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Schleicher J.,Friedrich - Schiller University of Jena | Guthke R.,Leibniz Institute for Natural Product Research and Infection Biology | Dahmen U.,University Hospital of Jena | Dirsch O.,University Hospital of Jena | And 2 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014

A hallmark of the nonalcoholic fatty liver disease is the accumulation of lipids. We developed a mathematical model of the hepatic lipid dynamics to simulate the fate of fatty acids in hepatocytes. Our model involves fatty acid uptake, lipid oxidation, and lipid export. It takes into account that storage of triacylglycerol within hepatocytes leads to cell enlargement reducing the sinusoids radius and impairing hepatic microcirculation. Thus oxygen supply is reduced, which impairs lipid oxidation. The analysis of our model revealed a bistable behavior (two stable steady states) of the system, in agreement with histological observations showing distinct areas of lipid accumulation in lobules. The first (healthy) state is characterized by intact lipid oxidation and a low amount of stored lipids. The second state in our model may correspond to the steatotic cell; it is marked by a high amount of stored lipids and a reduced lipid oxidation caused by impaired oxygen supply. Our model stresses the role of insufficient oxygen supply for the development of steatosis. We discuss implications of our results in regard to the experimental design aimed at exploring lipid metabolism reactions under steatotic conditions. Moreover, the model helps to understand the reversibility of lipid accumulation and predicts the reversible switch to show hysteresis. The system can switch from the steatotic state back to the healthy state by reduction of fatty acid uptake below the threshold at which steatosis started. The reversibility corresponds to the observation that caloric restriction can reduce the lipid content in the liver. © 2013 Elsevier B.V.


Reuken P.A.,Friedrich - Schiller University of Jena | Pletz M.W.,Friedrich - Schiller University of Jena | Baier M.,University Hospital of Jena | Pfister W.,University Hospital of Jena | And 2 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2012

Background Third-generation cephalosporins (TGC) constitute the empirical first-line therapy for spontaneous bacterial peritonitis (SBP). Hospitalisation, invasive procedures and use of antibiotics may challenge this concept due to an increase in enterococci and other TGC-resistant microorganisms. Aim To determine prevalence, risk factors and outcome of ascitic fluid infections caused by enterococci. Methods All independent episodes of culture-positive ascitic fluid between 2000 and 2011 in a German tertiary centre were analysed retrospectively. Results Out of 244 positive ascitic fluid cultures, 90 episodes of monomicrobial SBP and 25 episodes of monomicrobial bacterascites (BA) in patients with decompensated cirrhosis were identified. Enterococcus spp. were isolated in 32 (28%) episodes. We noticed a profound increase in the frequency of enterococcal infection over the study period from 11% to 35% (P = 0.007). Univariate risk factors for enterococcal SBP/BA included nosocomial infection (OR = 4.56; 95% CI 1.90-10.97), previous use of antibiotics (OR = 5.63; 95% CI 1.81-17.49) and recent gastrointestinal endoscopy (OR = 3.17; 95% CI 1.33-7.54). Nosocomial infection (OR = 3.29; P = 0.011) and recent antibiotic therapy (OR = 3.88; P = 0.025) remained independent risk factors for enterococcal infection in multivariate logistic regression and these factors contributed also to the model when only SBP cases were considered. In subjects with monomicrobial SBP who were treated with TGC or ciprofloxacin, the probability of 90-day survival was 12% in enterococcal infection compared to 50% in non-enterococcal SBP (P = 0.022 in log-rank test). Conclusion Because of the increasing prevalence of enterococcal spontaneous bacterial peritonitis and its poor prognosis when treated inappropriately, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with risk factors. © 2012 Blackwell Publishing Ltd.


Liu A.,Huazhong University of Science and Technology | Liu A.,Friedrich - Schiller University of Jena | Fang H.,Friedrich - Schiller University of Jena | Fang H.,Anhui Medical University | And 2 more authors.
Liver Transplantation | Year: 2013

Lithium has long been widely used in the treatment of bipolar mood disorders. Recent studies have demonstrated that lithium is able to decrease ischemia/reperfusion (I/R) injury in the brain, kidneys, and heart. Because lithium may act on a number of stress and survival pathways, it is of great interest to explore this compound also in the setting of liver I/R injury. In this study, we aimed to evaluate the effects of lithium in a model of liver I/R injury in rats. Chronic treatment with lithium (2 mmol/kg for 3 days before ischemia) decreased I/R injury, whereas acute treatment with a single dose of lithium (2 mmol/kg 1 hour before ischemia) did not confer any protection in a partial hepatic I/R model. Furthermore, rats subjected to chronic lithium treatment had a significantly better survival rate (60%) than saline-treated rats (27%) in a total hepatic I/R survival model. Chronic lithium treatment protected against liver I/R injury, as indicated by lower serum aminotransferase levels, fewer I/R-associated histopathological changes, lower hepatic inflammatory cytokine levels, less neutrophil infiltration, and lower hepatic high-mobility group box expression and serum levels. The mechanism of action of lithium appears to involve its ability to inhibit glycogen synthase kinase 3β activation, modulate mitogen-activated protein kinase activation, inhibit hepatic apoptosis, and induce autophagy. On the basis of these data, we conclude that lithium treatment may be a simple and applicable preconditioning intervention for protecting against liver I/R injury. © 2013 American Association for the Study of Liver Diseases.


Pfeifer R.,University Hospital of Jena | Weitzel S.,University Hospital of Jena | Gunther A.,University Hospital of Jena | Berrouschot J.,Clinic of Neurology | And 3 more authors.
Resuscitation | Year: 2013

Background and purpose: We investigated the inter-observer variability in interpretation of median nerve SSEPs with regard to neurological prognosis in survivors of cardiac arrest (CA). Methods: Four experienced neurologists analyzed 163 median nerve SSEPs on the basis of a pre-defined classification of SSEPs into five patterns (A-E), with consideration of cortical potentials up to a latency of 150. ms. Of these, 133 recordings were from CA survivors and 30 were from healthy volunteers. The experts were blinded to whether a SSEP finding was from a CA survivor or a healthy volunteer. They were also unaware of the neurological outcome for the resuscitated patients. Three categories were defined for decision making. These were "good neurological outcome" represented by patterns A-C, "poor neurological outcome" (patterns D and E), and "not evaluable". Experts' agreement was calculated using the kappa-coefficient. Results: The mean correct prediction by the experts was 81.8% (range 76.3-86.6%) in resuscitated patients with good neurological outcome. In those with poor neurological outcome, however, correct prediction was achieved in only 63% (60.5-66%). All SSEPs from healthy volunteers were classified as "good neurological outcome". The kappa-coefficient (κ) for all decision-making classifications was 0.75; for patients with poor outcome it was 0.76 and for those with good outcome 0.88. The predictive value for poor neurological outcome of the SSEP pattern D achieved a specificity of 93.5% and that of E a specificity of 98.4%. Conclusion: Our study demonstrates good inter-observer agreement in the interpretation of median nerve SSEPs in CA survivors on the basis of a pre-defined SSEP evaluation set. The strongest correlation with poor outcome was found for pattern E, bilateral absence of the N20 peak. © 2013 Elsevier Ireland Ltd.


Bekhite M.M.,University Hospital of Jena | Bekhite M.M.,Tanta University | Figulla H.-R.,University Hospital of Jena | Sauer H.,Justus Liebig University | Wartenberg M.,University Hospital of Jena
International Journal of Cardiology | Year: 2013

Aims: To investigate the effects of static magnetic fields (MFs) on cardiomyogenesis of mouse embryonic stem (ES) cell-derived embryoid bodies and Flk-1+ cardiac progenitor cells and to assess the impact of cytosolic calcium [Ca2+]c and reactive oxygen species (ROS). Methods and results: Embryoid bodies and ES cell-derived Flk-1+ cardiovascular progenitor cells were exposed to static MFs. The expression of cardiac genes was evaluated by RT-PCR; sarcomeric structures were assessed by immunohistochemistry; intracellular ROS and [Ca2+]c of ES cells were examined by H2DCF-DA- and fluo-4-based microfluorometry. Treatment of embryoid bodies with MFs dose-dependent increased the number of contracting foci and cardiac areas as well as mRNA expression of the cardiac genes MLC2a, MLC2v, α-MHC and β-MHC. In Flk-1+ cells MFs (1 mT) elevated both [Ca2+]c and ROS, increased expression of the cardiogenic transcription factors Nkx-2.5 and GATA-4 as well as cardiac genes. This effect was due to Ca2+ influx, since extracellular Ca2+ chelation abrogated ROS production and MF-induced cardiomyogenesis. Furthermore absence of extracellular calcium impaired sarcomere structures. Neither the phospholipase C inhibitor U73122 nor thapsigargin inhibited MF-induced increase in [Ca2+]c excluding involvement of intracellular calcium stores. ROS were generated through NAD(P)H oxidase, since NOX-4 but not NOX-1 and NOX-2 mRNA was upregulated upon MF exposure. Ablation of NOX-4 by sh-RNA and treatment with the NAD(P)H oxidase inhibitor diphenylen iodonium (DPI) totally abolished MF-induced cardiomyogenesis. Conclusion: The ability of static MFs to enhance cardiomyocyte differentiation of ES cells allows high throughput generation of cardiomyocytes without pharmacological or genetic modification. © 2012 Elsevier Ireland Ltd.

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