Olaf Dirsch

National Institute for Research in Computer Science and Control, Le Chesney, Île-de-France, France

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Publications (101)286.27 Total impact

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    ABSTRACT: The accurate identification of fat droplets is a prerequisite for the automatic quantification of steatosis in histological images. A major challenge in this regard is the distinction between clustered fat droplets and vessels or tissue cracks. We present a new method for the identification of fat droplets that utilizes adjacency statistics as shape features. Adjacency statistics are simple statistics on neighbor pixels. The method accurately identified fat droplets with sensitivity and specificity values above 90%. Compared with commonly-used shape features, adjacency statistics greatly improved the sensitivity toward clustered fat droplets by 29% and the specificity by 17%. On a standard personal computer, megapixel images were processed in less than 0.05s. The presented method is simple to implement and can provide the basis for the fast and accurate quantification of steatosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Computer methods and programs in biomedicine 06/2015; 121(2). DOI:10.1016/j.cmpb.2015.05.009 · 1.09 Impact Factor
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    ABSTRACT: Background: The aetiology of biliary atresia (BA) is still unresolved. The study's aim was to investigate the distribution of extracellular matrix proteins and cellular adhesion molecules in children with BA compared to other cholestatic liver disease (CLD) and normal liver architecture (NLA). Patients: Liver biopsies were obtained from children with BA (n=13), CLD (n=6) and NLA (n=8). Method: We systematically analysed ultra thin frozen sections from the liver hilum stained with 25 monoclonal antibodies for cellular characterisation, extracellular matrix proteins and adhesion molecules. Results: 2 changes were specifically found in BA: laminin beta1 was reduced in children with BA vs. NLA and CLD. Conversely, integrin alpha 3 was increased in BA vs. NLA and CLD (p<0.05). Furthermore, we detected changes in a similar pattern for both BA and CLD vs. NLA: in BA and CLD perlecan was increased. On the contrary, integrin beta1 and entactin were decreased vs. NLA (p<0.05). Discussion: Extracellular matrix proteins and adhesion molecules mediate cellular polarity and integrity, development of tubular structures, and proliferation. Therefore, our findings can be important for the understanding of the genesis of BA. Conclusion: The composition of extracellular matrix proteins and adhesion molecules in children with BA differs from NLA and other CLD in distribution of laminin beta1 and integrin alpha 3, which may have implications for genetic, immunologic and environmental associations in BA. © Georg Thieme Verlag KG Stuttgart · New York.
    Klinische Pädiatrie 01/2015; 227(1):15-22. DOI:10.1055/s-0034-1389906 · 1.90 Impact Factor
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    ABSTRACT: Liver dysfunction has been known to occur frequently in cases of sepsis. Baicalein, the main active ingredient of the Scutellaria root, exerts anti-inflammatory and anti-apoptotic properties in endotoxic shock. However, the role of baicalein in polymicrobial sepsis-induced liver injury and its regulatory mechanisms remain unclear. In this study, we aimed to investigate the protective effects of baicalein on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were treated with baicalein (100mg/kg, i.p) at 1h, 6h and 12h following CLP. Baicalein significantly improved the survival of septic mice. Treatment with baicalein ameliorated the CLP-induced liver injury, as indicated by the lower serum aminotransferase levels and the fewer histopathologic abnormalities. Baicalein reduced the neutrophil infiltration and the hepatic inflammatory cytokine expression and release. It also decreased the hepatic and the serum high-mobility group box 1 and macrophage migration inhibitory factor levels in septic mice. Moreover, baicalein significantly inhibited the mitogen-activated protein kinases (MAPKs) activation and suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB). In conclusion, these results suggest that baicalein treatment could protect against the sepsis-induced liver injury, and improve the survival of mice with polymicrobial sepsis. The mechanism of the protective action of baicalein seems to involve its ability to reduce inflammatory response, inhibit hepatic apoptosis, and to suppress MAPKs and NF-κB activation. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 12/2014; 748. DOI:10.1016/j.ejphar.2014.12.014 · 2.68 Impact Factor
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    ABSTRACT: Quantitative analysis of histologic slides is of importance for pathology and also to address surgical questions. Recently, a novel application was developed for the automated quantification of whole-slide images. The aim of this study was to test and validate the underlying image analysis algorithm with respect to user friendliness, accuracy, and transferability to different histologic scenarios. The algorithm splits the images into tiles of a predetermined size and identifies the tissue class of each tile. In the training procedure, the user specifies example tiles of the different tissue classes. In the subsequent analysis procedure, the algorithm classifies each tile into the previously specified classes. User friendliness was evaluated by recording training time and testing reproducibility of the training procedure of users with different background. Accuracy was determined with respect to single and batch analysis. Transferability was demonstrated by analyzing tissue of different organs (rat liver, kidney, small bowel, and spleen) and with different stainings (glutamine synthetase and hematoxylin-eosin). Users of different educational background could apply the program efficiently after a short introduction. When analyzing images with similar properties, accuracy of >90% was reached in single images as well as in batch mode. We demonstrated that the novel application is user friendly and very accurate. With the "training" procedure the application can be adapted to novel image characteristics simply by giving examples of relevant tissue structures. Therefore, it is suitable for the fast and efficient analysis of high numbers of fully digitalized histologic sections, potentially allowing "high-throughput" quantitative "histomic" analysis.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 12/2014; DOI:10.1097/PAI.0000000000000120 · 2.06 Impact Factor
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    Archives of Toxicology 12/2014; 88(12):2071-5. DOI:10.1007/s00204-014-1384-6 · 5.08 Impact Factor
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    ABSTRACT: Fatty liver is a common disease in the western society. Different stimuli, such as obesity or abuse of alcohol, cause the liver to store fat within liver cells, the so called hepatocytes. This growth induced by storage of fat influences the perfusion of the overlying structures, i. e. sinusoids, liver lobules, liver lobes, and consequently the liver itself. The scales of these structures reach from few µm (size of a hepatocyte) to several cm (size of liver). In view of finite element (FE) simulations, the necessity of introducing different scales becomes obvious. For the description of growth effects in the liver the relevant quantities are: perfusion of the liver and amount of substances that are needed for production of fat (glycogen and fatty acids). In this work we present a multiphasic continuum mechanical model for the description of micro-perfusion in the liver lobule using a homogenized multiphasic approach based on the theory of porous media (TPM). Into this model we inserted a zero-dimensional (0D) kinetic model calculating rates of all relevant substances. So far, the model focuses on the time dependent and spatial zonation of glycogen, since production of fat heavily depends on the stored glycogen. Additionally, a possible method for incorporating fatty acids and therefor also growth will be presented. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)
    PAMM 12/2014; 14(1). DOI:10.1002/pamm.201410040
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    ABSTRACT: Ischemic preconditioning exerts a protective effect in hepatic ischemia/reperfusion injury. The exact mechanism of ischemic preconditioning action remains largely unknown. Recent studies suggest that autophagy plays an important role in protecting against ischemia/reperfusion injury. However, the role of autophagy in ischemic preconditioning-afforded protection and its regulatory mechanisms in liver ischemia/reperfusion injury remain poorly understood. This study was designed to determine whether ischemic preconditioning could protect against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy.
    Critical Care Medicine 12/2014; 42(12):e762-71. DOI:10.1097/CCM.0000000000000659 · 6.15 Impact Factor
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    ABSTRACT: Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.
    Mediators of Inflammation 11/2014; 2014:629507. DOI:10.1155/2014/629507 · 2.42 Impact Factor
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    ABSTRACT: Ischemia/reperfusion (I/R) is a pathophysiologic process that occurs during hemorrhagic shock, liver resection and liver transplantation. Baicalein, the main active ingredient of the Scutellaria root, exerts anti-inflammatory and anti-apoptotic properties in the setting of I/R injury in the heart and brain. However, the role of baicalein in liver I/R injury and its regulatory mechanisms remain poorly understood. This study was designed to evaluate the effects of baicalein in a model of liver I/R in mice and to explore the possible mechanisms. Baicalein (100mg/kg) was intraperitoneally injected 1h before warm ischemia. Pretreatment with baicalein protected against liver I/R injury, as indicated by the decreased serum aminotransferase levels and the reduced histopathologic abnormalities. Baicalein also significantly reduced cellular hepatic apoptosis in response to I/R injury. Moreover, pretreatment with baicalein significantly inhibited nuclear factor-kappa B (NF-κB) activation and the subsequent proinflammatory cytokine production, and decreased leukocyte infiltration. In vitro studies, baicalein treatment inhibited the proinflammatory cytokine production via the modulation of NF-κB signaling pathway in lipopolysaccharide-stimulated macrophages. Taken together, these results suggest that baicalein could protect against liver I/R injury via inhibition of inflammation by down-regulating NF-κB activity, and suppression of cellular hepatic apoptosis. Copyright © 2014. Published by Elsevier B.V.
    International Immunopharmacology 11/2014; DOI:10.1016/j.intimp.2014.11.014 · 2.71 Impact Factor
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    ABSTRACT: The liver has the unique capability of regeneration from various injuries. Different animal models and in vitro methods are used for studying the processes and mechanisms of liver regeneration. Animal models were established either by administration of hepatotoxic chemicals or by surgical approach. The administration of hepatotoxic chemicals results in the death of liver cells and in subsequent hepatic regeneration and tissue repair. Surgery includes partial hepatectomy and portal vein occlusion or diversion: hepatectomy leads to compensatory regeneration of the remnant liver lobe, whereas portal vein occlusion leads to atrophy of the ipsilateral lobe and to compensatory regeneration of the contralateral lobe. Adaptation of modern radiological imaging technologies to the small size of rodents made the visualization of rodent intrahepatic vascular anatomy possible. Advanced knowledge of the detailed intrahepatic 3D anatomy enabled the establishment of refined surgical techniques. The same technology allows the visualization of hepatic vascular regeneration. The development of modern histological image analysis tools improved the quantitative assessment of hepatic regeneration. Novel image analysis tools enable us to quantify reliably and reproducibly the proliferative rate of hepatocytes using whole-slide scans, thus reducing the sampling error. In this review, the refined rodent models and the newly developed imaging technology to study liver regeneration are summarized. This summary helps to integrate the current knowledge of liver regeneration and promises an enormous increase in hepatological knowledge in the near future. © 2014 S. Karger AG, Basel.
    European Surgical Research 11/2014; 54(3-4):97-113. DOI:10.1159/000368573 · 1.43 Impact Factor
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    ABSTRACT: The use of mouse models in experimental research is of enormous importance for the study of hepatic physiology and pathophysiological disturbances. However, due to the small size of the mouse, technical details of the intraoperative monitoring procedure suitable for the mouse were rarely described. Previously we have reported a monitoring procedure to obtain hemodynamic parameters for rats. Now, we adapted the procedure to acquire systemic and hepatic hemodynamic parameters in mice, a species ten-fold smaller than rats. This film demonstrates the instrumentation of the animals as well as the data acquisition process needed to assess systemic and hepatic hemodynamics in mice. Vital parameters, including body temperature, respiratory rate and heart rate were recorded throughout the whole procedure. Systemic hemodynamic parameters consist of carotid artery pressure (CAP) and central venous pressure (CVP). Hepatic perfusion parameters include portal vein pressure (PVP), portal flow rate as well as the flow rate of the common hepatic artery (table 1). Instrumentation and data acquisition to record the normal values was completed within 1.5 h. Systemic and hepatic hemodynamic parameters remained within normal ranges during this procedure. This procedure is challenging but feasible. We have already applied this procedure to assess hepatic hemodynamics in normal mice as well as during 70% partial hepatectomy and in liver lobe clamping experiments. Mean PVP after resection (n= 20), was 11.41±2.94 cmH2O which was significantly higher (P<0.05) than before resection (6.87±2.39 cmH2O). The results of liver lobe clamping experiment indicated that this monitoring procedure is sensitive and suitable for detecting small changes in portal pressure and portal flow rate. In conclusion, this procedure is reliable in the hands of an experienced micro-surgeon but should be limited to experiments where mice are absolutely needed.
    Journal of Visualized Experiments 10/2014; DOI:10.3791/51955
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    ABSTRACT: Liver dysfunction is a serious complication in the early phase following major liver resection or liver transplantation and might be aggravated by the translocation of bacteria and lipopolysaccharide (LPS). As a preventive strategy, granulocyte colony-stimulating factor (G-CSF) is prophylactically applied in patients who are subjected to major surgery. However, we previously demonstrated that G-CSF can induce LPS sensitization. In this study, we aimed to evaluate the effects of G-CSF pretreatment on hepatic microcirculatory disturbances and postoperative liver dysfunction after 70 % partial hepatectomy (PH) in rats. PH alone was well tolerated by all animals (100 % survival rate, slight liver damage and inflammation). LPS application after 70 % PH caused moderate inflammation, microcirculatory disturbances and hepatic damage and led to a 24-h survival rate of 30 % after the operations. In the G-CSF-LPS-PH group, all of the rats died within 4 h with severe inflammatory responses and liver damage (i.e., pronounced erythrocyte congestion and neutrophil infiltration). Portal hypertension and microcirculatory disorders (i.e., inhomogeneous perfusion, sinusoidal dilatation and reductions on functional capillary density) were more pronounced in the G-CSF-LPS-PH group. In conclusion, increased circulating LPS levels were associated with an imbalanced inflammatory response and microcirculatory dysfunction that preceded liver damage and subsequent dysfunction following surgery. G-CSF-pretreatment aggravated microcirculatory disturbances and liver damage, which might have been related to G-CSF-induced LPS sensitization.
    Histochemie 07/2014; DOI:10.1007/s00418-014-1242-x · 2.93 Impact Factor
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    ABSTRACT: Extended partial hepatectomy (PH) in patients is leading to portal hyperperfusion but reduced hepatic arterial perfusion (HAP), and is invariably causing focal hepatic venous outflow obstruction (FHVOO). We observed in a rat model that PH in combination with right median hepatic vein ligation (RMHV-L) caused confluent parenchymal necrosis interspersed with viable portal tracts in the obstructed territory and large sinusoidal vascular canals in the border zone. Lack of HAP impaired the spontaneous course of recovery in terms of enlarged parenchymal necrosis, delayed regeneration, and the absence of draining vascular canals. We aimed to investigate whether pharmacological intervention modulates the imbalance between portal venous and hepatic arterial inflow, aggravates the liver damage, and delays the recovery process after FHVOO in liver-resected rats. Male Lewis rats were subjected to 70% PH and RMHV-L. Molsidomine or NG-nitro-L-arginine methyl ester (L-NAME) or saline were applied daily. Hepatic damage, microcirculation, regeneration, and vascular remodeling were evaluated at postoperative days 1, 2, and 7. Animals subjected to RMHV-L only were used as "no HAP" control. Significant increase of portal venous inflow with a concomitant decrease in HAP was observed in all groups after PH. Molsidomine treatment did neither affect hepatic hemodynamics nor the spontaneous recovery. In contrast, L-NAME treatment further decreased HAP which impaired hepatic microcirculation, aggravated parenchymal damage, decelerated recovery, and impaired the formation of sinusoidal canals. Reduction of HAP through inhibition of nitric oxide production worsened the recovery from FHVOO. Drugs increasing HAP need to be evaluated to reverse the hyperperfusion-induced impairment of the spontaneous course after FHVOO.
    Transplantation 04/2014; 97(10). DOI:10.1097/TP.0000000000000089 · 3.78 Impact Factor
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    ABSTRACT: Histological alterations often constitute a fingerprint of toxicity and diseases. The extent to which these alterations are cause or consequence of compromised organ function, and the underlying mechanisms involved is a matter of intensive research. In particular, liver disease is often associated with altered tissue microarchitecture, which in turn may compromise perfusion and functionality. Research in this field requires the development and orchestration of new techniques into standardized processing pipelines that can be used to reproducibly quantify tissue architecture. Major bottlenecks include the lack of robust staining, and adequate reconstruction and quantification techniques. To bridge this gap, we established protocols employing specific antibody combinations for immunostaining, confocal imaging, three-dimensional reconstruction of approximately 100-μm-thick tissue blocks and quantification of key architectural features. We describe a standard procedure termed 'liver architectural staining' for the simultaneous visualization of bile canaliculi, sinusoidal endothelial cells, glutamine synthetase (GS) for the identification of central veins, and DAPI as a nuclear marker. Additionally, we present a second standard procedure entitled 'S-phase staining', where S-phase-positive and S-phase-negative nuclei (stained with BrdU and DAPI, respectively), sinusoidal endothelial cells and GS are stained. The techniques include three-dimensional reconstruction of the sinusoidal and bile canalicular networks from the same tissue block, and robust capture of position, size and shape of individual hepatocytes, as well as entire lobules from the same tissue specimen. In addition to the protocols, we have also established image analysis software that allows relational and hierarchical quantifications of different liver substructures (e.g. cells and vascular branches) and events (e.g. cell proliferation and death). Typical results acquired for routinely quantified parameters in adult mice (C57Bl6/N) include the hepatocyte volume (5,128.3 ± 837.8 μm(3)) and the fraction of the hepatocyte surface in contact with the neighbouring hepatocytes (67.4 ± 6.7 %), sinusoids (22.1 ± 4.8 %) and bile canaliculi (9.9 ± 3.8 %). Parameters of the sinusoidal network that we also routinely quantify include the radius of the sinusoids (4.8 ± 2.25 μm), the branching angle (32.5 ± 11.2°), the length of intersection branches (23.93 ± 5.9 μm), the number of intersection nodes per mm(3) (120.3 × 103 ± 42.1 × 10(3)), the average length of sinusoidal vessel per mm(3) (5.4 × 10(3) ± 1.4 × 10(3)mm) and the percentage of vessel volume in relation to the whole liver volume (15.3 ± 3.9) (mean ± standard deviation). Moreover, the provided parameters of the bile canalicular network are: length of the first-order branches (7.5 ± 0.6 μm), length of the second-order branches (10.9 ± 1.8 μm), length of the dead-end branches (5.9 ± 0.7 μm), the number of intersection nodes per mm(3) (819.1 × 10(3) ± 180.7 × 10(3)), the number of dead-end branches per mm(3) (409.9 × 10(3) ± 95.6 × 10(3)), the length of the bile canalicular network per mm(3) (9.4 × 10(3) ± 0.7 × 10(3) mm) and the percentage of the bile canalicular volume with respect to the total liver volume (3.4 ± 0.005). A particular strength of our technique is that quantitative parameters of hepatocytes and bile canalicular as well as sinusoidal networks can be extracted from the same tissue block. Reconstructions and quantifications performed as described in the current protocols can be used for quantitative mathematical modelling of the underlying mechanisms. Furthermore, protocols are presented for both human and pig livers. The technique is also applicable for both vibratome blocks and conventional paraffin slices.
    Archives of Toxicology 04/2014; 88(5). DOI:10.1007/s00204-014-1243-5 · 5.08 Impact Factor
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    ABSTRACT: The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte 'know' when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.
    PLoS ONE 04/2014; 9(4):e93207. DOI:10.1371/journal.pone.0093207 · 3.53 Impact Factor
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    ABSTRACT: The woodchuck model is an informative model for studies on hepadnaviral infection. In this study, woodchuck hepatitis virus (WHV) transgenic (Tg) mouse models based on C57BL/6 mice were established to study the pathogenesis associated with hepadnaviral infection. Two lineages of WHV Tg mice harboring the WHV wild-type (1217) and a mutated WHV genome lacking surface antigen (1281) were generated. WHV replication intermediates were detected by Southern blotting. DNA vaccines against WHV proteins were applied by intramuscular injection. WHV-specific immune responses were analyzed by flow cytometry and ELISA. The presence of WHV transgenes resulted in liver-specific but sex- and age- dependent WHV replication in Tg mice. Pathological changes in the liver including hepatocellular dysplasia were observed in aged Tg mice, suggesting that the presence of WHV transgenes may lead to liver diseases. Interestingly, Tg mice of the lineage 1281 spontaneously developed T- and B-cell responses to WHV core protein (WHcAg). DNA vaccination induced specific immune responses to WHV proteins in WHV Tg mice, indicating the tolerance break. The magnitude of the induced WHcAg-specific immune responses was dependent on the effectiveness of different DNA vaccines and was associated with a decrease in WHV loads in mice. In conclusion, sex- and age-dependent viral replication, development of autoimmune responses to viral antigens, pathological changes in the liver in the WHV Tg mice and the possibility of breaking immune tolerance to WHV transgenes will allow future studies on pathogenesis related to hepadnaviral infection and therapeutic vaccines.
    Journal of Virology 11/2013; DOI:10.1128/JVI.02086-13 · 4.65 Impact Factor
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    ABSTRACT: Computer-assisted automatic quantification (CAQ) was developed as an alternative method for diagnosis of hepatic steatosis in order to compensate for observer-dependent bias Here we aim to demonstrate that CAQ can provide an accurate and precise result in analysis of fatty content, but that it is inappropriate to validate CAQ by comparison with a conventional pathologist estimation (PE). Male rats were fed with a methionine-choline-deficient plus high-fat (MCD+HF) diet for 3days, 1week or 2weeks to induce mild, moderate or severe steatosis. Samples were collected from all liver lobes. Severity of hepatic steatosis was assessed by an experienced pathologist who estimated the percentage of hepatocytes containing lipid droplets. Fatty content was quantified by PE, CAQ, and biochemical analysis (BA). CAQ, PE and BA can correctly reflect severe fatty change. However, in the case of mild and moderate steatosis, PE could not reflect the true fatty content (r between PE and BA was <0). The result of CAQ correlated well with that of BA amongst the various degrees of severity of hepatic steatosis. In conclusion, due to a difference between event-based and surface-based analysis, it is inappropriate to validate the CAQ of hepatic steatosis by comparison with PE.
    11/2013; 18(4). DOI:10.1109/JBHI.2013.2282999
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    ABSTRACT: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
    Archives of Toxicology 08/2013; DOI:10.1007/s00204-013-1078-5 · 5.08 Impact Factor
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    ABSTRACT: Lipopolysaccharide (LPS) binding protein (LBP) is an acute phase protein, which upregulated in response to surgical interventions. LBP plays an important role in modulating LPS-induced inflammatory response. We investigated the expression of LBP and the translocation of LPS in rat models of hepatic ischemia reperfusion injury and liver transplantation (LTx). We also elucidated the effect of LBP on the inflammatory response. In this study, cold ischemia (CI), warm ischemia/reperfusion (WI/R), and LTx models were used to model relevant physiologic situations during LTx. Serum and effluent protein levels as well as hepatic-mRNA and protein levels of LBP were examined. LBP released into the effluent during CI was used in a macrophage-LPS-stimulation assay to investigate the role of LBP in modulating the LPS-induced inflammatory response. Blocking experiments using an LBP-inhibitory peptide were performed to confirm the relevance of LPS/LBP for the induction of the inflammatory response. Impairment of the intestinal barrier and translocation of LPS into the liver was visualized by immunohistochemistry. Induction of tumor necrosis factor-alpha (TNF-α) mRNA expression in the liver was taken as indicator of the inflammatory response. Upregulation of LBP in serum and/or liver tissue was observed after WI/R, CI and LTx, respectively. The LBP released during CI enhanced the LPS induced inflammatory response in vitro as indicated by an induction of TNF-α. On the other hand, blocking LBP using LBP inhibitory peptide, suppressed the induction of TNF-α in vitro markedly. After LTx, elevated serum LBP levels were associated with post-operative LPS translocation and production of inflammatory cytokines. Our findings suggest that translocation of LPS occurs after LTx and that LBP is mediating the LPS-induced inflammatory response after LTx. Blocking LBP using LBP-inhibitory peptide might represent a novel strategy to reduce the I/R-induced inflammatory response.
    Cytokine 08/2013; 64(1). DOI:10.1016/j.cyto.2013.07.025 · 2.87 Impact Factor

Publication Stats

1k Citations
286.27 Total Impact Points

Institutions

  • 2014
    • National Institute for Research in Computer Science and Control
      Le Chesney, Île-de-France, France
  • 2013–2014
    • Friedrich Schiller University Jena
      • • Clinic of General, Visceral and Vascular Surgery
      • • Institute of Pathology
      Jena, Thuringia, Germany
    • Leibniz Research Center for Working Enviroment and Human Factors
      Dortmund, North Rhine-Westphalia, Germany
  • 2011–2014
    • Universitätsklinikum Jena
      • Institute of Pathology
      Jena, Thuringia, Germany
  • 2010–2014
    • Berlin Heart
      Berlín, Berlin, Germany
    • Deutsches Herzzentrum Berlin
      Berlín, Berlin, Germany
  • 2001–2009
    • University Hospital Essen
      • Surgical Clinic (Outpatient and Inpatient)
      Essen, North Rhine-Westphalia, Germany
  • 2005–2008
    • Institute for Pathology, Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2005–2007
    • University of Cologne
      • Institute of Pathology
      Köln, North Rhine-Westphalia, Germany
  • 2001–2006
    • University of Duisburg-Essen
      • Department of Internal and Integrative Medicine
      Essen, North Rhine-Westphalia, Germany