TY - JOUR A1 - Jazbutyte, Virginija A1 - Stumpner, Jan A1 - Redel, Andreas A1 - Lorenzen, Johan M. A1 - Roewer, Norbert A1 - Thum, Thomas A1 - Kehl, Franz T1 - Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo JF - PLoS One N2 - The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17b- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94615.5% vs. 17.163.62%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model. KW - smooth muscle cells KW - estrogens KW - heart KW - anesthetics KW - immunostaining KW - endothelial cells KW - gene expression KW - myocardial infarction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151258 VL - 7 IS - 8 ER - TY - THES A1 - Mayer, Rafaela T1 - OxPAPC as an endogenous agonist of TRPA1 channels on nociceptors T1 - OxPAPC als endogener Agonist von TRPA1 Kanälen auf Nozizeptoren N2 - Non-steroidal antiinflammatory drugs are most commonly used for inflammatory and postoperative pain. But they lack effectiveness and specificity, leading to severe side effects, like gastric ulcers, asthma and severe bleeding. Oxidized 1-palmitoyl-2-arachinidonoyl-sn-glycero-3-phosphocholine (OxPAPC) plays an important role in inflammatory pain. PAPC is a common phosphatidylcholine of membranes, which can be oxidized by reactive oxygen species. In preliminary experiments, our group found that local injection of OxPAPC in rat paws induces hyperalgesia. In this study we examined the effect of OxPAPC on transient receptor potential A1 (TRPA1), an ion channel expressed in C-fiber neurons. Furthermore, we investigated if intracellular cysteine residues of TRPA1 were necessary for agonist-channel-interactions and if a subsequent TRPA1 activation could be prevented by OxPAPC scavengers. To answer these questions, we performed calcium imaging using HEK-293 cells stably expressing hTRPA1, or transiently expressing the triple mutant channel hTRPA1-3C and naïve DRG neurons. Cells were incubated with the ratiometric, fluorescent dye Fura-2/AM and stimulated with OxPAPC. The change of light emission after excitation with 340 and 380 nm wavelengths allowed conclusions regarding changes of intracellular calcium concentrations after TRPA1 activation. In our investigation we proved evidence that OxPAPC activates TRPA1, which caused a flow of calcium ions into the cytoplasm. The TRPA1-specific channel blocker HC-030031 eliminated this agonist-induced response. TRPA1-3C was not completely sensitive to OxPAPC. The peptide D-4F and the monoclonal antibody E06 neutralized OxPAPC-induced TRPA1 activation. In this work, the importance of OxPAPC as a key mediator of inflammatory pain and as a promising target for drug design is highlighted. Our results indicate that TRPA1 activation by OxPAPC involves cysteine-dependent mechanisms, but there are other, cysteine-independent activation mechanisms as well. Potential pharmaceuticals for the treatment of inflammatory pain are D-4F and E06, whose efficiency has recently been confirmed in the animal model by our research group. N2 - Nichtsteroidale Antiphlogistika werden bei Entzündungs- und postoperativen Schmerzen eingesetzt. Ihre mangelnde Effektivität und Spezifität kann jedoch starke Nebenwirkungen wie Magen-Darmulzera, Analgetikaasthma und Blutungen hervorgerufen. Hyperalgesie kann in Entzündungsprozessen lokal durch das oxidierte Phospholipid 1-Palmitoyl-2-Arachinidonoyl-sn-Glycero-3- Phosphocholin (OxPAPC) induziert werden, welches durch Oxidation mit reaktiven Sauerstoffspezies entsteht. Vorarbeiten unserer Arbeitsgruppe zeigten, dass OxPAPC nach intraplantarer Injektion in Rattenpfoten Hyperalgesie hervorruft. In dieser Arbeit steht die Interaktion zwischen OxPAPC und dem „transient receptor potential A 1“ Kanal (TRPA1), einem Ionenkanal von C-Faser-Neuronen, im Fokus. Es wurde untersucht, ob intrazelluläre Cysteinreste zur Aktivierung durch oxidierte Phospholipide beitragen und ob diese durch einen OxPAPC-spezifischen Antagonismus verhindert werden kann. Zur Klärung der Fragestellung verwendeten wir HEK-293 Zellen, die entweder hTRPA1 stabil oder den an drei Positionen mutierten hTRPA1-C3 transient exprimierten und native DRG Neurone. Die Änderung der intrazellulären Kalziumionenkonzentration nach Kanalmodulation mit OxPAPC wurde mittels ratiometrischer Fura-2/AM-Experimente bestimmt. Wir zeigten, dass OxPAPC zur Aktivierung von TRPA1 führt, welche sich nach Zugabe des spezifischen Antagonisten HC-030031 als reversibel erwies. Sind drei Cysteine des intrazelllulären Aminoterminus von TRPA1 mutiert, wurde ein Anstieg der intrazellulären Kalziumkonzentration durch OxPAPC verringert. Das Peptid D-4F und der monoklonale Antikörper E06 neutralisierten die Wirkung von OxPAPC auf den Kanal. Das in Entzündungsprozessen gebildete OxPAPC ist ein endogener Agonist von TRPA1 Kanälen und stellt damit eine potentielle pharmakologische Zielsubstanz für die Entwicklung von Analgetika dar. Naheliegend ist, dass die Aktivierung von TRPA1 durch OxPAPC über Cysteinbindungsstellen erfolgen kann. Jedoch sind weitere, cysteinunabhängige Mechanismen ebenfalls wahrscheinlich. D-4F und E06 sind vielversprechende neuartige Substanzen für die Behandlung von Entzündungsschmerz. Ihre analgetische Wirkung wurde bereits im Tiermodell durch unsere Arbeitsgruppe bestätigt. KW - Schmerzforschung KW - Phospholipide KW - Entzündung KW - Schmerztherapie KW - Ionenkanal KW - TRPA1 channel KW - Oxidized Phospholipids KW - Inflammatory Pain KW - Nociceptor KW - DRG Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175890 ER - TY - THES A1 - Reinhold, Ann-Kristin T1 - New players in neuropathic pain? microRNA expression in dorsal root ganglia and differential transcriptional profiling in primary sensory neurons T1 - Neue Ansätze bei neuropathischem Schmerz: microRNA-Expression in Spinalganglien und eine differenzierte Transkriptionsanalyse von primären sensorischen Neuronen N2 - Neuropathic pain, caused by neuronal damage, is a severely impairing mostly chronic condition. Its underlying molecular mechanisms have not yet been thoroughly understood in their variety. In this doctoral thesis, I investigated the role of microRNAs (miRNAs) in a murine model of peripheral neuropathic pain. MiRNAs are small, non-coding RNAs known to play a crucial role in post-transcriptional gene regulation, mainly in cell proliferation and differentiation. Initially, expression patterns in affected dorsal root ganglia (DRG) at different time points after setting a peripheral nerve lesion were studied. DRG showed an increasingly differential expression pattern over the course of one week. Interestingly, a similar effect, albeit to a smaller extent, was observed in corresponding contralateral ganglia. Five miRNA (miR-124, miR-137, miR-183, miR-27b, and miR-505) were further analysed. qPCR, in situ hybridization, and bioinformatical analysis point towards a role for miR-137 and -183 in neuropathic pain as both were downregulated. Furthermore, miR-137 is shown to be specific for non-peptidergic non-myelinated nociceptors (C fibres) in DRG. As the ganglia consist of highly heterocellular tissue, I also developed a neuron-specific approach. Primarily damaged neurons were separated from intact adjacent neurons using fluorescence-activated cell-sorting and their gene expression pattern was analysed using a microarray. Thereby, not only were information obtained about mRNA expression in both groups but, by bioinformatical tools, also inferences on miRNA involvement. The general expression pattern was consistent with previous findings. Still, several genes were found differentially expressed that had not been described in this context before. Among these are corticoliberin or cation-regulating proteins like Otopetrin1. Bioinformatical data conformed, in part, to results from whole DRG, e.g. they implied a down-regulation of miR-124, -137, and -183. However, these results were not significant. In summary, I found that a) miRNA expression in DRG is influenced by nerve lesions typical of neuropathic pain and that b) these changes develop simultaneously to over-expression of galanin, a marker for neuronal damage. Furthermore, several miRNAs (miR-183, -137) exhibit distinct expression patterns in whole-DRG as well as in neuron-specific approaches. Therefore, further investigation of their possible role in initiation and maintenance of neuropathic pain seems promising. Finally, the differential expression of genes like Corticoliberin or Otopetrin 1, previously not described in neuropathic pain, has already resulted in follow-up projects. N2 - Neuropathischer Schmerz, d.h. Schmerz durch neuronale Schäden, ist eine stark beeinträchtigendes, oft chronisches Leiden. Die hierfür verantwortlichen molekularen Geschehen sind in ihrer Breite bislang nur unzureichend verstanden. In meiner Promotion habe ich die Rolle von microRNAs (miRNAs) in einem Mäusemodell des peripheren neuropathischen Schmerzes untersucht. MiRNAs sind kleine, nicht kodierende RNAs, die für posttranskriptionelle Genregulation, besonders Zellproliferation und –differenzierung verantwortlich sind. Im Experiment wurde zunächst ihre Expression in den Dorsalganglien geschädigter Nerven analysiert. Hier zeigte sich im Verlauf einer Woche ein zunehmend differentielles Expressionsmuster. Bemerkenswert war ein ähnlicher, wenn auch geringerer Effekt in kontralateralen Ganglien. In einem weiteren Schritt wurden fünf ausgewählte miRNAs (miR-124, miR-137, miR-183, miR-27b und miR-505) weiter analysiert. qPCR, In-situ-Hybridisierung und bioinformatische Untersuchungen deuteten auf Minderexpression von miR-137 und -183 bei neuropathischem Schmerz hin. Weiterhin stellte sich miR-137 als spezifisch für nicht-peptiderge nicht-myelinisierte Nozizeptoren in Dorsalganglien heraus. Da Dorsalganglien aus äußerst heterozellulärem Gewebe bestehen, entwickelte ich im Folgenden einen neuronenspezifischen Ansatz: Primär geschädigte sowie intakte benachbarte Neuronen wurden durch fluoreszenz¬aktivierte Zellsortierung (FACS) selektiert und ihre Genexpression jeweils in einem Microarray analysiert. Hierdurch konnten nicht nur direkte Informationen über mRNA-Expression in beiden Gruppen gewonnen, sondern durch bioinformatische Techniken auch Rückschlüsse auf miRNA-Expression gezogen werden. Das generelle Expressionsmuster entsprach der einschlägigen Literatur, allerdings zeigten sich auch bislang nicht beschriebene Veränderungen. Hierzu gehören Corticoliberin sowie Otopetrin1. Die bioinformatische Analyse bestätigte teilweise die Ergebnisse aus der ersten, ganglienweiten Untersuchung: Sie wiesen auf eine Minderexpression von miR-124, -137 und -183 hin, allerdings waren diese Ergebnisse nicht signifikant. Zusammengefasst zeigte sich, dass sich a) die Expression von miRNA in Dorsalganglien nach neuropathischen Läsionen ändert, und b) diese Veränderungen parallel zum neuropathischen Phänotyp entwickeln. Weiterhin wiesen mehrere miRNAs markante Expressionsmuster sowohl in ganglienweiten wie in neuronenspezifischen Untersuchugen auf. Daher scheint die weitere Untersuchung ihrer Rolle in Entwicklung und Aufrechterhaltung von neuropathischem Schmerz vielversprechend. Schließlich hat die Entdeckung von Expressionsveränderungen bei Genen wie Corticoliberin und Otopetrin1, bislang nicht im Zusammenhang mit neuropathischem Schmerz beschrieben, bereits zu Nachfolgeprojekten geführt. KW - Schmerzforschung KW - miRNS KW - Neuralgie KW - Neuropathic pain KW - microRNA KW - Neuropathischer Schmerz KW - Axonschaden KW - axonal damage KW - neuronal tracing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140314 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Salvador, Ellaine A1 - Pastorin, Giorgia A1 - Förster, Carola T1 - Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate JF - International Journal of Nanomedicine N2 - In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell® system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCN-TFITC rapid dissociation as an intermediate phase. KW - endothelial cells KW - cytotoxicity KW - blood-brain barrier KW - fluorescein isothiocyanate KW - aggregation KW - molecular dynamics KW - fluorescence microscopy KW - Transwell® system KW - multiwalled carbon nanotube KW - mice Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149233 VL - 10 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Dandekar, Thomas A1 - Förster, Carola T1 - Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia JF - HIV/AIDS: Research and Palliative Care N2 - Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein–protein interaction networks were constructed by mapping DEGs into protein–protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis. KW - microarray KW - differentially expressed genes KW - protein-protein interaction network KW - gene ontology KW - encephalitis dementia KW - human immunodeficiency virus Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149494 VL - 7 ER - TY - THES A1 - Kurrek, Matthias M. T1 - Simulation To Establish Benchmark Outcome Measures T1 - Simulation zur Erstellung von Benchmarks für Outcomes N2 - Following the early experiences in aviation, medical simulation has rapidly evolved into one of the most novel educational tools of the last three decades. In addition to its use in training individuals or teams in crisis resource management, simulation has been studied as a tool to evaluate technical and non-technical skills of individuals as well as, more recently, entire medical teams. It is usually fairly difficult to obtain clinical reference data from critical events to refute claims that the management of actual events fell below what could reasonably be expected and we demonstrated the use of rank order statistics to calculate quantiles with confidence limits for management times of critical obstetrical events using data from realistic simulation. This approach could be used to describe the distribution of treatment times in order to assist in deciding what performance may constitute an outlier. It can also identify particular challenges of clinical practice and allow the development of educational curricula. While the information derived from simulation has to be interpreted with a high degree of caution for a clinical context, it may represent a further ‘added value’ or important step in establishing simulation as a training tool and to provide information that could be used in an appropriate clinical context for adverse events. Large amounts of data (such as from a simulation registry) would allow the calculation of acceptable confidence intervals for the required outcome parameters as well as actual tolerance limits. N2 - Es ist auf Grund der Rarität von vielen Notfällen normalerweise nicht möglich genug klinische Daten zur Auswertung zur Verfügung zu haben, um sagen zu können, ob das Management eines bestimmten Falles innerhalb von ‚normalen’ Grenzwerten fällt. In dieser wissenschaftlichen Arbeit zeigten wir das ‚Rank Order Statistiks’ dafür benutzt werden könnten, die Resultate von simulierten Notfällen in der Geburtshilfe als Bandbreite von ‚normalen’ klinischen Leistungen darzustellen. Dieses Vorgehen würde es erlauben, eine klinische Leistung mit einer Datenbank von vergleichbaren simulierten Zwischenfällen abzugleichen, um entscheiden zu können, ob die klinische Leistung innerhalb von ‚normalen’ Werten ausgefallen ist. Dieses Vorgehen verschafft außerdem Einblick, welche Probleme besondere Schwierigkeiten bereiten sodass ggf. gezielte Fortbildungen vorbereitet werden könnten. Obwohl die Daten der Simulation mit gewisser Vorsicht zu interpretieren sind, repräsentiert dieses Vorgehen eine neue Anwendung von Simulation, die für die Auswertung von klinischen Notfällen von großer Bedeutung sein könnte. Es wird in diesem Zusammenhang allerdings notwendig sein, relativ große Datenbanken von vielen simulierten Notfällen zu erstellen und auszuwerten, um die gesuchten Werte mit genug Genauigkeit kalkulieren zu können. KW - Simulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143882 ER - TY - JOUR A1 - Mambretti, Egle M. A1 - Kistner, Katrin A1 - Mayer, Stefanie A1 - Massotte, Dominique A1 - Kieffer, Brigitte L. A1 - Hoffmann, Carsten A1 - Reeh, Peter W. A1 - Brack, Alexander A1 - Asan, Esther A1 - Rittner, Heike L. T1 - Functional and structural characterization of axonal opioid receptors as targets for analgesia JF - Molecular Pain N2 - Background Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. µ-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in naïve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function. Results Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\(^2\), N-MePhe\(^4\), Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in naïve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In vitro, using β-arrestin-2/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization. Conclusion MOPs are present and functional in the axonal membrane from naïve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia. KW - µ-Opioid receptor KW - hypertonic solution KW - fentanyl KW - calcitonin gene-related peptide KW - DAMGO KW - internalization KW - peripheral nerve KW - ultrastructure Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145917 IS - 12 ER - TY - JOUR A1 - Rosenbaum, Corinna A1 - Schick, Martin Alexander A1 - Wollborn, Jakob A1 - Heider, Andreas A1 - Scholz, Claus-Jürgen A1 - Cecil, Alexander A1 - Niesler, Beate A1 - Hirrlinger, Johannes A1 - Walles, Heike A1 - Metzger, Marco T1 - Activation of Myenteric Glia during Acute Inflammation In Vitro and In Vivo JF - PLoS One N2 - Background Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network. Methods and Results In this study, we analyzed the biological effects of a systemic LPS-induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response. Conclusion and Significance Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine. KW - gene expression KW - gastrointestinal tract KW - inflammatory bowel disease KW - central nervous system KW - systemic inflammatory response syndrome KW - inflammation KW - astrocytes KW - cytokines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146544 VL - 11 IS - 3 ER - TY - JOUR A1 - Grundgeiger, T. A1 - Albert, M. A1 - Reinhardt, D. A1 - Happel, O. A1 - Steinisch, A. A1 - Wurmb, T. T1 - Real-time tablet-based resuscitation documentation by the team leader: evaluating documentation quality and clinical performance JF - Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine N2 - Background Precise and complete documentation of in-hospital cardiopulmonary resuscitations is important but data quality can be poor. In the present study, we investigated the effect of a tablet-based application for real-time resuscitation documentation used by the emergency team leader on documentation quality and clinical performance of the emergency team. Methods Senior anaesthesiologists either used the tablet-based application during the simulated resuscitation for documentation and also used the application for the final documentation or conducted the full documentation at the end of the scenario using the local hospital information system. The latter procedure represents the current local documentation method. All scenarios were video recorded. To assess the documentation, we compared the precision of intervention delivery times, documentation completeness, and final documentation time. To assess clinical performance, we compared adherence to guidelines for defibrillation and adrenaline administration, the no-flow fraction, and the time to first defibrillation. Results The results showed significant benefits for the tablet-based application compared to the hospital information system for precision of the intervention delivery times, the final documentation time, and the no-flow fraction. We observed no differences between the groups for documentation completeness, adherence to guidelines for defibrillation and adrenaline administration, and the time to first defibrillation. Discussion In the presented study, we observed that a tablet-based application can improve documentation data quality. Furthermore, we demonstrated that a well-designed application can be used in real-time by a member of the emergency team with possible beneficial effects on clinical performance. Conclusion The present evaluation confirms the advantage of tablet-based documentation tools and also shows that the application can be used by an active member of an emergency team without compromising clinical performance. KW - cardiac arrest documentation KW - cardiopulmonary resuscitation KW - simulation KW - no-flow fraction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146582 VL - 24 IS - 51 ER - TY - JOUR A1 - Altieri, Barbara A1 - Sbiera, Silviu A1 - Della Casa, Silvia A1 - Weigand, Isabel A1 - Wild, Vanessa A1 - Steinhauer, Sonja A1 - Fadda, Guido A1 - Kocot, Arkadius A1 - Bekteshi, Michaela A1 - Mambretti, Egle M. A1 - Rosenwald, Andreas A1 - Pontecorvi, Alfredo A1 - Fassnacht, Martin A1 - Ronchi, Cristina L. T1 - Livin/BIRC7 expression as malignancy marker in adrenocortical tumors JF - Oncotarget N2 - Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R. The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression. Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability. In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy. KW - cancer KW - livin KW - BIRC7 KW - adrenocortical cancer KW - adrenal tumor KW - caspase-3 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171887 VL - 8 IS - 6 ER - TY - JOUR A1 - Herbert, M. K. A1 - Schmidt, R. F. T1 - Activation of normal and inflamed fine articular afferent units by serotonin N2 - In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 p,g 5-HT excited about 43% of group 111 (CV: 2.5-20 m/sec) and 73% of group IV units (CV: < 2.5 mjsec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group 111 units (CV: > 16 mjsec) and group li units (CV: > 20 m/sec) were never excited by 5-HT. Repetitiveadministration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was gteatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fineafferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed bothin group 111 and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. lt is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group 111 units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages. KW - Medizin KW - Serotonin (5-HT) KW - Articular afferent KW - Joint pain KW - Inflammation Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59952 ER - TY - JOUR A1 - Herbert, M. K. A1 - Holzer, P. T1 - Nitric oxide mediates the amplification by interleukin-1β of neurogenic vasodilatation in the rat skin N2 - No abstract available. KW - Medizin KW - Afferent nerve stimulation KW - Capsaicin KW - Cutaneous hyperemia KW - lnterleukin-lβ KW - Neurogenie inflammation KW - Nitric oxide (NO) Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59969 ER - TY - JOUR A1 - Neuhaus, Winfried A1 - Burek, Malgorzata A1 - Djuzenova, Cholpon C A1 - Thal, Serge C A1 - Koepsell, Hermann A1 - Roewer, Norbert A1 - Förster, Carola Y T1 - Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells N2 - During stroke the blood–brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907% after 6 h OGD and was still higher (210%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells. KW - Blut-Hirn-Schranke KW - Schlaganfall KW - Glucosetransportproteine KW - NMDA-Antagonist KW - NMDA-Rezeptor KW - blood-brain barrier KW - MK801 KW - NMDAR KW - stroke KW - glut1 KW - sglt1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67241 ER - TY - JOUR A1 - Wahlen, Bianca M. A1 - Roewer, Norbert A1 - Kranke, Peter T1 - Use of local anaesthetics and adjuncts for spinal and epidural anaesthesia and analgesia at German and Austrian University Hospitals: an online survey to access current standard practice N2 - Background: The present anonymous multicenter online survey was conducted to evaluate the application of regional anaesthesia techniques as well as the used local anaesthetics and adjuncts at German and Austrian university hospitals. Methods: 39 university hospitals were requested to fill in an online questionnaire, to determine the kind of regional anaesthesia and preferred drugs in urology, obstetrics and gynaecology. Results: 33 hospitals responded. No regional anaesthesia is conducted in 47% of the minor gynaecological and 44% of the urological operations; plain bupivacaine 0.5% is used in 38% and 47% respectively. In transurethral resections of the prostate and bladder no regional anaesthesia is used in 3% of the responding hospitals, whereas plain bupivacaine 0.5% is used in more than 90%. Regional anaesthesia is only used in selected major gynaecological and urological operations. On the contrary to the smaller operations, the survey revealed a large variety of used drugs and mixtures. Almost 80% prefer plain bupivacaine or ropivacaine 0.5% in spinal anaesthesia in caesarean section. Similarly to the use of drugs in major urological and gynaecological operations a wide range of drugs and adjuncts is used in epidural anaesthesia in caesarean section and spontaneous delivery. Conclusions: Our results indicate a certain agreement in short operations in spinal anaesthesia. By contrast, a large variety concerning the anaesthesiological approach in larger operations as well as in epidural analgesia in obstetrics could be revealed, the causes of which are assumed to be primarily rooted in particular departmental structures. KW - Anästhesiologie KW - anaesthetics KW - University Hospital Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67847 ER - TY - JOUR A1 - Schuster, Frank A1 - Wessig, Carsten A1 - Schimmer, Christoph A1 - Johannsen, Stephan A1 - Lazarus, Marc A1 - Aleksic, Ivan A1 - Leyh, Rainer A1 - Roewer, Norbert T1 - In vitro contracture test results and anaesthetic management of a patient with emery-dreifuss muscular dystrophy for cardiac transplantation JF - Case Reports in Anesthesiology N2 - Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required. KW - Emery-Dreifuss muscular dystrophy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123413 VL - 2012 IS - 349046 ER - TY - JOUR A1 - Burek, Malgorzata A1 - Salvador, Ellaine A1 - Förster, Carola Y. T1 - Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an In Vitro Blood Brain Barrier Model JF - Journal of Visualized Experiments N2 - Epithelial and endothelial cells (EC) are building paracellular barriers which protect the tissue from the external and internal environment. The blood-brain barrier (BBB) consisting of EC, astrocyte end-feet, pericytes and the basal membrane is responsible for the protection and homeostasis of the brain parenchyma. In vitro BBB models are common tools to study the structure and function of the BBB at the cellular level. A considerable number of different in vitro BBB models have been established for research in different laboratories to date. Usually, the cells are obtained from bovine, porcine, rat or mouse brain tissue (discussed in detail in the review by Wilhelm et al. 1). Human tissue samples are available only in a restricted number of laboratories or companies 2,3. While primary cell preparations are time consuming and the EC cultures can differ from batch to batch, the establishment of immortalized EC lines is the focus of scientific interest. Here, we present a method for establishing an immortalized brain microvascular EC line from neonatal mouse brain. We describe the procedure step-by-step listing the reagents and solutions used. The method established by our lab allows the isolation of a homogenous immortalized endothelial cell line within four to five weeks. The brain microvascular endothelial cell lines termed cEND 4 (from cerebral cortex) and cerebEND 5 (from cerebellar cortex), were isolated according to this procedure in the Förster laboratory and have been effectively used for explanation of different physiological and pathological processes at the BBB. Using cEND and cerebEND we have demonstrated that these cells respond to glucocorticoid- 4,6-9 and estrogen-treatment 10 as well as to pro-infammatory mediators, such as TNFalpha 5,8. Moreover, we have studied the pathology of multiple sclerosis 11 and hypoxia 12,13 on the EC-level. The cEND and cerebEND lines can be considered as a good tool for studying the structure and function of the BBB, cellular responses of ECs to different stimuli or interaction of the EC with lymphocytes or cancer cells. KW - in vitro cell culture models KW - blood-brain barrier KW - neuroscience KW - immunology KW - brain KW - microvascular endothelial cells KW - immortalization KW - cEND Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126702 VL - 66 IS - e4022 ER - TY - JOUR A1 - Dietz, U. A. A1 - Wichelmann, C. A1 - Wunder, C. A1 - Kauczok, J. A1 - Spor, L. A1 - Strauß, A. A1 - Wildenauer, R. A1 - Jurowich, C. A1 - Germer, C. T. T1 - Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia JF - Hernia N2 - Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result. KW - synthetic mesh KW - giant ventral hernia KW - laparostomy KW - open abdomen KW - vacuum conditioning Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126732 VL - 16 IS - 4 ER - TY - JOUR A1 - Kober, Christina A1 - Rohn, Susanne A1 - Weibel, Stephanie A1 - Geissinger, Ulrike A1 - Chen, Nanhai G. A1 - Szalay, Aladar A. T1 - Microglia and astrocytes attenuate the replication of the oncolytic vaccinia virus LIVP 1.1.1 in murine GL261 gliomas by acting as vaccinia virus traps JF - Journal of Translational Medicine N2 - Background Oncolytic virotherapy is a novel approach for the treatment of glioblastoma multiforme (GBM) which is still a fatal disease. Pathologic features of GBM are characterized by the infiltration with microglia/macrophages and a strong interaction between immune- and glioma cells. The aim of this study was to determine the role of microglia and astrocytes for oncolytic vaccinia virus (VACV) therapy of GBM. Methods VACV LIVP 1.1.1 replication in C57BL/6 and \(Foxn1^{nu/nu}\) mice with and without GL261 gliomas was analyzed. Furthermore, immunohistochemical analysis of microglia and astrocytes was investigated in non-, mock-, and LIVP 1.1.1-infected orthotopic GL261 gliomas in C57BL/6 mice. In cell culture studies virus replication and virus-mediated cell death of GL261 glioma cells was examined, as well as in BV-2 microglia and IMA2.1 astrocytes with M1 or M2 phenotypes. Co-culture experiments between BV-2 and GL261 cells and apoptosis/necrosis studies were performed. Organotypic slice cultures with implanted GL261 tumor spheres were used as additional cell culture system. Results We discovered that orthotopic GL261 gliomas upon intracranial virus delivery did not support replication of LIVP 1.1.1, similar to VACV-infected brains without gliomas. In addition, recruitment of \(Iba1^+\) microglia and \(GFAP^+\) astrocytes to orthotopically implanted GL261 glioma sites occurred already without virus injection. GL261 cells in culture showed high virus replication, while replication in BV-2 and IMA2.1 cells was barely detectable. The reduced viral replication in BV-2 cells might be due to rapid VACV-induced apoptotic cell death. In BV-2 and IMA 2.1 cells with M1 phenotype a further reduction of virus progeny and virus-mediated cell death was detected. Application of BV-2 microglial cells with M1 phenotype onto organotypic slice cultures with implanted GL261 gliomas resulted in reduced infection of BV-2 cells, whereas GL261 cells were well infected. Conclusion Our results indicate that microglia and astrocytes, dependent on their activation state, may preferentially clear viral particles by immediate uptake after delivery. By acting as VACV traps they further reduce efficient virus infection of the tumor cells. These findings demonstrate that glia cells need to be taken into account for successful GBM therapy development. KW - GBM KW - tumor microenvironment KW - microglia KW - polarization KW - VACV KW - OSC KW - IMA2.1 KW - BV-2 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126517 VL - 13 IS - 216 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Sohajda, Tamás A1 - Puskas, Istaván A1 - Roewer, Norbert A1 - Förster, Carola A1 - Broscheit, Jens-Albert T1 - Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin JF - Molecules N2 - We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔG(CR)(solv = -9.98 kcal·mol ⁻¹), which has a minimal ΔG(OR)(solv) of -67.01 kcal·mol⁻¹. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (ΔG(bind)) value of -5.57 ± 0.02 kcal·mol⁻¹, an equilibrium binding constant (K(b)) of 79.89 ± 2.706 μM, and a ligand efficiency index (LE(lig)) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations. KW - quantum mechanics KW - free energy of solvation KW - torsional energy KW - trimethyl-β-cyclodextrin KW - midazolam KW - transition state KW - molecular docking KW - Gibbs free energy of binding Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119186 VL - 19 IS - 10 ER - TY - JOUR A1 - Schick, Martin A. A1 - Baar, Wolfgang A1 - Flemming, Sven A1 - Schlegel, Nicolas A1 - Wollborn, Jakob A1 - Held, Christopher A1 - Schneider, Reinhard A1 - Brock, Robert W. A1 - Roewer, Norbert A1 - Wunder, Christian T1 - Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model JF - Intensive Care Medicine Experimental N2 - Background Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring. Methods Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days. Results All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days. Conclusions The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI. KW - CASP KW - animal model KW - acute kidney injury KW - sepsis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126111 VL - 2 IS - 34 ER -