The study was

conducted with Institutional Review Board approval from each participating center. General demographic data included gender, ethnicity, ��-catenin signaling age at infection, duration of infection to biopsy, source of infection (vertical, transfusion, and unknown), and body mass index (BMI) Z-scores. The putative date of infection was defined as the date of birth in those who acquired HCV vertically, or the date of transfusion or any surgery, presumed exposure to contaminated needles during hospitalization; if none of the above was known, these data were excluded from the calculation of duration of infection to biopsy. Laboratory values within 3 months of the initial and follow-up biopsies including complete blood count, serum alanine aminotransferase (ALT), total and direct bilirubin, prothrombin time, albumin, and HCV RNA quantification by polymerase chain reaction (PCR) were retrieved from retrospective chart review. Viral genotype was included when available. All Pexidartinib price biopsies were scored for inflammation, fibrosis, and steatosis by a single pathologist to guarantee uniformity of interpretation. They were coded in a uniform manner and the pathologist was blinded to clinical data, the sequence of the biopsies, and the histologic scoring originally performed.[22] Liver biopsies

were evaluated for necroinflammation (grade) with the modified Histology Activity Index (HAI) and fibrosis (stage) by Ishak classification.[22] Demographic data and laboratory values were correlated with histologic grading (grade of inflammation 0-18) and staging (stage of fibrosis 0-6) from the initial and repeat biopsies to assess if there were significant

histologic changes between the biopsies and to identify any factors that predicted progression of liver disease in these children and adolescents. If there were more than two biopsies performed on the same patient, the first and last biopsies were used for statistical analysis. For comparative purposes, necroinflammatory scores were collapsed to none/minimal (HAI: 0-3), mild (4-6), moderate (7-9), and marked ≥10. Fibrosis scores were collapsed to none (stage 0), portal/periportal (stages 1-2), bridging fibrosis and cirrhosis (stages 3-6). Data were organized to enable determination of changes selleck products from the first to the last liver biopsy. Percentages, means, and SDs were calculated in the usual way. For categorical/binary variables, contingency table analysis was used to assess the relationship between two variables with reference to the likelihood ratio chi-square for the P value. The likelihood ratio chi-square was used because it is robust with small sample sizes and small cell sizes. For continuous variables, a standard t test was used for comparison of means between two groups (adjusting for heterogeneity of variance as appropriate) and a standard analysis of variance (ANOVA) for comparison of means among three or more groups. No adjustment was made for multiple comparisons.

The study was

conducted with Institutional Review Board approval from each participating center. General demographic data included gender, ethnicity, find more age at infection, duration of infection to biopsy, source of infection (vertical, transfusion, and unknown), and body mass index (BMI) Z-scores. The putative date of infection was defined as the date of birth in those who acquired HCV vertically, or the date of transfusion or any surgery, presumed exposure to contaminated needles during hospitalization; if none of the above was known, these data were excluded from the calculation of duration of infection to biopsy. Laboratory values within 3 months of the initial and follow-up biopsies including complete blood count, serum alanine aminotransferase (ALT), total and direct bilirubin, prothrombin time, albumin, and HCV RNA quantification by polymerase chain reaction (PCR) were retrieved from retrospective chart review. Viral genotype was included when available. All Y27632 biopsies were scored for inflammation, fibrosis, and steatosis by a single pathologist to guarantee uniformity of interpretation. They were coded in a uniform manner and the pathologist was blinded to clinical data, the sequence of the biopsies, and the histologic scoring originally performed.[22] Liver biopsies

were evaluated for necroinflammation (grade) with the modified Histology Activity Index (HAI) and fibrosis (stage) by Ishak classification.[22] Demographic data and laboratory values were correlated with histologic grading (grade of inflammation 0-18) and staging (stage of fibrosis 0-6) from the initial and repeat biopsies to assess if there were significant

histologic changes between the biopsies and to identify any factors that predicted progression of liver disease in these children and adolescents. If there were more than two biopsies performed on the same patient, the first and last biopsies were used for statistical analysis. For comparative purposes, necroinflammatory scores were collapsed to none/minimal (HAI: 0-3), mild (4-6), moderate (7-9), and marked ≥10. Fibrosis scores were collapsed to none (stage 0), portal/periportal (stages 1-2), bridging fibrosis and cirrhosis (stages 3-6). Data were organized to enable determination of changes selleck inhibitor from the first to the last liver biopsy. Percentages, means, and SDs were calculated in the usual way. For categorical/binary variables, contingency table analysis was used to assess the relationship between two variables with reference to the likelihood ratio chi-square for the P value. The likelihood ratio chi-square was used because it is robust with small sample sizes and small cell sizes. For continuous variables, a standard t test was used for comparison of means between two groups (adjusting for heterogeneity of variance as appropriate) and a standard analysis of variance (ANOVA) for comparison of means among three or more groups. No adjustment was made for multiple comparisons.

TTR was recorded as the date of death or of last follow-up for patients who had not experienced a recurrence at the time of death or last follow-up, respectively. OS was defined as the interval between the dates of surgery and death.19 Total RNA was extracted from cell lines and frozen tumor specimens using Trizol Reagent (Invitrogen, Carlsbad, CA). Total RNA (5 μg) was reverse transcribed using oligo dT and SuperScript III reverse transcriptase according to the manufacturer’s instructions. The complementary DNA (cDNA) was diluted 1:50 in water and 4.5 μL of this mixture was used http://www.selleckchem.com/products/wnt-c59-c59.html as template

in a 10 μL quantitative PCR (qPCR) reaction. Amplification and detection were performed using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems, Foster City, CA). Briefly, the cycle conditions were as follows: 50°C for 2 minutes (required for optimal AmpErase UNG activity), template denaturation at 95°C for 10 minutes, 40 cycles of denaturation at 95°C for 15 seconds, and combined primer annealing/elongation at 60°C for 1 minute. In addition, qPCR of TATA-binding protein (TBP) was used as an endogenous control to normalize for differences in the amount of total RNA in each

sample. Relative expression of genes was calculated and expressed as 2-&Dgr;Ct (cycle threshold) as described.20 The following probes were used for detection: Hs00959010_m1 for OPN, Hs00354679_m1 for thrombin, Hs00236976_m1 selleck products for integrin-β1, and Hs00427620_m1 for TBP. Formalin-fixed and paraffin-embedded tissues (both tumor and nontumor liver tissues) were used for immunohistochemical staining. Following deparaffinization, 4-μm tissue sections were rehydrated and subjected to antigen retrieval by microwaving in 0.01 mol/L sodium citrate (pH 6) for 10 minutes. Sections were stained with monoclonal antimouse OPN antibody and find more thrombin antibody (Santa Cruz Biologicals, Santa Cruz, CA), using a two-step immunoperoxidase technique performed as described.18 Briefly, after microwave antigen retrieval tissue sections were incubated with primary antibodies for 60 minutes at room temperature.

Following 30 minutes of incubation with secondary antibody, the sections were developed in diaminobenzidine solution under microscopic observation and counterstained with hematoxylin. Negative controls were stained identically, but without primary antibody incubation. The intensity of positive staining was measured as described in the Supporting Information. Based on the intensity of thrombin or OPN in the central positive staining area in tumor section as a cutoff value, the intensity of thrombin or OPN was classified positive (thrombin+ ≥20%, and OPN+ ≥5% of tumor section) and negative (thrombin− <20%, and OPN− <5%). Conditioned media and cell lysate were prepared as described.21 The protein expression levels of thrombin, OPN, FAK, Phospho-FAK (Tyr397), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were evaluated by western blot.

Results indicated that stable overexpression of the miR-216a/217 cluster significantly promoted the migration ability of HepG2-miR-216a/217 and PLC/PRF/5-miR-216a/217 cells in vitro (Fig. 2E). These data indicated that overexpression of miR-216a/217 in

HCC with epithelial phenotypes induced EMT and enhanced migration abilities. Next, HLE cells with a mesenchymal phenotype were used as recipient cells for transfection of antagomir-miR-216a/217 (Genepharma, Shanghai, China). (Antagomirs, also known as anti-miRs or blockmirs, are a novel class of chemically engineered oligonucleotides used to silence endogenous miRNAs.) After the silencing of miR-216a/217 (Supporting Fig. 3A), striking morphological changes consistent with those of mesenchymal-to-epithelial transition (MET) were observed (Supporting Fig. 3B). Up-regulation of E-cadherin, an epithelial biomarker, and reduced expression of vimentin, a mesenchymal biomarker, Belinostat were also observed (Supporting Fig. 3C). Furthermore, we also PARP inhibitor examined the expression of miR-216a/217 on the proliferation and apoptosis of liver cancer cells. A significant increase in

cell proliferation was observed in PLC/PRF/5 at 72 hours after transfection of the p-miR-216a/217-overexpressing vector, whereas transfection of the antagomir-miR-216a/217 into HLE cells significantly decreased cell proliferation (Supporting Fig. 4A). The number of apoptotic cells (Annexin V+ cells) was not significantly affected in PLC/PRF/5 and HLE cells by modulating expression of the miR-216a/217 cluster (Supporting Fig. 4B). The recent discovery of the emergence of CSCs occurred, in part, as a result of miRNA-mediated EMT, which has provided a new avenue in understanding the regulatory mechanisms in CSCs and drug resistance. Because specific CSC markers have not been well defined for most CSCs, sphere-forming ability has emerged as a useful tool to evaluate the stemness characteristics of cells and for the

enhanced enrichment selleckchem of potential CSCs. Therefore, we evaluated HepG2-miR-216a/217 and PLC/PRF/5-miR-216a/217 cells for their ability to form tumor spheres. It was observed that HepG2-miR-216a/217 and PLC/PRF/5-miR-216a/217 generated 2∼3-fold more spheres than corresponding control cells (Fig. 3A,B). Flow cytometric analysis further demonstrated that sphere-forming cells derived from HepG2-miR-216a/217 and PLC/PRF/5-miR-216a/217 cells gave an enriched epithelial cell adhesion molecule (EpCAM)+ cell subpopulation, consistent with reported characteristics of liver CSCs[15] (Fig. 3C,D). The parental HepG2 had a small percentage of EpCAM+ cell subpopulation (12.6%), which was increased to 23.9% after transfection with miR-216a/217 (Fig. 3C). This suggests that the miR-216a/217 cluster may play an important role in regulating the stem-like traits of HCC cells by inducing EMT.

Our data show that chronic hepatocellular NF-κB activation is sufficient for liver fibrosis development by way of

recruitment and activation of macrophages. α-SMA, alpha-smooth muscle actin; ALT, alanine amino transferase; AST, aspartate amino transferase; CA, constitutively active; CT, control; DOX, doxycycline; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; HPF, high-power field; HPRT, hypoxanthine-guanine phosphoribosyltransferase gene; HSC, hepatic stellate cell; IKK, IκB kinase; LAP, liver activator protein; LPS, lipopolysaccharide; NASH, nonalcoholic steatohepatitis; ALK inhibitor NF-κB, nuclear factor-κB; Temsirolimus concentration PDGF, platelet-derived growth factor; RLU, relative light unit; SAA, serum amyloid A; TGF, transforming growth factor; tTA, tetracycline transactivator. We crossed mice carrying

a constitutively active human IKK2 (CAIKK2) allele17 under the control of a tissue-specific tetracycline-inducible system with animals expressing tetracycline-responsive transactivator (tTA) under the control of the rat liver activator protein (LAP) promotor.14 The generated mice were on a C57BL/6 and NMRI mixed background and were backcrossed at least four times to a C57BL/6 background. Studies were performed on male mice kept under specific pathogen-free conditions. The experiments were approved by the State of Baden-Württemberg in Germany and the University of Ulm Animal Care Committee. To avoid the embryonic activation of the IKK2/NF-κB system, all mice received 0.1 g/L doxycycline in drinking water until birth. In some cases, 4-week-old animals were readministered 0.1 g/L doxycycline (DOX) in drinking water for

3 days, or 12-week-old animals were readministered DOX for 3 weeks, to study whether a continuous CAIKK2 expression is required for the observed liver phenotype. Of note, CAIKK2 mice contain a bidirectional promoter, whose activation leads to simultaneous production of both IKK2 and Photinus pyralis luciferase.17 Mice were sacrificed by way of CO2 inhalation and blood was collected from vena cava inferior. After brief centrifugation, serum was collected and used for measurement of alanine and aspartate aminotransferase levels (ALT and AST; Reflotron selleck system, Roche). Livers were removed, weighed, and divided into pieces that were fixed in 10% formaldehyde for histological/immunohistochemical analysis, snap-frozen in liquid nitrogen for molecular or biochemical analysis, or rapidly frozen for immunofluorescence staining. For preparing whole liver extract, frozen livers were lysed in Dignam C buffer18 or in RIPA buffer.19 The lysate was centrifuged at 20,000g for 30 minutes at 4°C and the supernatant was recovered. Protein extracts were electrophoresed and subsequently blotted.

It seems likely that both the inflammatory nature of adipose tissue and the amount

of abdominal fat accumulation are critical factors in tissue damage. This is what we have previously observed for cardiac dysfunction and morpho-functional abnormalities.3, 4 Thus, both these targets should be addressed in the treatment. Indeed, NASH develops, and potentially progresses to cirrhosis, on a chronic inflammatory background.5, 6 However, liver disease seems to be associated with systemic degenerative disease and metabolic derangements independently of VAT accumulation.7 Adipose tissue is a dynamic organ resulting from the balance of new fat deposition and reabsorption. Several factors are involved in this turnover, such as diet, physical activity, but also inflammation, which is considered per MLN2238 se a major determinant of insulin resistance.8, 9 The portal/fatty acid flux theory suggests that visceral fat, via its unique location and enhanced lipolytic activity, releases toxic free fatty acids, which are delivered in high concentrations

directly to the liver. This leads to the accumulation and storage of hepatic fat and the development of hepatic insulin resistance.9 Nonetheless, a study by van der Poorten et al. has recently shown that visceral fat remained an Aurora Kinase inhibitor independent predictor of liver inflammation and fibrosis even when measures of insulin resistance, adipokines, and increasing age are considered.10 A 4-week aerobic program can result in a significant reduction of VAT, thus positively affecting the levels of circulating free fatty acids and hepatic lipid accumulation, but appears to be too short a time frame to reduce insulin resistance. see more Unfortunately, the disruption of inflammatory biomarkers has been not addressed by Johnson et al.1 This is what Promrat et al. were able to demonstrate,2 providing evidence

that patients undergoing consistent abdominal adipose tissue loss have improved lobular inflammation and also reduced insulin resistance. Altogether, these results support that both the disruption of inflammation and the reduction of VAT should be targets of therapeutic strategies to reduce local tissue damage. This has been supported for cardiac dysfunction11, 12 and there is some rationale also for treatment of both NAFLD and NASH. However, it must be recognized that it is frequently difficult to keep the patient focused on maintaining changes in lifestyle habits. Alexis Elias Malavazos M.D.*, Giulia Gobbo M.D.†, Roberta Francesca Zelaschi M.D.*, Emanuele Cereda M.D., Ph.D.

UICC TNM 7th Edition; 4. Extracapsular; Presenting Author: GUOSHENG WU Additional Authors: QINGCHUAN ZHAO, WEIZHONG WANG, HAI SHI, DONGLI CHEN, MIAN WANG, KAICHUN WU, ZENSHAN LI Corresponding Author: GUOSHENG WU Affiliations: Fourth Military Medical University Objective: Intestinal transplantation was performed using ABO identical donor (91.3%) or ABO compatible donor (8.5%). Up to date, only 4 cases of ABO incompatible intestinal transplantation

have been reported to Ganetespib the UNOS registry. We present a case of an ABO incompatible living-related intestinal transplant with a 10-month follow-up. Methods: A 14-year-old girl was referred with suspected bowel infarction for 10 days. Exploratory laparotomy revealed 4,000 ml of turbid foul-smelling fluid in the abdomen

selleck products and an extensive bowel necrosis, requiring removal of the third and fourth part of the duodenum, the entire small bowel and the ascending and the proximal transverse colon. The duodenum was closed just distal to the ampulla of Vater and a gastrostomy tube was placed for drainage. After discussion with her family, we decided to undertake a living-related intestinal transplant. Lab tests indicated her B blood-type but absence of ABO identical or compatible donors in her family. During a long waiting period for a cadaveric donor, she developed several episodes of recurrent aspiration and the lung cavitation. Her 48-year-old father with an AB blood-type was considered as donor. Induction therapy included Rituximab, ATG and plasma exchange. The donor’s distal 180 cm ileum was transplanted. Results: The recipient’s postoperative course was remarkable for one episode of acute rejection on postoperative day 15, which was successfully

treated with steroid bolus and ATG. Due to delayed gastric empty, selleck chemical a clear liquid diet was started on day 45 and she well tolerated a soft diet by day 60. Since discharge her weight is stable at 42 kg, she eats regular diet. The donor spent 6 days in hospital and has done well since discharge. Conclusion: Our preliminary experience suggests that ABO incompatible living donor bowel transplantation can be lifesaving when ABO identical or compatible donor is unavailable. Key Word(s): 1. Transplantation; 2. Small bowel; 3. short gut syndrome; 4. living donor; Presenting Author: GUOSHENG WU Additional Authors: WEIZHONG WANG, QINGCHUAN ZHAO, HAI SHI, DONGLI CHEN, MIAN WANG, ZENSHAN LI Corresponding Author: GUOSHENG WU Affiliations: Xijing Hospital of Digestive Diseases & State Key Laboratory of Cancer Biology, Fourth Military Medical University Objective: Solid pseudopapillary neoplasm (SPN) is a low-grade malignant tumor of the pancreas that typically afflicts women. Complete surgical resection is associated with a long-term survival. We present a case with a large SPN invading the mesenteric root, which was successfully treated using intestinal auto-transplantation.

UICC TNM 7th Edition; 4. Extracapsular; Presenting Author: GUOSHENG WU Additional Authors: QINGCHUAN ZHAO, WEIZHONG WANG, HAI SHI, DONGLI CHEN, MIAN WANG, KAICHUN WU, ZENSHAN LI Corresponding Author: GUOSHENG WU Affiliations: Fourth Military Medical University Objective: Intestinal transplantation was performed using ABO identical donor (91.3%) or ABO compatible donor (8.5%). Up to date, only 4 cases of ABO incompatible intestinal transplantation

have been reported to ABT-199 cost the UNOS registry. We present a case of an ABO incompatible living-related intestinal transplant with a 10-month follow-up. Methods: A 14-year-old girl was referred with suspected bowel infarction for 10 days. Exploratory laparotomy revealed 4,000 ml of turbid foul-smelling fluid in the abdomen

buy MDV3100 and an extensive bowel necrosis, requiring removal of the third and fourth part of the duodenum, the entire small bowel and the ascending and the proximal transverse colon. The duodenum was closed just distal to the ampulla of Vater and a gastrostomy tube was placed for drainage. After discussion with her family, we decided to undertake a living-related intestinal transplant. Lab tests indicated her B blood-type but absence of ABO identical or compatible donors in her family. During a long waiting period for a cadaveric donor, she developed several episodes of recurrent aspiration and the lung cavitation. Her 48-year-old father with an AB blood-type was considered as donor. Induction therapy included Rituximab, ATG and plasma exchange. The donor’s distal 180 cm ileum was transplanted. Results: The recipient’s postoperative course was remarkable for one episode of acute rejection on postoperative day 15, which was successfully

treated with steroid bolus and ATG. Due to delayed gastric empty, selleck inhibitor a clear liquid diet was started on day 45 and she well tolerated a soft diet by day 60. Since discharge her weight is stable at 42 kg, she eats regular diet. The donor spent 6 days in hospital and has done well since discharge. Conclusion: Our preliminary experience suggests that ABO incompatible living donor bowel transplantation can be lifesaving when ABO identical or compatible donor is unavailable. Key Word(s): 1. Transplantation; 2. Small bowel; 3. short gut syndrome; 4. living donor; Presenting Author: GUOSHENG WU Additional Authors: WEIZHONG WANG, QINGCHUAN ZHAO, HAI SHI, DONGLI CHEN, MIAN WANG, ZENSHAN LI Corresponding Author: GUOSHENG WU Affiliations: Xijing Hospital of Digestive Diseases & State Key Laboratory of Cancer Biology, Fourth Military Medical University Objective: Solid pseudopapillary neoplasm (SPN) is a low-grade malignant tumor of the pancreas that typically afflicts women. Complete surgical resection is associated with a long-term survival. We present a case with a large SPN invading the mesenteric root, which was successfully treated using intestinal auto-transplantation.

*** p-values: <0.001 compared with Child-Pugh, MELD and MELD-Na Disclosures: Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support: Grifols, Gambro Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Genzyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teaching: Schering Plough, Gambro, MSD, Gilead Paolo Caraceni - Advisory Committees or Review Panels: GSK; Speaking and Teaching: Baxter, Kedrion Tania M. Welzel - Advisory Committees or Review Panels: Novartis, Janssen, Gilead, Abbvie, Boehringer-Ingelheim+ Pere Gines - Advisory Committees or Review

Panels: Ferring ; Grant/Research Support: Sequana Medical, Grifols Francois Durand – Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead Paolo Angeli – Advisory Committees buy Lorlatinib or Review Panels: Sequana Medical Didier Samuel – Consulting: Astellas, MSD, BMS, Roche, Novartis, Gilead, LFB, Janssen-Cilag, Biotest, Abbvie Stefan Zeuzem – Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals

Julia Wendon – Consulting: Pulsion, Excalenz Mauro Bernardi – Consulting: CLS Behring GhmB, Baxter Healthcare; Speaking and Teaching: CLS Behring GhmB, PPTA Europe selleck inhibitor Vicente Arroyo – Speaking and Teaching: GRIFOLS The following people have nothing to disclose: Marco Pavesi, Alex Amorós, Javier Fernandez,

Peter Holland-Fischer, Rohit Sawhney, Rajeshwar Mookerjee, Richard Moreau, Carlo Alessandria, check details Wim Laleman, Jonel Trebicka, Thierry Gustot, Alexander L. Gerbes Background and aim: In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. In vitro studies of astrocyte cultures have shown mitochondrial dysfunction under hyperammonaemic conditions and in rat brain of in vivo liver failure models de novo lactate production has been observed. These findings support the hypothesis of a compromised brain metabolism during ALF. Yet, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen to glucose ratio of cerebral metabolic rates remains normal. We therefore wanted to investigate the relationship between the extracellular and total tissue lactate levels in brain cortex of a rat model with hyperammonaemia and systemic inflammation. Furthermore we assessed the mitochondrial function in brain tissue with high-resolution respirometry. Methods: Sedated and mechanically ventilated male Wistar rats were given either: ammonia (NH3)+lipopolysaccharide (LPS): NH3+saline; saline+LPS; or saline+saline. Ammonia/saline was infused for 120 minutes while extracellular brain lactate was measured with enzymatic biosensors (Sarissa Biomedical). After the animals were sacrificed the total lactate concentration in cerebral cortex was measured.

*** p-values: <0.001 compared with Child-Pugh, MELD and MELD-Na Disclosures: Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus; Grant/Research Support: Grifols, Gambro Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Genzyme, Vital therapies; Grant/Research Support: Astellas; Speaking and Teaching: Schering Plough, Gambro, MSD, Gilead Paolo Caraceni - Advisory Committees or Review Panels: GSK; Speaking and Teaching: Baxter, Kedrion Tania M. Welzel - Advisory Committees or Review Panels: Novartis, Janssen, Gilead, Abbvie, Boehringer-Ingelheim+ Pere Gines - Advisory Committees or Review

Panels: Ferring ; Grant/Research Support: Sequana Medical, Grifols Francois Durand – Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead Paolo Angeli – Advisory Committees buy Ixazomib or Review Panels: Sequana Medical Didier Samuel – Consulting: Astellas, MSD, BMS, Roche, Novartis, Gilead, LFB, Janssen-Cilag, Biotest, Abbvie Stefan Zeuzem – Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals

Julia Wendon – Consulting: Pulsion, Excalenz Mauro Bernardi – Consulting: CLS Behring GhmB, Baxter Healthcare; Speaking and Teaching: CLS Behring GhmB, PPTA Europe 3 Methyladenine Vicente Arroyo – Speaking and Teaching: GRIFOLS The following people have nothing to disclose: Marco Pavesi, Alex Amorós, Javier Fernandez,

Peter Holland-Fischer, Rohit Sawhney, Rajeshwar Mookerjee, Richard Moreau, Carlo Alessandria, selleck kinase inhibitor Wim Laleman, Jonel Trebicka, Thierry Gustot, Alexander L. Gerbes Background and aim: In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. In vitro studies of astrocyte cultures have shown mitochondrial dysfunction under hyperammonaemic conditions and in rat brain of in vivo liver failure models de novo lactate production has been observed. These findings support the hypothesis of a compromised brain metabolism during ALF. Yet, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen to glucose ratio of cerebral metabolic rates remains normal. We therefore wanted to investigate the relationship between the extracellular and total tissue lactate levels in brain cortex of a rat model with hyperammonaemia and systemic inflammation. Furthermore we assessed the mitochondrial function in brain tissue with high-resolution respirometry. Methods: Sedated and mechanically ventilated male Wistar rats were given either: ammonia (NH3)+lipopolysaccharide (LPS): NH3+saline; saline+LPS; or saline+saline. Ammonia/saline was infused for 120 minutes while extracellular brain lactate was measured with enzymatic biosensors (Sarissa Biomedical). After the animals were sacrificed the total lactate concentration in cerebral cortex was measured.