Verbesserung des Angiotensin II-induzierten kardialen Schadens durch die kurzkettige Fettsäure Propionat – einen Metaboliten der Darmmikrobiota

Hintergrund: Darmbakterien produzieren eine Vielzahl von Metaboliten, die durch den Wirt resorbiert werden und Auswirkungen auf dessen Physiologie haben. Kurzkettige Fettsäuren (engl. short-chain fatty acids, SCFA) wie z. B. Propionat (C3) sind Metabolite, die durch bakterielle Fermentierung aus nicht verdaulichen Polysacchariden (sogenannte Ballaststoffe oder Fasern) produziert werden. C3 ist durch seine Wirkung auf T-Zellen, insbesondere auf anti-inflammatorisch wirkende regulatorische T-Zellen (TREG), gekennzeichnet. Die essentielle Hypertonie (HTN) und der damit assoziierte kardiale Organschaden sind durch eine pro-inflammatorische Auslenkung der T-Zell-Homöostase charakterisiert. Experimentelle Strategien, welche die Funktion von TREG verbessern, vermindern bekanntermaßen den durch die HTN verursachten Endorganschaden. Die zugrundeliegende Hypothese ist somit, dass die SCFA C3 den hypertensiven kardialen Schaden positiv beeinflussen kann. Methodik: Zur Induktion der HTN in 12 Wochen alten männlichen NMRI Mäusen erfolgte die Implantation einer subkutanen osmotischen Minipumpe, die über 14 Tage 1,44mg/kg/d Angiotensin (Ang) II freisetzt. Um die intestinale bakteriellen Produktion von SCFA zu supprimieren, erhielten die Mäuse ein faserarmes Futter. Um die Effekte von C3 spezifisch zu untersuchen, wurden die Tiere entweder mit Natriumpropionat oder Natriumchlorid als Kontrolle im Trinkwasser behandelt. Die Inflammation wurde mittels Durchflusszytometrie, die kardiale Schädigung, mittels Echokardiographie, Immunfluoreszenz, Genexpressionsanalyse und in vivo elektrophysiologischer Untersuchung quantifiziert. Eine Blutdruckmessung erfolgte kontinuierlich mittels Telemetrie. TREG wurden durch anti-CD25 Antikörper (PC61) in mit Ang II infundierten C3-behandelten Mäusen depletiert, um den Wirkmechanismus von C3 aufzuklären. Ergebnisse: Die Behandlung mit C3 führte zu einem signifikant verbesserten Überleben nach 14 Tagen. C3 reduzierte sowohl die systemische inflammatorische Antwort auf Ang II, als auch die kardiale Hypertrophie und Fibrose. Begleitend kam es zu einer Reduktion der ins kardiale Gewebe infiltrierenden T-Helferzellen, zytotoxische T-Zellen und Makrophagen. Die Behandlung mit C3 bewirkte zudem einen reduzierten Anteil an Typ17-T-Helferzellen (TH17) in Herz und Milz. Dies führte zu einer reduzierten Anfälligkeit für ventrikuläre Tachyarrhythmien in C3-behandelten Mäusen. Die Verbesserung des kardialen Schadens und der Inflammation waren in TREG-depletierten Mäusen abgeschwächt. C3 führte außerdem unabhängig von der Wirkung auf TREG zu einer verzögert eintretenden, moderaten Reduktion des Blutdruckes. Schlussfolgerung: Die Daten unterstreichen die Bedeutung von aus unverdaulichen Polysacchariden gewonnenen bakteriellen Metaboliten für die kardiale Gesundheit. Die Wirkung dieser Metabolite auf TREG spielt beim kardioprotektiven Effekt von C3 eine zentrale Rolle. Die orale Gabe von C3 sowie die Förderung der intestinalen Produktion von C3 könnten eine vielversprechende Option in der Behandlung der hypertensiven Herzkrankheit darstellen.Background: Gut microbiota release a plethora of metabolites into the host and thereby affect the host physiology. Short-chain fatty acids (SCFA) such as propionate (C3) are metabolites produced from otherwise indigestible polysaccharides (so-called fiber) by bacterial fermentation in the intestine. C3 has been shown to influence immune cells, especially anti-inflammatory regulatory T cells (TREG). Essential hypertension (HTN) is characterized by a pro-inflammatory T cell response which promotes the damage to important organs such as the heart. Experimental approaches promoting TREG function have been shown to ameliorate hypertensive end-organ damage. We hypothesized that the SCFA C3 attenuates hypertensive cardiac damage. Methods: To induce hypertension in 12-week-old male NMRI mice, Angiotensin (Ang) II (1,44mg/kg/d) was infused subcutaneously for 14 days using osmotic minipumps. Mice were fed a fiber-depleted diet to suppress intestinal bacterial SCFA production. To specifically examine the effect of C3, mice were either administered sodium propionate or sodium chloride as control in drinking water. The inflammatory response was analyzed by flow cytometry. Cardiac organ damage was assessed using echocardiography, in vivo electrophysiology, and immunofluorescence. Blood pressure was measured by radiotelemetry. To assess the mode of action of C3, TREG were depleted in Ang II-infused C3-treated mice using an anti-CD25 antibody (PC61). Results: C3 treatment significantly improved survival along with a reduced inflammatory response to Ang II and ameliorated cardiac hypertrophy and fibrosis. Fewer T helper cells, cytotoxic T cells and macrophages infiltrated the hearts of C3-treated mice. C3 reduced the amount of T-helper type 17 (TH17) cells in hearts and spleens. This led to a reduced susceptibility to cardiac ventricular tachyarrhythmias. Improvement of cardiac damage and inflammation by C3 was abrogated in TREG-depleted mice. C3 had a moderate blood pressure-lowering effect confined to the second week of Ang II infusion, which was preserved in TREG-depleted mice. Conclusion: Our data highlight the importance of fiber-derived gut bacterial metabolites for cardiac health. TREG are central to the cardioprotective effect of C3 in hypertension. Treatment with C3 and/or augmentation of intestinal C3 production may prove of benefit in the treatment of hypertensive heart disease

Non-deterministic information systems and their domains

AbstractIn the theory of denotational semantics of programming languages Dedekind-complete, algebraic partial orders (domains) frequently have been considered since Scott's and Strachey's fundamental work in 1971 (Stoy, 1977). As Scott (1982) showed, these domains can be represented canonically by (deterministic) information systems. However, recently, more complicated constructions (such as power domains) have led to more general domains (Plotkin, 1976; Smyth and Plotkin, 1977; Smyth, 1983). We introduce non-deterministic information systems and establish the representation theorem similar to Scott (1982) for these more general domains. This result will be the basis for solving recursive domain equations

Context-Based Prevention and Handling of Exceptions for Human-Centric Mobile Services

Using smart mobile devices to support human-centric services is a frequent demand in business scenarios. As a particular challenge, tasks performed in a paper-driven way shall be digitally transformed with the use of mobile devices. With the goal to enable business applications supporting human-centric mobile services in mind, we developed a frame-work that extends existing process management technology with mobile activities running on smart mobile devices. Note that when considering the frequently changing conditions of mobile environments, the prevention and the proper handling of exceptions (e.g., lost connections) become crucial. The developed framework, therefore, aims to prevent exceptions and to provide a sophisticated exception handling service not supported by existing process management technology so far

Flexible Support of Healthcare Processes

Traditionally, healthcare information systems have focused on the support of predictable and repetitive clinical processes. Even though the latter can be often prespecified in formal process models, process flexibility in terms of dynamic adaptability is indispensable to cope with exceptions and unforeseen situations. Flexibility is further required to accommodate the need for evolving healthcare processes and to properly support healthcare process variability. In addition, process-aware information systems are increasingly used to support less structured healthcare processes (i.e., patient treatment processes), which can be characterized as knowledge-intensive. Healthcare processes of this category are neither fully predictable nor repetitive and, therefore, they cannot be fully prespecified at design time. The partial unpredictability of these processes, in turn, demands a certain amount of looseness. This chapter deals with the characteristic flexibility needs of both prespecified and loosely specified healthcare processes. In addition, it presents fundamental flexibility features required to address these flexibility needs as well as to accommodate them in healthcare practice

Context-Based Handling of Mobile Process Activities

Process technology constitutes a crucial component of information systems. In this context, high flexibility is required as business functions must be quickly adaptable to cope with dynamic business changes. As recent developments allow for the use of mobile devices in knowledge-intensive areas, it is often demanded to enhance process-aware information systems with mobile activity support. In general, the technical integration of this activity type with existing process management technology is challenging. For example, protocols governing the communication between mobile devices and process management systems must be adapted. If a mobile context shall be additionally considered, the integration gets even more complex. However, the use of a mobile context offers advantages. For example, the mobile activity execution time may be decreased if mobile activities are only assigned to those users whose location is beneficial. This chapter proposes an approach to enable the robust handling of single process activities on mobile devices based on a mobile process model

Using Smart Mobile Devices for Collecting Structured Data in Clinical Trials: Results From a Large-Scale Case Study

In future, more and more clinical trials will rely on smart mobile devices for collecting structured data from subjects during trial execution. Although there have been many projects demonstrating the benefits of mobile digital questionnaires, the scenarios considered in literature have been rather limited so far. In particular, the number of subjects is rather low in respective studies and a well controllable infrastructure is usually presumed, which not always applies in practice. This paper gives insights into the lessons learned in a clinical psychology trial when using tablets for mobile data collection. In particular, more than 1.700 subjects have participated so far, providing us with valuable feedback on collecting trial data with smart mobile devices in the large scale. Furthermore, issues related to an insufficient infrastructure (e.g., unstable Internet connections) have been addressed as well. Overall, the paper provides valuable insights gained during trial execution. In future, electronic questionnaires executable on smart mobile devices will replace paper-based ones

Integrating Mobile Tasks with Business Processes: A Self-Healing Approach

Process management technology constitutes a fundamental component of any service-driven computing environment. Process management facilitates both the composition of services at design time and their orchestration at run time. In particular, when applying the service paradigm to enterprise integration management, high flexibility is required. In this context, atomic as well as composite services representing the business functions should be quickly adaptable to cope with dynamic business changes. Furthermore, they should enable mobile and quick access to enterprise information. The growing maturity of smart mobile devices has fostered their prevalence in knowledge-intensive areas in the enterprise as well. As a consequence, process management technology needs to be enhanced with mobile task support. However, tasks hitherto executed stationarily, cannot be simply transferred in order to run on smart mobile devices. Many research groups focus on the partitioning of processes and the distributed execution of the resulting fragments on smart mobile devices. Opposed to this fragmentation concept, this chapter proposes an approach to enable the robust and flexible execution of single process tasks on smart mobile devices by provisioning self-healing techniques to address the smooth integration of mobile tasks with business processes

Data-Aware Interaction in Distributed and Collaborative Workflows: Modeling, Semantics, Correctness

IT support for distributed and collaborative workflows and related interactions between business partners is becoming increasingly important. For modeling such partner interactions as flow of message exchanges, different top-down approaches, covered under the term interaction modeling, are provided. Like for workflow models, correctness constitutes a fundamental challenge for interaction models as well; e.g., to ensure the boundedness and absence of deadlocks and lifelocks. Due to their distributed execution, in addition, interaction models should be message-deterministic and realizable, i.e., the same conversation (i.e. sequence of messages) should always lead to the same result, and it should be ensured that partners always have enough information about the messages they must or may send in a given context. So far, most existing approaches have addressed correctness of interaction models without explicitly considering the data exchanged through messages and used for routing decisions. However, data support is crucial for collaborative workflows and interaction models respectively. This paper therefore enriches interaction models with the data perspective. In particular, it defines the behavior of data-aware interaction models based on Data-Aware Interaction Nets, which use elements of both Interaction Petri Nets and Workflow Nets with Data. Finally, formal correctness criteria for Data-Aware Interaction Nets are derived, guaranteeing the boundedness and absence of deadlocks and lifelocks, and ensuring message-determinism as well as realizability