@article{CurtazSchmittHerbertetal.2020, author = {Curtaz, Carolin J. and Schmitt, Constanze and Herbert, Saskia-Laureen and Feldheim, Jonas and Schlegel, Nicolas and Gosselet, Fabien and Hagemann, Carsten and Roewer, Norbert and Meybohm, Patrick and W{\"o}ckel, Achim and Burek, Malgorzata}, title = {Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model}, series = {Fluids and Barriers of the CNS}, volume = {17}, journal = {Fluids and Barriers of the CNS}, doi = {10.1186/s12987-020-00192-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229940}, year = {2020}, abstract = {Background The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13.}, language = {en} } @article{BurekBurmesterSalvadoretal.2020, author = {Burek, Malgorzata and Burmester, Sandra and Salvador, Ellaine and M{\"o}ller-Ehrlich, Kerstin and Schneider, Reinhard and Roewer, Norbert and Nagai, Michiaki and F{\"o}rster, Carola Y.}, title = {Kidney Ischemia/Reperfusion Injury Induces Changes in the Drug Transporter Expression at the Blood-Brain Barrier in vivo and in vitro}, series = {Frontiers in Physiology}, volume = {11}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2020.569881}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216413}, year = {2020}, abstract = {Ischemia/reperfusion injury is a major cause of acute kidney injury (AKI). AKI is characterized by a sudden decrease in kidney function, systemic inflammation, oxidative stress, and dysregulation of the sodium, potassium, and water channels. While AKI leads to uremic encephalopathy, epidemiological studies have shown that AKI is associated with a subsequent risk for developing stroke and dementia. To get more insights into kidney-brain crosstalk, we have created an in vitro co-culture model based on human kidney cells of the proximal tubule (HK-2) and brain microvascular endothelial cells (BMEC). The HK-2 cell line was grown to confluence on 6-well plates and exposed to oxygen/glucose deprivation (OGD) for 4 h. Control HK-2 cells were grown under normal conditions. The BMEC cell line cerebED was grown to confluence on transwells with 0.4 μm pores. The transwell filters seeded and grown to confluence with cereEND were inserted into the plates with HK-2 cells with or without OGD treatment. In addition, cerebEND were left untreated or treated with uremic toxins, indole-3-acetic acid (IAA) and indoxyl sulfate (IS). The protein and mRNA expression of selected BBB-typical influx transporters, efflux transporters, cellular receptors, and tight junction proteins was measured in BMECs. To validate this in vitro model of kidney-brain interaction, we isolated brain capillaries from mice exposed to bilateral renal ischemia (30 min)/reperfusion injury (24 h) and measured mRNA and protein expression as described above. Both in vitro and in vivo systems showed similar changes in the expression of drug transporters, cellular receptors, and tight junction proteins. Efflux pumps, in particular Abcb1b, Abcc1, and Abcg2, have shown increased expression in our model. Thus, our in vitro co-culture system can be used to study the cellular mechanism of kidney and brain crosstalk in renal ischemia/reperfusion injury.}, language = {en} } @article{LehmannOehlerZuberetal.2020, author = {Lehmann, Martin and Oehler, Beatrice and Zuber, Jonas and Malzahn, Uwe and Walles, Thorsten and Muellenbach, Ralf M. and Roewer, Norbert and Kredel, Markus}, title = {Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography}, series = {Acta Anaesthesiologica Scandinavica}, volume = {64}, journal = {Acta Anaesthesiologica Scandinavica}, number = {4}, doi = {10.1111/aas.13525}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213575}, pages = {517-525}, year = {2020}, abstract = {Background: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post-operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity. Methods: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left-sided open or video-thoracoscopic procedures have been investigated. Pre-operative measurements with EIT and spirometry were compared with data obtained 3 days post-operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx′ (ipsilateral/contralateral). Thus, COVx′ shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two-way ANOVA for repeated measurements (side, time). Results: The perioperative shift of COVx′ was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right-sided surgery (COVx′-1.97 pixel matrix points, P < .001), but not after the left-sided surgery (COVx′-0.61, P = .425). The forced vital capacity (\%predicted) decreased from 94 (83-109)\% (median [quartiles]; [left-sided]) and 89 (80-97)\% (right-sided surgery) to 61 (59-66)\% and 62 (40-72)\% (P < .05), respectively. The perioperative changes in forced vital capacity (\%predicted) were weakly associated with the shift of COVx′. Conclusion: Only after right-sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups.}, language = {en} } @article{BauerOpitzFilseretal.2019, author = {Bauer, Maria and Opitz, Anne and Filser, J{\"o}rg and Jansen, Hendrik and Meffert, Rainer H. and Germer, Christoph T. and Roewer, Norbert and Muellenbach, Ralf M. and Kredel, Markus}, title = {Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications}, series = {BMC Anesthesiology}, volume = {19}, journal = {BMC Anesthesiology}, doi = {10.1186/s12871-019-0805-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200730}, pages = {132}, year = {2019}, abstract = {Background Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. Methods This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. Results Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0-17.3); first day: 17.8 (16.9-18.2), p < 0.004; third day: 17.4 (16.2-18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC\%predicted) (median: 93, 58, 64\%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC\%predicted on the third postoperative day (r = - 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC\%predicted was only decreased on the first postoperative day (median FVC\%predicted on the preoperative, first and third day: 85, 81 and 88\%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. Conclusions After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation.}, language = {en} } @article{SchusterJohannsenIsbaryetal.2018, author = {Schuster, Frank and Johannsen, Stephan and Isbary, Susanne and T{\"u}rkmeneli, Ismail and Roewer, Norbert}, title = {In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine}, series = {BMC Anesthesiology}, volume = {18}, journal = {BMC Anesthesiology}, number = {182}, doi = {10.1186/s12871-018-0644-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176991}, year = {2018}, abstract = {Background: The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH. Methods: Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D'Agostino \& Pearson test for normal distribution and student's t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant. Results: There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (- 3.0 [- 5.2-0.2] mN) compared to MHS (- 7.5 [- 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9-6.1] mN) compared to MHN (- 0.7 [- 1.3-0.0] mN) (p < 0.0001). Conclusions: This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.}, language = {en} } @article{JohannsenSchickRoeweretal.2018, author = {Johannsen, Stephan and Schick, Martin and Roewer, Norbert and Schuster, Frank}, title = {Microdialysis and ultrasound elastography for monitoring of localized muscular reaction after pharmacological stimulation in rats}, series = {BMC Research Notes}, volume = {11}, journal = {BMC Research Notes}, number = {636}, doi = {10.1186/s13104-018-3742-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176977}, year = {2018}, abstract = {Objective: Halothane and caffeine are known to cause skeletal muscular contractions in vitro and have been proven to induce circumscribed metabolic reactions when injected into rat skeletal muscle. In this study 26 rats were investigated by either continuous application of calcium 160 mM or bolus injection of caffeine 160 mM or halothane 10\% vol via a microdialysis probe in the tibialis anterior muscle. Tissue elasticity at the injection site was monitored by ultrasound strain elastography. Aim of this study was to detect (I) changes in local lactate concentrations and (II) whether these can be attributed to a muscular contraction detected by ultrasound elastography. Results: Localized metabolic reactions were verified by increasing intramuscular lactate concentrations following continuous application of calcium (0.6 [0.3;0.6] to 3.6 [3.0;4.3] mmol/l after 60 min) and bolus application of caffeine (0.2 [0.2;0.3] to 1.6 [0.9;1.9] mmol/l after 30 min) and halothane (0.3 [0.1;0.3] to 4.7 [4.3;6.3] mmol/l after 30 min). However, ultrasound elastography did not detect any differences in tissue elasticity compared to control animals. The authors identified potential limitations of the study conditions, which might be crucial to avoid for future investigations.}, language = {en} } @article{ChenLotzRoeweretal.2018, author = {Chen, Shasha and Lotz, Christopher and Roewer, Norbert and Broscheit, Jens-Albert}, title = {Comparison of volatile anesthetic-induced preconditioning in cardiac and cerebral system: molecular mechanisms and clinical aspects}, series = {European Journal of Medical Research}, volume = {23}, journal = {European Journal of Medical Research}, number = {10}, doi = {10.1186/s40001-018-0308-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175509}, year = {2018}, abstract = {Volatile anesthetic-induced preconditioning ( APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio- and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed.}, language = {en} } @article{WollbornWunderStixetal.2015, author = {Wollborn, Jakob and Wunder, Christian and Stix, Jana and Neuhaus, Winfried and Bruno, Rapahel R. and Baar, Wolfgang and Flemming, Sven and Roewer, Norbert and Schlegel, Nicolas and Schick, Martin A.}, title = {Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression}, series = {Journal of Pharmacology and Pharmacotherapeutics}, volume = {6}, journal = {Journal of Pharmacology and Pharmacotherapeutics}, number = {1}, doi = {10.4103/0976-500X.149138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149336}, pages = {13-23}, year = {2015}, abstract = {Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.}, language = {en} } @article{ShityakovPuskasPapaietal.2015, author = {Shityakov, Sergey and Pusk{\´a}s, Istv{\´a}n and P{\´a}pai, Katalin and Salvador, Ellaine and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {Sevoflurane-sulfobutylether-\(\beta\)-cyclodextrin complex: preparation, characterization, cellular toxicity, molecular modeling and blood-brain barrier transport studies}, series = {Molecules}, volume = {20}, journal = {Molecules}, doi = {10.3390/molecules200610264}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148543}, pages = {10264-10279}, year = {2015}, abstract = {The objective of the present investigation was to study the ability of sulfobutylether-\(\beta\)-cyclodextrin (SBECD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBE\(\beta\)CD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (P\(_{app}\)). In addition, SEV binding affinity to SBE\(\beta\)CD was confirmed by a minimal Gibbs free energy of binding (ΔG\(_{bind}\)) value of -1.727 ± 0.042 kcal・mol\(^{-1}\) and an average binding constant (K\(_{b}\)) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.}, language = {en} } @article{MuellenbachRoewerKranke2013, author = {M{\"u}llenbach, Ralf Michael and Roewer, Norbert and Kranke, Peter}, title = {Quality Assurance Would Be Welcome}, series = {Deutsches {\"A}rzteblatt international}, volume = {110}, journal = {Deutsches {\"A}rzteblatt international}, number = {27-28}, doi = {10.3238/arztebl.2013.0485a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128844}, pages = {485}, year = {2013}, abstract = {No abstract available.}, language = {en} } @article{JazbutyteStumpnerRedeletal.2012, author = {Jazbutyte, Virginija and Stumpner, Jan and Redel, Andreas and Lorenzen, Johan M. and Roewer, Norbert and Thum, Thomas and Kehl, Franz}, title = {Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151258}, pages = {e42032}, year = {2012}, abstract = {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.}, language = {en} } @article{ShityakovRoewerFoersteretal.2017, author = {Shityakov, Sergey and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {In silico modeling of indigo and Tyrian purple single-electron nano-transistors using density functional theory approach}, series = {Nanoscale Research Letters}, volume = {12}, journal = {Nanoscale Research Letters}, number = {439}, doi = {10.1186/s11671-017-2193-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158332}, year = {2017}, abstract = {The purpose of this study was to develop and implement an in silico model of indigoid-based single-electron transistor (SET) nanodevices, which consist of indigoid molecules from natural dye weakly coupled to gold electrodes that function in a Coulomb blockade regime. The electronic properties of the indigoid molecules were investigated using the optimized density-functional theory (DFT) with a continuum model. Higher electron transport characteristics were determined for Tyrian purple, consistent with experimentally derived data. Overall, these results can be used to correctly predict and emphasize the electron transport functions of organic SETs, demonstrating their potential for sustainable nanoelectronics comprising the biodegradable and biocompatible materials.}, language = {en} } @article{KredelKunzmannSchlegeletal.2017, author = {Kredel, Markus and Kunzmann, Steffen and Schlegel, Paul-Gerhardt and W{\"o}lfl, Matthias and Nordbeck, Peter and B{\"u}hler, Christoph and Lotz, Christopher and Lepper, Philipp M. and Wirbelauer, Johannes and Roewer, Norbert and Muellenbach, Ralf M.}, title = {Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock}, series = {American Journal of Case Reports}, volume = {18}, journal = {American Journal of Case Reports}, doi = {10.12659/AJCR.902485}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158193}, pages = {723-727}, year = {2017}, abstract = {Background: The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. Case Report: A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. Conclusions: In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option.}, language = {en} } @article{ShityakovPuskasRoeweretal.2014, author = {Shityakov, Sergey and Pusk{\´a}s, Istv{\´a}n and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens}, title = {Three-dimensional quantitative structure-activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors}, series = {Advances and Applications in Bioinformatics and Chemistry}, volume = {7}, journal = {Advances and Applications in Bioinformatics and Chemistry}, doi = {10.2147/AABC.S56478}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120226}, pages = {11-21}, year = {2014}, abstract = {The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure-activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q (2) of 0.795 (0.687) and r (2) of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r (2) of 0.821 (CoMFA) and r (2) of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) values were confirmed by molecular docking into the CYP3A4 active site with r (2) of 0.66. The results obtained from this study are useful for a better understanding of the effects of anthocyanin derivatives on inhibition of carcinogen activation and cellular DNA damage.}, language = {en} } @article{SchickBaarBrunoetal.2015, author = {Schick, Martin Alexander and Baar, Wolfgang and Bruno, Raphael Romano and Wollborn, Jakob and Held, Christopher and Schneider, Reinhard and Flemming, Sven and Schlegel, Nicolas and Roewer, Norbert and Neuhaus, Winfried and Wunder, Christian}, title = {Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0137247}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126068}, pages = {e0137247}, year = {2015}, abstract = {Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6\% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6\% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1-4.0\% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6\% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion}, language = {en} } @article{SchickBaarFlemmingetal.2014, author = {Schick, Martin A. and Baar, Wolfgang and Flemming, Sven and Schlegel, Nicolas and Wollborn, Jakob and Held, Christopher and Schneider, Reinhard and Brock, Robert W. and Roewer, Norbert and Wunder, Christian}, title = {Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model}, series = {Intensive Care Medicine Experimental}, volume = {2}, journal = {Intensive Care Medicine Experimental}, number = {34}, doi = {10.1186/s40635-014-0034-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126111}, year = {2014}, abstract = {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.}, language = {en} } @article{WurmbVollmerSefrinetal.2015, author = {Wurmb, Thomas and Vollmer, Tina and Sefrin, Peter and Kraus, Martin and Happel, Oliver and Wunder, Christian and Steinisch, Andrias and Roewer, Norbert and Maier, Sebastian}, title = {Monitoring of in-hospital cardiac arrest events with the focus on Automated External Defibrillators - a retrospective observational study}, series = {Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine}, volume = {23}, journal = {Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine}, number = {87}, doi = {10.1186/s13049-015-0170-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125756}, year = {2015}, abstract = {Background Patients with cardiac arrest have lower survival rates, when resuscitation performance is low. In In-hospital settings the first responders on scene are usually nursing staff without rhythm analysing skills. In such cases Automated External Defibrillators (AED) might help guiding resuscitation performance. At the Wuerzburg University Hospital (Germany) an AED-program was initiated in 2007. Aim of the presented study was to monitor the impact of Automated External Defibrillators on the management of in-hospital cardiac arrest events. Methods The data acquisition was part of a continuous quality improvement process of the Wuerzburg University Hospital. For analysing the CPR performance, the chest compression rate (CCR), compression depth (CCD), the no flow fraction (NFF), time interval from AED-activation to the first compression (TtC), the time interval from AED-activation to the first shock (TtS) and the post schock pause (TtCS) were determined by AED captured data. A questionnaire was completed by the first responders. Results From 2010 to 2012 there were 359 emergency calls. From these 53 were cardiac arrests with an AED-application. Complete data were available in 46 cases. The TtC was 34 (32-52) seconds (median and IQR).The TtS was 30 (28-32) seconds (median and IQR) . The TtCS was 4 (3-6) seconds (median and IQR) . The CCD was 5.5 ± 1 cm while the CCR was 107 ± 11/min. The NFF was calculated as 41 \%. ROSC was achieved in 21 patients (45 \%), 8 patients (17 \%) died on scene and 17 patients (37 \%) were transferred under ongoing CPR to an Intensive Care Unit (ICU). Conclusion The TtS and TtC indicate that there is an AED-user dependent time loss. These time intervals can be markedly reduced, when the user is trained to interrupt the AED's "chain of advices" by placing the electrode-paddles immediately on the patient's thorax. At this time the AED switches directly to the analysing mode. Intensive training and adaption of the training contents is needed to optimize the handling of the AED in order to maximize its advantages and to minimize its disadvantages.}, language = {en} } @article{SchusterWessigSchimmeretal.2012, author = {Schuster, Frank and Wessig, Carsten and Schimmer, Christoph and Johannsen, Stephan and Lazarus, Marc and Aleksic, Ivan and Leyh, Rainer and Roewer, Norbert}, title = {In vitro contracture test results and anaesthetic management of a patient with emery-dreifuss muscular dystrophy for cardiac transplantation}, series = {Case Reports in Anesthesiology}, volume = {2012}, journal = {Case Reports in Anesthesiology}, number = {349046}, doi = {10.1155/2012/349046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123413}, year = {2012}, abstract = {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.}, language = {en} } @article{WurmbSchlerethKredeletal.2014, author = {Wurmb, Thomas Erik and Schlereth, Stefan and Kredel, Markus and Muellenbach, Ralf M. and Wunder, Christian and Brederlau, J{\"o}rg and Roewer, Norbert and Kenn, Werner and Kunze, Ekkehard}, title = {Routine Follow-Up Cranial Computed Tomography for Deeply Sedated, Intubated, and Ventilated Multiple Trauma Patients with Suspected Severe Head Injury}, series = {BioMed Research International}, journal = {BioMed Research International}, number = {361949}, doi = {10.1155/2014/361949}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120084}, year = {2014}, abstract = {Background. Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome. We investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients. Methods. The study design is a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan. We defined 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies. Results. A progression of intracranial injury was found in 63 patients (42\%) and 18 patients (12\%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54\%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44\%) had therapeutic consequences due to the results of the follow-up cCT. Conclusion. We found new diagnosis or progression of intracranial pathology in 54\% of the patients. In 54\% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT. In trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial.}, language = {en} } @article{ShityakovSohajdaPuskasetal.2014, author = {Shityakov, Sergey and Sohajda, Tam{\´a}s and Puskas, Istav{\´a}n and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin}, series = {Molecules}, volume = {19}, journal = {Molecules}, number = {10}, doi = {10.3390/molecules191016861}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119186}, pages = {16861-76}, year = {2014}, abstract = {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.}, language = {en} }