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Background and aims Chronic liver disease (CLD) patients and liver transplant (LT) recipients have an increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19). The immunogenicity of COVID-19 vaccines in CLD patients and LT recipients is poorly understood. The present study aimed to evaluate the immunogenicity of COVID-19 vaccines in CLD patients and LT recipients. Methods We searched electronic databases for eligible studies. Two reviewers independently conducted the literature search, extracted the data and assessed the risk of bias of included studies. The rates of detectable immune response were pooled from single-arm studies. For comparative studies, we compared the rates of detectable immune response between patients and healthy controls. The meta-analysis was conducted using the Stata software with a random-effects model. Results In total, 19 observational studies involving 4191 participants met the inclusion criteria. The pooled rates of detectable humoral immune response after two doses of COVID-19 vaccination in CLD patients and LT recipients were 95% (95% confidence interval [CI] = 88%-99%) and 66% (95% CI = 57%-74%) respectively. After two doses of vaccination, the humoral immune response rate was similar in CLD patients and healthy controls (risk ratio [RR] = 0.96; 95% CI = 0.90-1.02; p = .14). In contrast, LT recipients had a lower humoral immune response rate after two doses of vaccination than healthy controls (RR = 0.68; 95% CI = 0.59-0.77; p < .01). Conclusions Our meta-analysis demonstrated that COVID-19 vaccination induced strong humoral immune responses in CLD patients but poor humoral immune responses in LT recipients.

In vivo liver decellularization has become a promising strategy to study in vivo liver engineering. However, long-term survival after in vivo liver decellularization has not yet been achieved due t...

Numerous hepatic function, disease and pharmacological experiments are performed on rat livers. Many of these experiments rely on an accurate understanding of the rat liver anatomy. In this short paper, we present an in silico rat liver atlas which is constructed from the micro-CT images of explanted rat livers. The atlas consists of the parametric mesh for four liver lobes and a paracaval portion. 1D and 3D cubic Hermite mesh are used to represent the rat liver vessels and lobes, respectively. We discuss potential applications that can be performed from the in silico atlas.

The selection of the appropriate species is one of the key issues in experimental medicine. Bile duct ligation is the mostly used experimental model in rodents to explore special aspects of occlusive cholestasis. We aimed to clarify if rats or mice are suitable for the same or different aspects in cholestasis research.We induced biliary occlusion by ligation and transection of the common bile duct (tBDT) in rats and mice (each n = 25). Recovery from surgical stress was assessed by daily scoring (stress score, body weight). At five different time points (days 1, 3, 7, 14, 28 after tBDT) we investigated hepatic morphometric and architectural alterations (Haematoxylin-Eosin staining, Elastica van Gieson staining) and the proliferative activities of parenchyma cells (Bromodeoxyuridine staining); as well as established systemic markers for liver synthesis, hepatocellular damage and renal dysfunction.We found substantial differences regarding survival (rats: 100%, 25/25 vs. mice 92%, 22/25, p = 0.07) and body weight gain (p0.05 at postoperative days 14 and 28 (POD)). Rats showed a faster and progressive hepatobiliary remodelling than mice (p0.05 at POD 7+14+28), resulting in: i) stronger relative loss of hepatocellular mass (rats by 31% vs. mice by 15% until POD 28; p0.05 at POD 7+14+28); ii) rapidly progressing liver fibrosis (p0.05 at POD 14); iii) a faster and stronger proliferative response of parenchyma cells (hepatocytes: p0.05 at POD 1+14+18; cholangiocytes: p0.05 at POD 1+3+7+28); and iv) only tiny bile infarcts compared to mice (p0.05 at POD 1+3+7+14). Both species showed comparable elevated markers of hepatocellular damage and serum bilirubin.The key difference between rats and mice are the severity and dynamics of histological alterations, possibly accounting for their different susceptibilities for (septic) complications with low survival (mice).

Patients with malignant biliary obstruction do not seem to benefit from "two-stage hepatectomy" due to an impairment of liver regeneration. We designed a novel model of "repeated regeneration stimuli" in rats mimicking a "two-stage hepatectomy" with selective or complete biliary occlusion mimicking Klatskin tumors III° or IV°. Using this new model, we wanted to investigate (1) the impact of preexistent cholestasis of different extent on the time course of liver regeneration and (2) the dynamics of hepatobiliary remodeling under regeneration conditions.Rats were subjected to a sequence of three operations: surgical induction of biliary occlusion, followed by "repeated regeneration stimuli" consisting of ligation of the left branch of the portal vein (supplying 70% of the liver volume, sPVL) as first stage and a 70%-hepatectomy (70%PHx) as second stage. Biliary occlusion (1st procedure) was induced by ligating and transection of either the common (100%, tBDT) or the left bile duct (70%, sBDT). A sham operation without ligating the bile duct was performed as control (0%, Sham). Two weeks later, on day 14 (POD14), the sPVL (2nd procedure) was performed. Another week later (POD 21), the 70%PHx (3rd procedure) took place and animals were observed for 1 week (POD 28). The first experiment (Total biliary occlusion (tBDT) led to a 2.4-fold increase in whole liver volume due to severe biliary proliferation within 14 days. In contrast, partial biliary occlusion (sBDT) caused only a volume gain of the obstructed liver lobes due to biliary proliferates, resulting in a minor increase of total liver volume (1.7-fold) without an increase in bilirubin levels.As expected, sPVL caused substantial volume gain (tBDT: 3-fold; sBDT: 2.8-fold; Sham 2.8-fold) of FLR and a substantial volume loss (tBDT: 0.9-fold; sBDT: 0.6-fold; Sham: 0.4-fold) of the portally deprived "future resected lobes" compared to the preoperative liver volume. The subsequent 70%PHx promoted a further volume gain of the FLR in all groups (tBDT: 4-fold; sBDT: 3-fold; Sham 3-fold compared to original volume) until POD 28. Hepatobiliary remodeling: After tBDT, we identified histologically three phases of hepatobiliary remodeling in the FLR. Following tBDT, biliary proliferates developed, replacing about 15% of the hepatocellular tissue. After sPVL we found incomplete restoration of the hepatocellular tissue with a visible reduction of the biliary proliferates. The 70%PHx led to an almost complete recovery of the hepatocellular tissue in the FLR with a nearly normal liver architecture. In contrast, after sBDT and Sham we observed a near normal liver morphology in the FLR at all time points. CT-scanning of the explanted livers and subsequent 3D reconstruction visualized the development of extrahepatic biliary collaterals. Collaterals were detected in 0/5 cases 1 week after sPVL (first regeneration stimulus), and in even more cases (3/5) 1 week after the 70%PHx (second regeneration stimulus). Histological workup identified the typical biliary cuboid epithelium as inner lining of the collaterals and peribiliary glands.Liver volume of the FLR increased in cholestatic rats mainly due to biliary proliferates. Application of repeated regeneration stimuli in the style of a "two-stage hepatectomy" promoted almost full restoration of hepatocellular tissue and architecture in the FLR by reestablishing biliary drainage via formation of biliary collaterals. Further exploration of the dynamics in hepatobiliary modeling using this model might help to better understand the underlying mechanism.

ZusammenfassungUm den Erfordernissen der medizinischen Versorgung aktuell und in Zukunft Rechnung zu tragen, wird die medizinische Aus- und Weiterbildung zunehmend kompetenzbasiert ausgerichtet. Grundlage bilden handlungsorientiert formulierte Lernziele, die in kompetenzorientierten Lernzielkatalogen zusammengeführt werden. Der Nationale Kompetenzbasierte Lernzielkatalog Medizin (NKLM) kann als fächerübergreifende Basis für ein Kerncurriculum herangezogen werden. Bereits 2013 sind für die chirurgischen Fachdisziplinen mit dem speziellen Teil des Nationalen Kompetenzbasierten Lernzielkataloges Chirurgie (NKLC) Handlungskompetenzen definiert worden, die die Studierenden nach Abschluss des Praktischen Jahres in Bezug auf konkrete Krankheitsbilder erreicht haben sollen. Mit dem nun ergänzten allgemeinen Teil des NKLC wurden disziplinübergreifend Kompetenzen definiert und von allen chirurgischen Fachdisziplinen konsentiert, die für sämtliche chirurgische Fachdisziplinen gleichermaßen Gültigkeit haben und von Vertreterinnen und Vertretern aller Fachdisziplinen in die Lehre einbezogen werden sollten. Der nun vollständige NKLC liegt den Fakultäten, Lehrenden und Lernenden zur Erprobung vor (verfügbar unter: https://www.dgch.de/index.php?id=190&L=528). Leitgedanke für den gesamten Entwicklungsprozess waren das Erreichen der grundsätzlichen Weiterbildungsbefähigung und die Patientensicherheit beim Berufseinstieg.

Zusammenfassung Hintergrund Die Verwendung videobasierter Analysekonzepte gewinnt in der medizinischen Ausbildung zunehmend an Bedeutung. In erster Linie dienen diese Tools dazu, Informationen über die individuelle Performance eines Kandidaten zu bekommen und Feedback zu geben. Die vorliegende Studie untersucht, ob die Videoanalyse praktischer Fertigkeiten auch für die Weiterentwicklung des chirurgischen Unterrichts genutzt werden kann. Material und Methoden Zunächst wurde die Durchführung einer chirurgischen Nahtübung (Dauer: 3 min) bei Studierenden des 10. Semesters (n = 38) videobasiert dokumentiert. Im Anschluss folgte die Analyse des Videomaterials anhand von 10 spezifischen Kriterien. Die Analyse diente dann als Grundlage für die Entwicklung fehlerpräventiver Übungen. Nachfolgend wurden die Effekte der fehlerpräventiven Übungen auf die Ergebnisqualität der Nahtübung im Rahmen eines Pilotversuchs in einem 2-Gruppen-Vergleich untersucht. Ergebnisse Die Videosequenzen wurden von 2 Experten unabhängig voneinander begutachtet. Es konnten typische Fehler bei der Handhabung des chirurgischen Instrumentariums, der Handhabung des Nahtmaterials sowie im Bewegungsablauf beobachtet werden. Die daraufhin entwickelten zusätzlichen Übungseinheiten fokussierten sich auf die identifizierten Fehlerbereiche (z. B. Handhabung des Nadelhalters und des Nahtmaterials). Die Ergebnisse des 2-Gruppen-Vergleichs (vor und nach Integration der fehlerpräventiven Übungen in das Kurskonzept) zeigten, dass das Absolvieren der zusätzlichen Übungseinheiten einen mittelstarken Effekt auf die Ergebnisqualität einer Nahtübung hatte (Cohens d = 0,73). Schlussfolgerung Die Videoanalyse praktischer Fertigkeiten scheint eine geeignete Basis für die Weiterentwicklung des chirurgischen Unterrichts darzustellen. Typische Fehler können in Bezug auf Art und Häufigkeit identifiziert werden und es lassen sich fehlerpräventive Übungen entwickeln, die einen positiven Effekt auf die Ergebnisqualität einer praktischen Aufgabe haben.

ZusammenfassungDer „Masterplan Medizinstudium 2020“ der Bundesregierung darf in der Chirurgie keinesfalls als „beiläufiges Werk unter Vielen“ unterschätzt werden. Daher nimmt die chirurgische Arbeitsgemeinschaft Lehre (CAL) der Deutschen Gesellschaft für Chirurgie (DGCH) in ihrem Positionspapier zu den geplanten Maßnahmen im „Masterplan Medizinstudium 2020“ Stellung und diskutiert die Herausforderungen, Konsequenzen und Aufgaben, vor die der „Masterplan Medizinstudium 2020“ die Fachvertreter der chirurgischen Fachgesellschaften und die in der Lehre engagierten Chirurgen stellt.

Journal of Clinical and Experimental Hepatology 12(3), 755-766 (2022). doi:10.1016/j.jceh.2021.12.008, Published by Elsevier, Amsterdam [u.a.]

Inflammation, which is induced by the immune response, is recognized as the driving factor in many diseases, including infections and inflammatory diseases, metabolic disorders and cancers. Genetic variations in pivotal genes associated with the immune response, particularly single nucleotide polymorphisms (SNPs), may account for predisposition and clinical outcome of diseases. Lipopolysaccharide (LPS)-binding protein (LBP) functions as an enhancer of the host response to LPS, the main component of the outer membrane of gram-native bacteria. Given the crucial role of LBP in inflammation, we will review the impact of SNPs in the LBP gene on infections and inflammatory diseases, metabolic disorders and cancers.

Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for “rejuvenation” of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.

Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.

Numerous hepatic function, disease and pharmacological experiments are performed on rat livers. Many of these experiments rely on an accurate understanding of the rat liver anatomy. In this short paper, we present an

BACKGROUND: Prostate cancer (PCa) is the most common type of cancer among men in Western countries. Despite numerous therapeutic options, few treatments are available for patients with end-stage disease. In the present study, different somatostatin receptors (SSTs) and the chemokine receptor CXCR4 were evaluated for their suitability as novel therapeutic targets in PCa. MATERIALS AND METHODS: The expression of SST subtypes 1, 2A, 3, and 5 and of CXCR4 was evaluated in 276 PCa tumor samples on a tissue microarray (TMA) in 23 whole-block tumor samples and in 3 PCa cell lines by immunohistochemistry using well-characterized monoclonal antibodies. RESULTS: Overall, the frequency and intensity of expression of SSTs and CXCR4 were very low among the PCa samples investigated. Specifically, SST5, SST2A, and SST3 were expressed, albeit at low intensity, in 10.5%, 9.1%, and 0.7% of the TMA samples, respectively. None of the TMA samples showed SST1 or CXCR4 expression. Only a single small-cell-type neuroendocrine carcinoma that was coincidentally included among the whole-block samples exhibited strong SST2A, SST5, and CXCR4 and moderate SST3 expression. Independent of the tumor cells, the tumor capillaries in many of the PCa samples were strongly positive for SST2A, SST3, SST5, or CXCR4 expression. SST expression in the tumor cells was associated with advanced tumor grade and stage. CONCLUSION: Overall, SST and CXCR4 expression levels are clearly of no therapeutic relevance in PCa. SST- or CXCR4-based therapy might be feasible, however, in rare cases of small-cell-type neuroendocrine carcinoma of the prostate.

Cervical cancer (CC) arises from premalignant cervical intraepithelial neoplasia (CIN) induced by a persistent infection with human papillomaviruses. The multi-stepwise disease progression is driven by genetic and epigenetic alterations. Our previous studies demonstrated a clear downregulation of inter-α-trypsin-inhibitor-heavy chain 5 (ITIH5) at mRNA and protein levels in CC compared to CIN2/3 and normal cervical tissue. Initial in vitro functional analyses revealed a suppressive effect of ITIH5 on relevant mechanisms for cancer progression in conventional two dimensional (2D) cell culture model systems. Based on these studies, we aimed to investigate the functional relevance of ITIH5 in multicellular tumor spheroid (MCTS) models, which resemble in vivo tumors more closely. We successfully established CC cell line-derived MCTS using the hanging-drop technique. ITIH5 was ectopically overexpressed in HeLa and SiHa cells and its functional relevance was investigated under three dimensional (3D) culture conditions. We found that ITIH5 re-expression significantly suppressed tumor spheroid growth and spheroid invasiveness of both HeLa and SiHa spheroids. Immunohistochemical (IHC) analyses revealed a significant reduction in Ki-67 cell proliferation index and CAIX-positive areas indicative for hypoxia and acidification. Furthermore, we observed an increase in cPARP-positive cells suggesting a higher rate of apoptosis upon ITIH5 overexpression. An effect of ITIH5 expression on the susceptibility of cervical MCTS towards cytostatic drug treatment was not observed. Collectively, these data uncover pronounced anti-proliferative effects of ITIH5 under 3D cell culture conditions and provide further functional evidence that the downregulation of ITIH5 expression during cervical carcinogenesis could support cancer development.

Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion injury (IRI), but the underlying molecular mechanisms are not fully understood. High-mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic IRI. Here, we investigated whether CO could attenuate hepatic IRI via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with carbon monoxide-releasing molecule (CORM)-2. CORM-2-delivered CO ameliorated hepatic IRI, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses, and less severe ischemia/reperfusion-associated histopathologic changes. Treatment with CORM-2 significantly inhibited IRI-induced HMGB1 translocation and release. SIRT1 expression was increased by CORM-2 pretreatment. When CORM-2-induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic IRI was worsened, whereas SIRT1 activation by resveratrol reversed this trend. In vitro, CORM-2 reduced hypoxia/reoxygenation-induced HMGB1 translocation and release, these inhibitions were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in alpha mouse liver 12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. IRI increased HMGB1 acetylation, which was abolished by CORM-2 treatment via SIRT1. In conclusion, these results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic IRI. Liver Transplantation 23 510-526 2017 AASLD.

Annotating a dataset for training a Supervised Machine Learning algorithm is time and annotator’s attention intensive. Our goal was to create a tool that would enable us to create annotations of the dataset with minimal demands on expert’s time. Inspired by applications such as Tinder, we have created an annotation tool for describing microscopic images. A graphical user interface is used to select from a couple of images the one with the higher value of the examined parameter. Two experiments were performed. The first compares the speed of annotation of our application with the commonly used tool for processing microscopic images. In the second experiment, the texture description was compared with the annotations from MicrAnt application and commonly used application. The results showed that the processing time using our application is 3 times lower and the Spearman coefficient increases by 0.05 than using a commonly used application. In an experiment, we have shown that the annotations processed using our application increase the correlation of the studied parameter and texture descriptors compared with manual annotations .

Competency-based medical education is needed in order to meet the requirements of medical care currently and in the future. The basis of this are activity-based learning objectives that are merged in competency-based catalogues. A basis for a core curriculum of undergraduate medical training is the National Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). Already in 2013, for surgery, the competencies which medical students should have achieved after completing the practical year (PJ) in relation to surgical diseases were defined in the special part of the National Catalogue of Learning Objectives in Surgery (NKLC). In the now amended general part of the NKLC, interdisciplinary competencies were defined and consented from all surgical disciplines, that are relevant for all surgical disciplines and that all representatives from the different surgical disciplines should incorporate in their surgical training. The complete NKLC is now available for faculties, teachers and students for trial (available online: https://www.dgch.de/index.php?id=190L=528). The guiding principle for the entire development process was to make sure that students gain all competencies they need when starting to work as a medical doctor and therefor to increase patient safety.Um den Erfordernissen der medizinischen Versorgung aktuell und in Zukunft Rechnung zu tragen, wird die medizinische Aus- und Weiterbildung zunehmend kompetenzbasiert ausgerichtet. Grundlage bilden handlungsorientiert formulierte Lernziele, die in kompetenzorientierten Lernzielkatalogen zusammengeführt werden. Der Nationale Kompetenzbasierte Lernzielkatalog Medizin (NKLM) kann als fächerübergreifende Basis für ein Kerncurriculum herangezogen werden. Bereits 2013 sind für die chirurgischen Fachdisziplinen mit dem speziellen Teil des Nationalen Kompetenzbasierten Lernzielkataloges Chirurgie (NKLC) Handlungskompetenzen definiert worden, die die Studierenden nach Abschluss des Praktischen Jahres in Bezug auf konkrete Krankheitsbilder erreicht haben sollen. Mit dem nun ergänzten allgemeinen Teil des NKLC wurden disziplinübergreifend Kompetenzen definiert und von allen chirurgischen Fachdisziplinen konsentiert, die für sämtliche chirurgische Fachdisziplinen gleichermaßen Gültigkeit haben und von Vertreterinnen und Vertretern aller Fachdisziplinen in die Lehre einbezogen werden sollten. Der nun vollständige NKLC liegt den Fakultäten, Lehrenden und Lernenden zur Erprobung vor (verfügbar unter: https://www.dgch.de/index.php?id=190L=528). Leitgedanke für den gesamten Entwicklungsprozess waren das Erreichen der grundsätzlichen Weiterbildungsbefähigung und die Patientensicherheit beim Berufseinstieg.

Decellularized scaffolds can serve as an excellent three-dimensional environment for cell repopulation. They maintain tissue-specific microarchitecture of extracellular matrix proteins with important spatial cues for cell adhesion, migration, growth, and differentiation. However, criteria for quality assessment of the three-dimensional structure of decellularized scaffolds are rather fragmented, usually study-specific, and mostly semi-quantitative. Thus, we aimed to develop a robust structural assessment system for decellularized porcine liver scaffolds. Five scaffolds of different quality were used to establish the new evaluation system. We combined conventional semi-quantitative scoring criteria with a quantitative scaffold evaluation based on automated image analysis. For the quantitation, we developed a specific open source software tool (ScaffAn) applying algorithms designed for texture analysis, segmentation, and skeletonization. ScaffAn calculates selected parameters characterizing structural features of porcine liver scaffolds such as the sinusoidal network. After evaluating individual scaffolds, the total scores predicted scaffold interaction with cells in terms of cell adhesion. Higher scores corresponded to higher numbers of cells attached to the scaffolds. Moreover, our analysis revealed that the conventional system could not identify fine differences between good quality scaffolds while the additional use of ScaffAn allowed discrimination. This led us to the conclusion that only using the combined score resulted in the best discrimination between different quality scaffolds. Overall, our newly defined evaluation system has the potential to select the liver scaffolds most suitable for recellularization, and can represent a step toward better success in liver tissue engineering.

Video-based analysis concepts are being is increasingly applied in medical education. These tools are mainly used to obtain information about the individual performance of a candidate and to provide feedback. The present study explores whether video-based analysis of practical skills can also be used for the development of surgical training.First, the performance of students in semester 10 (n = 38) in a surgical suture exercise (duration: 3 min) was video-documented. The video material was then analysed using 10 specific criteria. The analysis then served as a basis for the development of error prevention exercises. In the following, the effects of the additional teaching units on the performance in the suture exercise were examined in a pilot study using a two-group comparison.The video sequences were reviewed independently by 2 experts. Typical errors could be observed in the handling of the surgical instruments, the handling of the suture material as well as in the motion sequence. Then, additional teaching units dealing with the identified error areas (handling of the instruments and the suture material) were developed. The results of the two-group comparison (before and after implementation of the new exercises) showed that completing the additional teaching units had a medium effect on the result quality of the suture exercise (Cohen's d = 0.73).Video analysis of practical skills seems to be a suitable basis for the development of surgical training. Typical errors can be identified in terms of type and frequency, and preventive exercises can be developed, which have a positive effect on the quality of the results of a practical task.Die Verwendung videobasierter Analysekonzepte gewinnt in der medizinischen Ausbildung zunehmend an Bedeutung. In erster Linie dienen diese Tools dazu, Informationen über die individuelle Performance eines Kandidaten zu bekommen und Feedback zu geben. Die vorliegende Studie untersucht, ob die Videoanalyse praktischer Fertigkeiten auch für die Weiterentwicklung des chirurgischen Unterrichts genutzt werden kann.Zunächst wurde die Durchführung einer chirurgischen Nahtübung (Dauer: 3 min) bei Studierenden des 10. Semesters (n = 38) videobasiert dokumentiert. Im Anschluss folgte die Analyse des Videomaterials anhand von 10 spezifischen Kriterien. Die Analyse diente dann als Grundlage für die Entwicklung fehlerpräventiver Übungen. Nachfolgend wurden die Effekte der fehlerpräventiven Übungen auf die Ergebnisqualität der Nahtübung im Rahmen eines Pilotversuchs in einem 2-Gruppen-Vergleich untersucht.Die Videosequenzen wurden von 2 Experten unabhängig voneinander begutachtet. Es konnten typische Fehler bei der Handhabung des chirurgischen Instrumentariums, der Handhabung des Nahtmaterials sowie im Bewegungsablauf beobachtet werden. Die daraufhin entwickelten zusätzlichen Übungseinheiten fokussierten sich auf die identifizierten Fehlerbereiche (z. B. Handhabung des Nadelhalters und des Nahtmaterials). Die Ergebnisse des 2-Gruppen-Vergleichs (vor und nach Integration der fehlerpräventiven Übungen in das Kurskonzept) zeigten, dass das Absolvieren der zusätzlichen Übungseinheiten einen mittelstarken Effekt auf die Ergebnisqualität einer Nahtübung hatte (Cohens d = 0,73).Die Videoanalyse praktischer Fertigkeiten scheint eine geeignete Basis für die Weiterentwicklung des chirurgischen Unterrichts darzustellen. Typische Fehler können in Bezug auf Art und Häufigkeit identifiziert werden und es lassen sich fehlerpräventive Übungen entwickeln, die einen positiven Effekt auf die Ergebnisqualität einer praktischen Aufgabe haben.

The "Masterplan Medizinstudium 2020" from the German Federal Government should not be underestimated as only one among many announcement. Thus, the Surgical Working Group on Medical Education (CAL) of the German Association of Surgeons (DGCH) comments on the intended measures of the "Masterplan Medizinstudium 2020" and discusses the challenges, consequences and duties arising from the "Masterplan Medizinstudium 2020" for the representatives of the surgical societies and those engaged in surgical undergraduate training.Der „Masterplan Medizinstudium 2020“ der Bundesregierung darf in der Chirurgie keinesfalls als „beiläufiges Werk unter Vielen“ unterschätzt werden. Daher nimmt die chirurgische Arbeitsgemeinschaft Lehre (CAL) der Deutschen Gesellschaft für Chirurgie (DGCH) in ihrem Positionspapier zu den geplanten Maßnahmen im „Masterplan Medizinstudium 2020“ Stellung und diskutiert die Herausforderungen, Konsequenzen und Aufgaben, vor die der „Masterplan Medizinstudium 2020“ die Fachvertreter der chirurgischen Fachgesellschaften und die in der Lehre engagierten Chirurgen stellt.

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration, which is controlled by Hippo signalling. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase of F-actin and phospho-Myosin, to compensate an overload of bile acids. Interestingly, these changes are sensed by the Hippo transcriptional co-activator YAP, which localizes to the apical F-actin-rich region and translocates to the nucleus in dependence of the acto-myosin system. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical-biochemical model of bile pressure and Hippo signalling, we explained this behaviour by the existence of a mechano-sensory mechanism that activates YAP in a switch-like manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory system that responds to critical levels of bile acids as readout of tissue status.

Background: Expectations towards surgeons in modern surgical practice are extremely high with minimal complication rates and maximal patient safety as paramount objectives. Both of these aims are highly dependent on individual technical skills that require sustained, focused, and efficient training outside the clinical environment. At the same time, there is an increasing moral and ethical pressure to reduce the use of animals in research and training, which has fundamentally changed the practice of microsurgical training and research. Various animal models were introduced and widely used during the mid-20th century, the pioneering era of experimental microsurgery. Since then, high numbers of ex vivo training concepts and quality control measures have been proposed, all aiming to reduce the number of animals without compromising quality and outcome of training. Summary: Numerous microsurgical training courses are available worldwide, but there is no general agreement concerning the standardization of microsurgical training. The major aim of this literature review and recommendation is to give an overview of various aspects of microsurgical training. We introduce here the findings of a previous survey-based analysis of microsurgical courses within our network. Basic principles behind microsurgical training (3Rs, good laboratory practice, 3Cs), considerations around various microsurgical training models, as well as several skill assessment tools are discussed. Recommendations are formulated following intense discussions within the European Society for Surgical Research (ESSR) and the International Society for Experimental Microsurgery (ISEM), based on scientific literature as well as on several decades of experience in the field of experimental (micro)surgery and preclinical research, represented by the contributing authors. Key Messages: Although ex vivo models are crucial for the replacement and reduction of live animal use, living animals are still indispensable at every level of training which aims at more than just a basic introduction to microsurgical techniques. Modern, competency-based microsurgical training is multi-level, implementing different objective assessment tools as outcome measures. A clear consensus on fundamental principles of microsurgical training and more active international collaboration for the sake of standardization are urgently needed.

// Anding Liu 1,2 , Enshuang Guo 3 , Jiankun Yang 1 , Renlong Li 3 , Yan Yang 1 , Shenpei Liu 1 , Jifa Hu 1 , Xiaojing Jiang 3 , Olaf Dirsch 2 , Uta Dahmen 2 , Jian Sun 4 and Mingwen Ouyang 5 1 Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena, Germany 3 Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China 4 Department of Biliopancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 5 Department of Anesthesiology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China Correspondence to: Mingwen Ouyang, email: // Keywords : ischemic preconditioning; steatosis; liver ischemia/reperfusion injury; autophagy; heme oxygenase-1, Pathology Section Received : April 25, 2016 Accepted : November 02, 2016 Published : November 10, 2016 Abstract Steatotic livers are more susceptible to ischemia/reperfusion (I/R) injury, which is ameliorated by ischemic preconditioning (IPC). Autophagy possesses protective action on liver I/R injury and declines in steatotic livers. The aim of this study was to test the hypothesis that the increased susceptibility of steatotic livers to I/R injury was associated with defective hepatic autophagy, which could be restored by IPC via heme oxygenase-1 (HO-1) signaling. Obesity and hepatic steatosis was induced using a high fat diet. Obesity impaired hepatic autophagy activity and decreased hepatic HO-1 expression. Induction of HO-1 restored autophagy activity and inhibited calpain 2 activity. Additionally, suppression of calpain 2 activity also restored autophagy activity. Mitochondrial dysfunction and hepatocellular injury were significantly increased in steatotic livers compared to lean livers in response to I/R injury. This increase in sensitivity to I/R injury was associated with defective hepatic autophagy activity in steatotic livers. IPC increased autophagy and reduced mitochondrial dysfunction and hepatocellular damage in steatotic livers following I/R injury. Furthermore, IPC increased HO-1 expression. Inhibition of HO-1 decreased the IPC-induced autophagy, increased calpain 2 activity and diminished the protective effect of IPC against I/R injury. Inhibition of calpain 2 restored autophagic defect and attenuated mitochondrial dysfunction in steatotic livers after I/R. Collectively, IPC might ameliorate steatotic liver damage and restore mitochondrial function via HO-1-mediated autophagy.

It is well known that isolation and cultivation of primary hepatocytes cause major gene expression alterations. In the present genome-wide, time-resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC and hepatitis B virus-infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease-induced expression alterations was observed. For example, expression changes in hepatocytes induced by 1-day cultivation and 1-day CCl4 exposure in vivo correlated with R = 0.615 (p

Die erfolgreiche Arbeit im Gesundheitswesen setzt das interprofessionelle Miteinander voraus. Jedoch lernt bisher jede Disziplin allein. Ein interprofessionelles Seminar, basierend auf dem Lehrkonzept des Konstruktivismus (erfahrungsorientiertes Lernen) sowie der videobasierten Reflexion mittels Tablet-PC, sensibilisiert bereits auf Ausbildungsebene fur dieses Thema.

Ventral or incisional hernia are a common disease pattern in general surgery. Most commonly, a mesh repair is used for reconstruction, whereby the mesh itself might cause complications, like infections or adhesions. Biological materials, like biocellulose, might reduce these clinical problems substantially. In this prospective rodent study, a biocellulose mesh (produced by Gluconacetobacter xylinus) was implanted either by a sublay technique or as supplementation of the abdominal wall. After an observation period of 90 days, animals were sacrificed. The adhesions after the reconstruction of the abdominal wall were moderate. The histologic investigations revealed that the biocellulose itself was inert, with a minimal regenerative response surrounding the mesh. The explanted mesh showed a minimal shrinkage (around 15%) as well as a minimal loss of tear-out force, which might be without clinical relevance. This is the first in vivo study describing biocellulose as a suitable mesh for the repair of ventral hernia in two different hernia models. The material seems to be a promising option for solving actual problems in modern hernia surgery.

Aging is often associated with a decreased autophagic activity that contributes to the high sensitivity of aged livers to ischemia reperfusion injury (IRI). Blood from young animals can positively affect aged animals. This study was designed to evaluate the effect of young plasma in a model of liver IRI in aged rats. Aged rats were treated with pooled plasma collected from young rats before ischemia. Administration of young plasma restored aging-induced suppression in hepatic autophagic activity and reduced liver IRI. Inhibition of the young-plasma-restored autophagic activity abrogated the beneficial effect of young plasma against liver IRI. Similarly, young serum restored autophagic activity and reduced cellular injury after hypoxia/reoxygenation (H/R) in primary old rat hepatocytes. Mechanistic studies showed thatadministration of young plasma increased AMPK phosphorylation and led to unc-51-like autophagy activating kinase (ULK)1 activation. Furthermore, AMPK-inhibition abrogated the young serum-induced ULK1 activation and autophagic activity and diminished the protective action of young serum against H/R injury in primary old rat hepatocytes, whereas AMPK-activation potentiated the effects of young serum. Young plasma could restore age-impaired autophagy, at least in part, via AMPK/ULK1 signaling. Restoration of age-impaired autophagic activity may be a critical contributing mechanism to young-plasma-afforded protection against liver IRI in aged rats.-Liu, A., Yang, J., Hu, Q., Dirsch, O., Dahmen, U., Zhang, C., Gewirtz, D. A., Fang, H., Sun, J. Young plasma attenuates age-dependent liver ischemia reperfusion injury.

Organ engineering is a novel strategy to generate liver organ substitutes that can potentially be used in transplantation. Recently, in vivo liver engineering, including in vivo organ decellularization followed by repopulation, has emerged as a promising approach over ex vivo liver engineering. However, postoperative survival was not achieved. The aim of this study is to develop a novel surgical technique of in vivo selective liver lobe perfusion in rats as a prerequisite for in vivo liver engineering. We generate a circuit bypass only through the left lateral lobe. Then, the left lateral lobe is perfused with heparinized saline. The experiment is performed with 4 groups (n = 3 rats per group) based on different perfusion times of 20 min, 2 h, 3 h, and 4 h. Survival, as well as the macroscopically visible change of color and the histologically determined absence of blood cells in the portal triad and the sinusoids, is taken as an indicator for a successful model establishment. After selective perfusion of the left lateral lobe, we observe that the left lateral lobe, indeed, turned from red to faint yellow. In a histological assessment, no blood cells are visible in the branch of the portal vein, the central vein, and the sinusoids. The left lateral lobe turns red after reopening the blocked vessels. 12/12 rats survived the procedure for more than one week. We are the first to report a surgical model for in vivo single liver lobe perfusion with a long survival period of more than one week. In contrast to the previously published report, the most important advantage of the technique presented here is that perfusion of 70% of the liver is maintained throughout the whole procedure. The establishment of this technique provides a foundation for in vivo partial liver engineering in rats, including decellularization and recellularization.

Organ engineering is a novel strategy to generate liver organ substitutes that can potentially be used in transplantation. Recently, in vivo liver engineering, including in vivo organ decellularization followed by repopulation, has emerged as a promising approach over ex vivo liver engineering. However, postoperative survival was not achieved. The aim of this study is to develop a novel surgical technique of in vivo selective liver lobe perfusion in rats as a prerequisite for in vivo liver engineering. We generate a circuit bypass only through the left lateral lobe. Then, the left lateral lobe is perfused with heparinized saline. The experiment is performed with 4 groups (n = 3 rats per group) based on different perfusion times of 20 min, 2 h, 3 h, and 4 h. Survival, as well as the macroscopically visible change of color and the histologically determined absence of blood cells in the portal triad and the sinusoids, is taken as an indicator for a successful model establishment. After selective perfusion of the left lateral lobe, we observe that the left lateral lobe, indeed, turned from red to faint yellow. In a histological assessment, no blood cells are visible in the branch of the portal vein, the central vein, and the sinusoids. The left lateral lobe turns red after reopening the blocked vessels. 12/12 rats survived the procedure for more than one week. We are the first to report a surgical model for in vivo single liver lobe perfusion with a long survival period of more than one week. In contrast to the previously published report, the most important advantage of the technique presented here is that perfusion of 70% of the liver is maintained throughout the whole procedure. The establishment of this technique provides a foundation for in vivo partial liver engineering in rats, including decellularization and recellularization.

Growth differentiation factor 11 (GDF11) has been implicated in a variety of aging conditions and the regulation of organ regeneration after injury; however, the role of GDF11 in liver ischemia reperfusion injury (IRI) is unknown. The aim of the current study was to investigate the possible role of GDF11 in liver IRI. We investigated the effects of GDF11 in liver IRI in both young (3 mo) and old (22 mo) mice in vivo, and in primary young and old mouse hepatocytes in vitro. Both serum and hepatic GDF11 protein expression levels increased with age and after IRI. Treatment with recombinant GDF11 significantly increased IRI-induced elevations of serum aminotransferase levels, worsened the histologic status of livers, and impaired liver regeneration. In contrast, inhibition of GDF11 activity with neutralizing Abs significantly decreased liver injury and improved liver regeneration after IRI. In vitro, treatment with recombinant GDF11 significantly delayed cell proliferation in cultured hepatocytes that were subjected to hypoxia/reoxygenation insult. Moreover, suppression of cell-cycle progression may be a key mechanism by which GDF11 inhibited hepatocyte regeneration. Collectively, rather than acting as a rejuvenating agent, GDF11 worsens hepatocellular injury and impairs liver regeneration after IRI.-Liu, A., Dong, W., Peng, J., Dirsch, O., Dahmen, U., Fang, H., Zhang, C., Sun, J. Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury.

Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of common key pathways in ischemic liver and hepatotoxic injury results in oxidative stress, inflammatory responses and apoptosis causing organ damage. Controlling liver damage before and during surgery is essential for the postoperative outcome. Nigella sativa has a long tradition as a natural remedy. In the essential oil, Thymoquinone (TQ) was identified as the main component and responsible for most of the therapeutic effects. Therefore, this systematic review aimed to summarize the hepatoprotective effects of TQ and its potential suitability to improve surgical outcome by reducing surgical ischemic injury and hepatotoxicity of neoadjuvant chemotherapy. The key findings can be summarized as TQ having strong antioxidant, anti-inflammatory, antifibrotic, anti-/proapoptotic and anticarcinogenic effects. Almost no side effects were reported irrespective of a large dose range, suggesting a wide therapeutic window. These results give rise to the expectation that TQ could evolve to a novel powerful drug to reduce hepatic injury.

Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in rodents. To determine which changes occur in the three‐dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five‐fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self‐joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five‐fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. Conclusion: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching. (Hepatology 2016;63:951–964)

Background/Aim: Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Materials and Methods: Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. Results: The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. Conclusions: A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged liver regeneration after rPVL + 70% PHx in the portally supplied caudate lobe. Both observations deserve more attention regarding the underlying mechanism in further studies.

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, to inhibit hepatic apoptosis, and to suppress MAPKs and NF-κB activation.

Differences in LPS responsiveness influence the outcome of patients with sepsis. The intensity of the response is highly variable in patients and strain dependent in rodents. However, the role of the liver for initiating the LPS response remains ill defined. We hypothesize that hepatic LPS uptake is a key event for initiating the LPS response. In the present study, the severity of the LPS-induced inflammatory response and the hepatic LPS uptake was compared in two rat strains (Lewis (LEW) rats and Brown Norway (BN) rats). Using a transplantation model, we demonstrated the decisive role of the liver. The expression of hepatic TNF-α, IL-6, and IL-1β mRNA levels in BN rats was significantly lower than that in LEW rats. LEW rats were sensitized to LPS via G-CSF pretreatment. Sensitization caused by G-CSF pretreatment induced severe liver injury and mortality in LEW rats, but not in BN rats (survival rate: 0% (LEW) versus 100% (BN), p<0.01). LEW rats presented with higher liver enzymes, more alterations in histology, and higher expression of caspase 3 and higher cytokines levels. One of the reasons could be the increased hepatic LPS uptake, which was only observed in LEW but not in BN livers. Using the transplantation model revealed the decisive role of the LPS responsiveness of the liver. Injection of LPS to the high-responding LEW recipient before transplantation of a low-responder BN liver resulted in a 50% survival rate. In contrast, injecting the same dose of LPS into the high-responding LEW recipient after transplanting the low-responding BN liver resulted in a 100% survival rate. The severity of inflammatory response in different strains might be related to the differences in hepatic LPS uptake. This observation suggests that the liver plays a genetically defined decisive role in modulating the inflammatory severity.

The identification of disease-associated modules based on protein-protein interaction networks (PPINs) and gene expression data has provided new insights into the mechanistic nature of diverse diseases. However, their identification is hampered by the detection of protein communities within large-scale, whole-genome PPINs. A presented successful strategy detects a PPIN’s community structure based on the maximal clique enumeration problem (MCE), which is a non-deterministic polynomial time-hard problem. This renders the approach computationally challenging for large PPINs implying the need for new strategies. We present ModuleDiscoverer, a novel approach for the identification of regulatory modules from PPINs and gene expression data. Following the MCE-based approach, ModuleDiscoverer uses a randomization heuristic-based approximation of the community structure. Given a PPIN of Rattus norvegicus and public gene expression data, we identify the regulatory module underlying a rodent model of non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD). The module is validated using single-nucleotide polymorphism (SNP) data from independent genome-wide association studies and gene enrichment tests. Based on gene enrichment tests, we find that ModuleDiscoverer performs comparably to three existing module-detecting algorithms. However, only our NASH-module is significantly enriched with genes linked to NAFLD-associated SNPs. ModuleDiscoverer is available at http://www.hki-jena.de/index.php/0/2/490 (Others/ModuleDiscoverer).

Background: Automated image analysis enables quantitative measurement of steatosis in histological images. However, spatial heterogeneity of steatosis can make quantitative steatosis scores unreliable. To improve the reliability, we have developed novel scores that are ""focused"" on steatotic tissue areas. Methods: Focused scores use concepts of tile-based hotspot analysis in order to compute statistics about steatotic tissue areas in an objective way. We evaluated focused scores on three data sets of images of rodent liver sections exhibiting different amounts of dietary-induced steatosis. The same evaluation was conducted with the standard steatosis score computed by most image analysis methods. Results: The standard score reliably discriminated large differences in steatosis (intraclass correlation coefficient ICC = 0.86), but failed to discriminate small (ICC = 0.54) and very small (ICC = 0.14) differences. With an appropriate tile size, mean-based focused scores reliably discriminated large (ICC = 0.92), small (ICC = 0.86) and very small (ICC = 0.83) differences. Focused scores based on high percentiles showed promise in further improving the discrimination of very small differences (ICC = 0.93). Conclusions: Focused scores enable reliable discrimination of small differences in steatosis in histological images. They are conceptually simple and straightforward to use in research studies.

Introduction. Sepsis is the primary cause of death from infection. We wanted to improve the outcome of sepsis by stimulating innate immunity in combination with modulating the severity of inflammatory responses in rats.Method. Sepsis was induced by the injection of feces suspension (control). A 5-day course of G-CSF treatment was given before the septic insult (G-CSF). The inflammatory response was decreased using various doses of the LPS-blocking peptide LBPK95A (5 mg/kg=100%Combi group,0.5 mg/kg=10%Combi group, and0.05 mg/kg=1%Combi group). Survival rates were observed. Bacterial clearance, neutrophil infiltration, tissue damage, and the induction of hepatic and systemic inflammatory responses were determined 2 h and 12 h after the septic insult.Results. High-dose LBPK95A (100% Combi) reduced the survival rate to 10%, whereas low-dose LBPK95A (10% and 1% Combi) increased the survival rates to 50% and 80%, respectively. The survival rates inversely correlated with multiorgan damage as indicated by the serum levels of ALT and urea. G-CSF treatment increased the white blood cell counts, hepatic neutrophil infiltration, and bacterial clearance in the liver, lung, and blood. The blockade of the LPS-LBP interaction decreased neutrophil infiltration, led to increased white blood cell count, and decreased hepatic neutrophil infiltration, irrespective of dose. However, bacterial clearance improved in the 1% and 10% Combi groups but worsened in the 100% Combi group. G-CSF increased TNF-αand IL-6 levels. Irrespective of dose, the blockade of the LPS-LBP interaction was associated with low systemic cytokine levels and delayed increases in hepatic TNF-αand IL-6 mRNA expression. The delayed increase in cytokines was associated with the phosphorylation of STAT3 and AKT.Conclusion. Our results revealed that increasing innate immunity by G-CSF pretreatment and decreasing inflammatory responses using LBPK95A improved the survival rates in a rat sepsis model and could be a novel strategy to treat sepsis.

Because of the lack of adequate organs, the number of patients with end-stage liver diseases, acute liver failure or hepatic malignancies waiting for liver transplantation is constantly increasing. Accepting aged liver grafts is one of the strategies expanding the donor pool to ease the discrepancy between the growing demand and the limited supply of donor organs. However, recipients of organs from old donors may show an increased posttransplantation morbidity and mortality due to enhanced ischemia-reperfusion injury. Energy metabolism, inflammatory response, and autophagy are 3 critical processes which are involved in the aging progress as well as in hepatic ischemia-reperfusion injury. Compared with young liver grafts, impairment of energy metabolism in aged liver grafts leads to lower adenosine triphosphate production and an enhanced generation of free radicals, both aggravating the inflammatory response. The aggravated inflammatory response determines the extent of hepatic ischemia-reperfusion injury and augments the liver damage. Autophagy protects cells by removal of damaged organelles, including dysfunctional mitochondria, a process impaired in aging and involved in ischemia-reperfusion-related apoptotic cell death. Furthermore, autophagic degradation of cellular compounds relieves intracellular adenosine triphosphate level for the energy depressed cells. Strategies targeting the mechanisms involved in energy metabolism, inflammatory response, and autophagy might be especially useful to prevent the increased risk for ischemia-reperfusion injury in aged livers after major hepatic surgery.