregulation assoziiert. Das Erkrankungsspektrum der NAFLD umfasst die benigne nicht-alkoholische Fettleber (NAFL) und die nicht-alkoholische Steatohepatitis (NASH), welche potentiell eine fortschreitende Leberfibrose bis hin zur NASH-assoziierten Leberzirrhose bedingen kann. In der vorliegenden Arbeit wurden genetische, lipidomische und radiologische Merkmale der pädiatrischen NAFLD untersucht. In einer Studie zur genetischen Prädisposition wurden 14 aus der Erwachsenenmedizin bekannte Einzelnukleotid-Polymorphismen in einer pädiatrischen Kohorte evaluiert. Hier wurde die Bedeutsamkeit der PNPLA3 148M Risikovariante sowohl für die Entwicklung der NAFLD als auch für den histologischen Schweregrad bei Kindern und Jugendlichen bestätigt. In der Untersuchung lipidomischer Profile aus dem Lebergewebe zeigte sich eine positive Assoziation bioaktiver Epoxyeicosanoide mit dem Grad der Steatose, während die Aktivität der Cytochrom P450 Epoxygenasen, als entscheidender enzymatischer Bildungsweg der Epoxyeicosanoide, mit steigendem Grad der Fibrose eingeschränkt war. Die Elastographie als radiologische Modalität zur Leberfibrosemessung wurde sowohl Ultraschall- als auch Magnetresonanz-basiert angewandt. Beide Methoden ergaben eine hohe diagnostische Genauigkeit in der Detektion moderater oder fortgeschrittener Fibrose. Weiterhin wurde ein neuer histologischer Score unter Einbeziehung der zonalen Verteilungsmuster der pädiatrischen NAFLD entwickelt. In der Zusammenschau zeigen die Ergebnisse der Arbeiten Beispiele für eine präzisere klinische Risikostratifizierung, ein nicht-invasives Monitoring und neue Konzepte zur therapeutischen Intervention der NAFLD im Kindes- und Jugendalter auf

study protocol for a randomized-controlled trial

Background Functional abdominal pain (FAP) is not only a highly prevalent disease but also poses a considerable burden on children and their families. Untreated, FAP is highly persistent until adulthood, also leading to an increased risk of psychiatric disorders. Intervention studies underscore the efficacy of cognitive behavioral treatment approaches but are limited in terms of sample size, long-term follow-up data, controls and inclusion of psychosocial outcome data. Methods/Design In a multicenter randomized controlled trial, 112 children aged 7 to 12 years who fulfill the Rome III criteria for FAP will be allocated to an established cognitive behavioral training program for children with FAP (n = 56) or to an active control group (focusing on age-appropriate information delivery; n = 56). Randomization occurs centrally, blockwise and is stratified by center. This study is performed in five pediatric gastroenterology outpatient departments. Observer- blind assessments of outcome variables take place four times: pre-, post-, 3- and 12-months post-treatment. Primary outcome is the course of pain intensity and frequency. Secondary endpoints are health-related quality of life, pain- related coping and cognitions, as well as selfefficacy. Discussion This confirmatory randomized controlled clinical trial evaluates the efficacy of a cognitive behavioral intervention for children with FAP. By applying an active control group, time and attention processes can be controlled, and long-term follow-up data over the course of one year can be explored

Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity

Experimentelle Kolitis in transgenen fat-1 Mäusen

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are the precursors of potent lipid mediators and play an important role in the regulation of inflammation. Generally, n-6 PUFA promote inflammation whereas n-3 PUFA have anti-inflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived proinflammatory eicosanoids. Recently discovered resolvins and protectins are potent anti- inflammatory lipid mediators derived directly from n-3 PUFA with distinct pathways of action. However, the role of the n-3 PUFA tissue status in the formation of these anti-inflammatory mediators has not been addressed. Here we show that an increased n-3 PUFA tissue status in transgenic mice that endogenously biosynthesize n-3 PUFA from n-6 PUFA leads to significant formation of anti-inflammatory resolvins and effective reduction of inflammation and tissue injury in colitis. The endogenous increase in n-3 PUFA and related products did not decrease n-6 PUFA-derived lipid mediators such as leukotriene B4 and prostaglandin E2. The observed inflammation protection might result from decreased NF-KB activity and expression of TNF-alpha, inducible NO synthase, and IL-1 beta, with enhanced mucoprotection probably because of the higher expression of Trefoil Factor 3, Toll-interacting protein, and Zonula occludens-1. These results thus establish the fat-1 transgenic mouse as a new experimental model for the study of n-3 PUFA-derived lipid mediators. They add insight into the molecular mechanisms of inflammation protection afforded by n-3 PUFA through formation of resolvins and protectins other than inhibition of n-6 PUFA-derived eicosanoid formation.Experimentelle Kolitis in transgenen fat-1 Mäusen. Omega-6 (n-6) und omega-3 (n-3) mehrfach ungesättigte Fettsäuren (PUFA) sind Vorläufer potenter Lipidmediatoren und spielen eine wichtige Rolle in der Regulation von Entzündungsreaktionen. Prinzipiell fördern n-6 PUFA entzündliche Prozesse, während n-3 PUFA anti-inflammatorische Wirkungsmechanismen aufweisen. Diese werden ihrer Eigenschaft zugeschrieben, die Bildung von n-6 PUFA-stämmigen proinflammatorischen Eicosanoiden zu hemmen. Die vor kurzem beschriebenen n-3-stämmigen Resolvine und Protektine sind potente anti-inflammatorische Lipidmediatoren mit einem distinkten Wirkungsmechanismus. In dieser Studie zeigen wir, dass ein erhöhter n-3 PUFA Status in transgenen Mäusen, welche endogen n-3 PUFA aus n-6 PUFA synthetisieren können, zu einer signifikanten Bildung von anti-inflammatorischen Resolvinen, und der effektiven Reduktion von Inflammation und Gewebeschaden in einem experimentellen Kolitismodell führt. Die endogene Erhöhung von n-3 PUFA und seiner Produkte senkte nicht den Gewebegehalt n-6 PUFA-stämmiger Lipidmediatoren wie Leukotrien B4 und Prostaglandin E2. Die in dieser Studie beobachtete Entzündungsprotektion könnte aus einer verminderten Aktivität von NF-KB und der geringeren Expression von TNF-alpha, iNOS und IL-1 beta resultieren. Weiter zeigte sich eine erweiterte Mukoprotektion, wahrscheinlich durch die erhöhte Expression von Trefoil Faktor 3, Toll-interactin Protein und Zona-occludens 1. Die Ergebnisse dieser Studie etablieren die transgene fat-1 Maus folglich als neues experimentelles Modell zur Studie n-3 PUFA-stämmiger Lipidmediatoren. Sie erweitern den Einblick in die molekularen Mechanismen der Entzündungsprotektion, welche n-3 PUFA durch die Bildung von bioaktiven Resolvinen und Protektinen vermitteln

Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.

Peer reviewed: TrueBACKGROUND AND AIMS: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids. METHODS: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors. RESULTS: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids. CONCLUSIONS: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity

Future business mobility: Intelligent integration of services for shared usage of electric car fleets

Innovative, environmentally friendly mobility concepts based on electric vehicles will change our social life. In order to reach the goal of bringing one million electric cars on Germany's streets until 2020 it is essential to leverage the potential of company car fleets. The research project "Shared E-Fleet", founded by the German Federal Ministry of Economics and Technology, addresses this issue. Within the project new concepts and technologies are developed to realize an integrated fleet management across multiple organisations considering the interaction between smart technology within the electric vehicle, smart energy and smart traffic systems. A cloud-based management platform enables the combination of different services resulting in innovative intermodal mobility concepts that compensate the limited range of electric cars (e-cars)

Roles of Lactose and Fructose Malabsorption and Dietary Outcomes in Children Presenting with Chronic Abdominal Pain

Intolerance to lactose or fructose is frequently diagnosed in children with chronic abdominal pain (CAP). However, the causal relationship remains a matter of discussion. A cohort of 253 patients, aged 7–12 years, presenting with unexplained CAP received standardized diagnostics. Additional diagnostic tests were performed based on their medical history and physical and laboratory investigations. Fructose and lactose hydrogen breath tests (H2BT) as well as empiric diagnostic elimination diets were performed in 135 patients reporting abdominal pain related to the consumption of lactose or fructose to evaluate carbohydrate intolerance as a potential cause of CAP. Carbohydrate malabsorption by H2BT was found in 55 (41%) out of 135 patients. An abnormal increase in H2BT was revealed in 30% (35/118) of patients after fructose consumption and in 18% (20/114) of patients after lactose administration. Forty-six percent (25/54) reported pain relief during a diagnostic elimination diet. In total, 17 patients had lactose malabsorption, 29 fructose malabsorption, and nine combined carbohydrate malabsorption. Carbohydrate intolerance as a cause of CAP was diagnosed at follow-up in only 18% (10/55) of patients with malabsorption after the elimination of the respective carbohydrate. Thus, carbohydrate malabsorption appears to be an incidental finding in children with functional abdominal pain disorders, rather than its cause. Therefore, testing of carbohydrate intolerance should only be considered in children with a strong clinical suspicion and with the goal to prevent long-term unnecessary dietary restrictions in children suffering from CAP