Primary human hepatocyte cultures were transfected with genomic RNAs of HCV genotypes 1a, 1b, and 2a (1 μg/106 cells) using FuGENE6 (Roche). On day 6 postinfection, the small RNA (≤200-nucleotide) fraction was enriched from HCV-infected cell RNA using a mirVana isolation BMS-777607 kit (Ambion). Four micrograms of each sample together with positive control (synthetic Arabidopsis thaliana mir-157a, which is not present in the human genome) was spiked in and was hybridized to the microarray slide (BioMicro

System). After 16 hours, the hybridized microarray was washed with a standard sodium citrate solution to remove unhybridized probes. After 3 hours of Klenow exonuclease-1 incubation, exo(-) Klenow enzyme was added to extend the miRNAs hybridized to the chip-attached templates in a primer extension step. During this step, biotinylated dATP was

incorporated as a final portion of the extension through the designed polythymidine region. Detection of this template-hybridized miRNA was performed using streptovidin-conjugated Alexa-fluor-555, which binds to the biotinylated stretch of A’s at the 3′-end of the captured miRNA. Fluorescence data sets were collected using GenePix 4000 scanner (Axon). Details of the procedure are described in Yeung et al.14 Primary hepatocytes were transfected with HCV1a genomic RNA (1 μg/106 cells) in triplicate. Parallel cultures were transfected with DLC-1 complementary DNA (cDNA) expression vector (50 ng/106 cells for 6 hours) prior to transfection with HCV 1a genomic RNA. Six days posttransfection, the cells were released with 0.05%

trypsin treatment and were resuspended at 104/100 μL in (phosphate-buffered www.selleckchem.com/products/PLX-4720.html saline containing 2% fetal bovine serum) processed for Ki67 immunostaining (BD Biosciences) according learn more to the manufacturer’s instructions. Primary human hepatocytes were transfected with HCV genotypes 1a, 1b, and 2a (1 μg/106 cells) as described.12 Virus released in the culture medium was filtered through 0.25-μm filters from infected cells.12 Viral RNA replication was evaluated at indicated times after infection as outlined above, and the efficiency of virus released in the culture media was validated using the World Health Organization’s HCV standards (Acrometrix, Benicia, CA). Primary human hepatocyte culture was cotransfected with luciferase reporter containing DLC-1 3′ untranslated region (UTR) (50 ng/106 cells), miR-141 (50 nM/106 cells, antagomir) or miR-141 (50 nM/106 cells, Mimic) using Lipofectamine 2000 (Invitrogen). Luciferase assays (Promega) were performed on the third day after transfection according to the manufacturer’s instructions. The results are given as the mean ± SE. Statistical analysis of the data was performed using the Student t test, Fisher’s exact test, or otherwise as described. To assess virus infection-associated changes in host gene expression, we analyzed alterations in miRNAs in primary human hepatocytes infected with HCV genotypes 1a, 1b, and 2a (Supporting Information Fig. 1).

5-month-old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase. NAM administration markedly reduced hepatic SAM content, prevented DNA hypermethylation, and normalized the expression of critical Pifithrin �� genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More importantly, NAM treatment prevented the development of fatty liver and fibrosis in GNMT-KO mice. Because GNMT expression is down-regulated in patients with cirrhosis, and because some subjects with GNMT mutations have spontaneous liver disease, the clinical implications of the present findings

are obvious, at least with respect to these latter individuals. Because NAM has been used for many years to treat a broad spectrum of diseases (including pellagra and diabetes) without significant side effects, it should be considered in subjects with GNMT mutations. Conclusion: The findings of this study indicate that the anomalous accumulation of SAM in GNMT-KO mice can be corrected by NAM treatment leading to the normalization of the expression of many genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis, as well as reversion of the appearance

of the pathologic phenotype. (HEPATOLOGY 2010) Expression of glycine N-methyltransferase (GNMT) is predominant in hepatocytes, where it selleck chemicals comprises about 1% of the total soluble protein, but is also found in other tissues such as pancreas and prostate.1 GNMT catalyzes the conversion of glycine into sarcosine (methylglycine), which is then oxidized to regenerate glycine (Fig. 1). The function of this futile cycle is to catabolize excess S-adenosylmethionine (SAM) synthesized by the liver after an increase in methionine concentration (for example, after a protein-rich meal) to maintain

a constant SAM/S-adenosylhomocysteine (SAH) ratio and avoid aberrant methylation reactions.1, 2 Accordingly, individuals learn more with GNMT mutations that lead to inactive forms of the enzyme have elevated blood levels of methionine and SAM, but the concentration of total homocysteine (the product of SAH hydrolysis) is normal.3, 4GNMT knockout (KO) mice recapitulate the situation observed in individuals with mutations of the GNMT gene5, 6 and have elevated methionine and SAM both in serum and liver. These findings indicate that the hepatic reduction in total transmethylation flux caused by the absence of GNMT cannot be compensated by other methyltransferases that are abundant in the liver, such as guanidinoacetate N-methyltransferase, phosphatidylethanolamine N-methyltransferase, or nicotinamide N-methyltransferase (NNMT), and that this situation leads to the accumulation of hepatic SAM and increased transport of this molecule to the blood.

5-month-old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase. NAM administration markedly reduced hepatic SAM content, prevented DNA hypermethylation, and normalized the expression of critical Selleck BTK inhibitor genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More importantly, NAM treatment prevented the development of fatty liver and fibrosis in GNMT-KO mice. Because GNMT expression is down-regulated in patients with cirrhosis, and because some subjects with GNMT mutations have spontaneous liver disease, the clinical implications of the present findings

are obvious, at least with respect to these latter individuals. Because NAM has been used for many years to treat a broad spectrum of diseases (including pellagra and diabetes) without significant side effects, it should be considered in subjects with GNMT mutations. Conclusion: The findings of this study indicate that the anomalous accumulation of SAM in GNMT-KO mice can be corrected by NAM treatment leading to the normalization of the expression of many genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis, as well as reversion of the appearance

of the pathologic phenotype. (HEPATOLOGY 2010) Expression of glycine N-methyltransferase (GNMT) is predominant in hepatocytes, where it JQ1 mw comprises about 1% of the total soluble protein, but is also found in other tissues such as pancreas and prostate.1 GNMT catalyzes the conversion of glycine into sarcosine (methylglycine), which is then oxidized to regenerate glycine (Fig. 1). The function of this futile cycle is to catabolize excess S-adenosylmethionine (SAM) synthesized by the liver after an increase in methionine concentration (for example, after a protein-rich meal) to maintain

a constant SAM/S-adenosylhomocysteine (SAH) ratio and avoid aberrant methylation reactions.1, 2 Accordingly, individuals selleck chemical with GNMT mutations that lead to inactive forms of the enzyme have elevated blood levels of methionine and SAM, but the concentration of total homocysteine (the product of SAH hydrolysis) is normal.3, 4GNMT knockout (KO) mice recapitulate the situation observed in individuals with mutations of the GNMT gene5, 6 and have elevated methionine and SAM both in serum and liver. These findings indicate that the hepatic reduction in total transmethylation flux caused by the absence of GNMT cannot be compensated by other methyltransferases that are abundant in the liver, such as guanidinoacetate N-methyltransferase, phosphatidylethanolamine N-methyltransferase, or nicotinamide N-methyltransferase (NNMT), and that this situation leads to the accumulation of hepatic SAM and increased transport of this molecule to the blood.

In these patients, palliative treatment is possible, employing systemic therapy. Genetic profiling has suggested that HCC progression is attributed Y-27632 solubility dmso to a number of altered signaling pathways as well as epigenetic mechanisms. Thus, as in other tumor entities,

targeted agents are investigated as novel therapeutic options. Along this line, angiogenesis inhibition is a prime therapeutic target in solid tumors, especially in highly vascularized HCC. Since the successful completion of the SHARP study in 2007,2 the antiproliferative and angiostatic multi–tyrosin kinase inhibitor (TKI), sorafenib, has been approved as the first systemic agent for treatment of patients with unresectable or metastatic HCC and preserved liver function. Sorafenib primarily inhibits BRAF/vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor tyrosin kinases mediating

cell proliferation and angiogenesis; it also blocks many additional kinases, given its lack of selectivity.3 The mechanism underlying the antitumor effect of sorafenib is complex, and even RAF-independent signaling has recently been described as a significant pathway of sorafenib-induced cell death.4 At present, sorafenib represents the only drug with statistically significant, but clinically modest, benefit in terms of improvement in overall survival (OS), time to Cabozantinib progression (TTP), and disease control rate. Efficacy of sorafenib in HCC was demonstrated in two

large randomized, controlled trials (RCT): SHARP and the Asia-Pacific study,2, 5 sorafenib significantly reduces the risk of death and prolongs median OS by approximately 3 months. Survival benefit is based on an extended TTP. Sorafenib does not induce tumor-size reduction, and radiologic response has to be confirmed by a decrease in viable tumor mass. Therefore, to identify novel drugs with activity in HCC in future and check details ongoing trials, modified Response Evaluation Criteria In Solid Tumors criteria have been proposed.6 FGF3/4, fibroblast growth factors 3 and 4; FGFR, FGF receptor; HCC, hepatocellular carcinoma; OS, overall survival; RCT, randomized, controlled trial; TKI, multi–tyrosin kinase inhibitor; TTP, time to progression; VEGFR, vascular endothelial growth factor receptor. Sorafenib is associated with relevant toxicities, especially in patients with compromised liver function (stage Child-Pugh B). Patients with cirrhosis suffer from fatigue, and in such patients, sorafenib may cause a rapid deterioration in quality of life. Therefore, predictive (bio)markers to guide therapy with sorafenib are urgently needed. Many clinical parameters and serum markers as well as genomic signatures have been suggested; for example, development of hypertension and diarrhea, known side effects of sorafenib, under therapy seem to be associated with a favorable outcome.

In these patients, palliative treatment is possible, employing systemic therapy. Genetic profiling has suggested that HCC progression is attributed LEE011 supplier to a number of altered signaling pathways as well as epigenetic mechanisms. Thus, as in other tumor entities,

targeted agents are investigated as novel therapeutic options. Along this line, angiogenesis inhibition is a prime therapeutic target in solid tumors, especially in highly vascularized HCC. Since the successful completion of the SHARP study in 2007,2 the antiproliferative and angiostatic multi–tyrosin kinase inhibitor (TKI), sorafenib, has been approved as the first systemic agent for treatment of patients with unresectable or metastatic HCC and preserved liver function. Sorafenib primarily inhibits BRAF/vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor tyrosin kinases mediating

cell proliferation and angiogenesis; it also blocks many additional kinases, given its lack of selectivity.3 The mechanism underlying the antitumor effect of sorafenib is complex, and even RAF-independent signaling has recently been described as a significant pathway of sorafenib-induced cell death.4 At present, sorafenib represents the only drug with statistically significant, but clinically modest, benefit in terms of improvement in overall survival (OS), time to CAL-101 clinical trial progression (TTP), and disease control rate. Efficacy of sorafenib in HCC was demonstrated in two

large randomized, controlled trials (RCT): SHARP and the Asia-Pacific study,2, 5 sorafenib significantly reduces the risk of death and prolongs median OS by approximately 3 months. Survival benefit is based on an extended TTP. Sorafenib does not induce tumor-size reduction, and radiologic response has to be confirmed by a decrease in viable tumor mass. Therefore, to identify novel drugs with activity in HCC in future and selleck inhibitor ongoing trials, modified Response Evaluation Criteria In Solid Tumors criteria have been proposed.6 FGF3/4, fibroblast growth factors 3 and 4; FGFR, FGF receptor; HCC, hepatocellular carcinoma; OS, overall survival; RCT, randomized, controlled trial; TKI, multi–tyrosin kinase inhibitor; TTP, time to progression; VEGFR, vascular endothelial growth factor receptor. Sorafenib is associated with relevant toxicities, especially in patients with compromised liver function (stage Child-Pugh B). Patients with cirrhosis suffer from fatigue, and in such patients, sorafenib may cause a rapid deterioration in quality of life. Therefore, predictive (bio)markers to guide therapy with sorafenib are urgently needed. Many clinical parameters and serum markers as well as genomic signatures have been suggested; for example, development of hypertension and diarrhea, known side effects of sorafenib, under therapy seem to be associated with a favorable outcome.

Animal procedures were conducted in accordance with French government policies (Services Vétérinaires de la Santé et de la Production Animale, Ministère de l’Agriculture). Acute liver injury was induced by a single intraperitoneal (ip) injection of CCl4 (0.5 mL/kg body weight, 1:5 dilution in MO), LEE011 concentration as in Serriere-Lanneau et al.21 Control animals received MO. When indicated, mice were treated either with respective vehicle,

IL-6 (0.5 mg/kg, subcutaneous), the CB2 agonist JWH-133 (3 mg/kg, ip), the NO donor SIN-1 (10 mg/kg, ip), or the MMP-2/MMP-9 inhibitor CTTHWGFTLC (13 mg/kg, ip), administered before CCl4 administration. No mortality was observed throughout treatments. Liver samples were taken from several lobes and either fixed in buffered formalin or snap frozen in liquid nitrogen and stored at −80°C until use. Experiments were performed on screening assay 4-9 animals/group. Two-thirds hepatectomy was performed as previously described,22 while animals were

under isoflurane anesthesia. After ventral laparotomy, the left lateral, left median, and right median lobes were ligated and excised. The removed liver specimens were weighed and snap-frozen in liquid nitrogen to serve as control. Alanine and aspartate aminotransferase activity was measured on an automated analyzer in the Biochemistry Department of Mondor Hospital. Results are the mean from 15 animals/group. Liver cells were digested by two-step collagenase perfusion. Cell suspension was centrifuged at 50 g rpm for 2 minutes. The pellet contained hepatocytes, and nonparenchymal cells were purified from the supernatant by density gradient centrifugation with 25%-50% Percoll. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed on paraffin-embedded tissue sections, using the In Situ Cell Death Detection Kit, POD (Roche). TUNEL-positive area from two to three fields (magnification ×100)/animal were quantified with ImageJ. Results are expressed as percent of total area, and were quantified from seven to eight animals/group. Immunohistochemistry was carried out on paraffin-embedded liver tissue sections as previously described.10 Immunohistochemical

detection of proliferating cell nuclear antigen (PCNA) was performed using the MOM immunodetection kit (Vector) and a mouse monoclonal selleck kinase inhibitor anti-PCNA (1/1750; Santa Cruz Biotechnology). The number of labeled hepatocytes per 2000 hepatocytes was quantified in tissue sections (magnification ×200) from 4-6 mice/group. Immunohistochemical detection of F4/80 and myeloperoxidase was performed using rat anti-mouse F4/80 (1:20; Serotec) and rabbit anti-human myeloperoxidase (1:750; Dako), respectively, followed by biotinylated secondary antibody (anti-rat, 1/50; Serotec or anti-rabbit, 1/100; Santa Cruz Biotechnology). The signal was amplified with alkaline phosphatase–conjugated streptavidin (1/20; Serotec), and revealed using the liquid permanent red chromogen system (Dako).

Animal procedures were conducted in accordance with French government policies (Services Vétérinaires de la Santé et de la Production Animale, Ministère de l’Agriculture). Acute liver injury was induced by a single intraperitoneal (ip) injection of CCl4 (0.5 mL/kg body weight, 1:5 dilution in MO), Cilomilast supplier as in Serriere-Lanneau et al.21 Control animals received MO. When indicated, mice were treated either with respective vehicle,

IL-6 (0.5 mg/kg, subcutaneous), the CB2 agonist JWH-133 (3 mg/kg, ip), the NO donor SIN-1 (10 mg/kg, ip), or the MMP-2/MMP-9 inhibitor CTTHWGFTLC (13 mg/kg, ip), administered before CCl4 administration. No mortality was observed throughout treatments. Liver samples were taken from several lobes and either fixed in buffered formalin or snap frozen in liquid nitrogen and stored at −80°C until use. Experiments were performed on LDE225 ic50 4-9 animals/group. Two-thirds hepatectomy was performed as previously described,22 while animals were

under isoflurane anesthesia. After ventral laparotomy, the left lateral, left median, and right median lobes were ligated and excised. The removed liver specimens were weighed and snap-frozen in liquid nitrogen to serve as control. Alanine and aspartate aminotransferase activity was measured on an automated analyzer in the Biochemistry Department of Mondor Hospital. Results are the mean from 15 animals/group. Liver cells were digested by two-step collagenase perfusion. Cell suspension was centrifuged at 50 g rpm for 2 minutes. The pellet contained hepatocytes, and nonparenchymal cells were purified from the supernatant by density gradient centrifugation with 25%-50% Percoll. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed on paraffin-embedded tissue sections, using the In Situ Cell Death Detection Kit, POD (Roche). TUNEL-positive area from two to three fields (magnification ×100)/animal were quantified with ImageJ. Results are expressed as percent of total area, and were quantified from seven to eight animals/group. Immunohistochemistry was carried out on paraffin-embedded liver tissue sections as previously described.10 Immunohistochemical

detection of proliferating cell nuclear antigen (PCNA) was performed using the MOM immunodetection kit (Vector) and a mouse monoclonal selleck inhibitor anti-PCNA (1/1750; Santa Cruz Biotechnology). The number of labeled hepatocytes per 2000 hepatocytes was quantified in tissue sections (magnification ×200) from 4-6 mice/group. Immunohistochemical detection of F4/80 and myeloperoxidase was performed using rat anti-mouse F4/80 (1:20; Serotec) and rabbit anti-human myeloperoxidase (1:750; Dako), respectively, followed by biotinylated secondary antibody (anti-rat, 1/50; Serotec or anti-rabbit, 1/100; Santa Cruz Biotechnology). The signal was amplified with alkaline phosphatase–conjugated streptavidin (1/20; Serotec), and revealed using the liquid permanent red chromogen system (Dako).

Animal procedures were conducted in accordance with French government policies (Services Vétérinaires de la Santé et de la Production Animale, Ministère de l’Agriculture). Acute liver injury was induced by a single intraperitoneal (ip) injection of CCl4 (0.5 mL/kg body weight, 1:5 dilution in MO), Epigenetics inhibitor as in Serriere-Lanneau et al.21 Control animals received MO. When indicated, mice were treated either with respective vehicle,

IL-6 (0.5 mg/kg, subcutaneous), the CB2 agonist JWH-133 (3 mg/kg, ip), the NO donor SIN-1 (10 mg/kg, ip), or the MMP-2/MMP-9 inhibitor CTTHWGFTLC (13 mg/kg, ip), administered before CCl4 administration. No mortality was observed throughout treatments. Liver samples were taken from several lobes and either fixed in buffered formalin or snap frozen in liquid nitrogen and stored at −80°C until use. Experiments were performed on VX-809 molecular weight 4-9 animals/group. Two-thirds hepatectomy was performed as previously described,22 while animals were

under isoflurane anesthesia. After ventral laparotomy, the left lateral, left median, and right median lobes were ligated and excised. The removed liver specimens were weighed and snap-frozen in liquid nitrogen to serve as control. Alanine and aspartate aminotransferase activity was measured on an automated analyzer in the Biochemistry Department of Mondor Hospital. Results are the mean from 15 animals/group. Liver cells were digested by two-step collagenase perfusion. Cell suspension was centrifuged at 50 g rpm for 2 minutes. The pellet contained hepatocytes, and nonparenchymal cells were purified from the supernatant by density gradient centrifugation with 25%-50% Percoll. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed on paraffin-embedded tissue sections, using the In Situ Cell Death Detection Kit, POD (Roche). TUNEL-positive area from two to three fields (magnification ×100)/animal were quantified with ImageJ. Results are expressed as percent of total area, and were quantified from seven to eight animals/group. Immunohistochemistry was carried out on paraffin-embedded liver tissue sections as previously described.10 Immunohistochemical

detection of proliferating cell nuclear antigen (PCNA) was performed using the MOM immunodetection kit (Vector) and a mouse monoclonal learn more anti-PCNA (1/1750; Santa Cruz Biotechnology). The number of labeled hepatocytes per 2000 hepatocytes was quantified in tissue sections (magnification ×200) from 4-6 mice/group. Immunohistochemical detection of F4/80 and myeloperoxidase was performed using rat anti-mouse F4/80 (1:20; Serotec) and rabbit anti-human myeloperoxidase (1:750; Dako), respectively, followed by biotinylated secondary antibody (anti-rat, 1/50; Serotec or anti-rabbit, 1/100; Santa Cruz Biotechnology). The signal was amplified with alkaline phosphatase–conjugated streptavidin (1/20; Serotec), and revealed using the liquid permanent red chromogen system (Dako).

1 Increased circulating levels of gut-derived endotoxin2 and specific sensitivity to endotoxin have been shown in cirrhosis,3 which could worsen further hepatic impairment. However, the effects of changing gut flora on liver function in patients with cirrhosis remain unclear. Treatment with synbiotics improved the Child-Pugh class as a result of significant improvements in serum bilirubin and albumin levels and in prothrombin activity.4 Additionally, probiotics reduced endotoxemia and improved the Child-Pugh score, although not significantly, in patients with compensated cirrhosis.5 Finally, treatment with paromomycin and neomycin for 3-6

months significantly improved serum albumin levels6 and the Child-Pugh score, mainly because of a decreased incidence of ascites and encephalopathy,7 respectively. Herein, we present preliminary data on the RXDX-106 ic50 effects of rifaximin, a virtually unabsorbable antibiotic with broad-spectrum buy LY2109761 antimicrobial activity and an excellent safety profile8 on endotoxemia

and liver function and disease severity in 9 liver transplant candidates with alcoholic cirrhosis (male, n = 7; mean age = 56 ± 6 years; Child-Pugh class B/C: 5/4). All patients abstained from alcohol for at least 1 year before inclusion. Plasma endotoxin levels were detected by the Limulus amebocyte lysate chromogenic learn more endpoint assay (Hycult Biotech, Uden, The Netherlands). Clinical infection, upper gastrointestinal bleeding, and use of antibiotics or prebiotics 6 weeks before or during the

study were exclusion criteria. Patients were evaluated after an 8-week observational period and after an 8-week course of rifaximin (1,200 mg/day). All measures remained unchanged during the observational period. Rifaximin significantly reduced plasma endotoxin levels, together with a significant increase in serum albumin levels and significant decreases in serum total bilirubin levels and international normalized ratio. Child-Pugh and model for end-stage liver disease scores decreased significantly after treatment (Table 1). In conclusion, intestinal decontamination by rifaximin could be a feasible, safe approach to prevent endotoxin-induced liver injury and improve liver function and disease severity in patients with decompenstaed cirrhosis. The present findings should be confirmed in a placebo-controlled trial. Georgios N. Kalambokis M.D.*, Epameinondas V. Tsianos M.D., Ph.D., F.E.B.G., A.G.A.F.*, * 1st Division of Internal Medicine and Hepato-Gastroenterology Unit University Hospital, Ioannina, Greece. “
“On April 2, 2012, Nelson Fausto, Professor and former Chairman of the Department of Pathology at Washington University School of Medicine, died at the age of 75.

1 Increased circulating levels of gut-derived endotoxin2 and specific sensitivity to endotoxin have been shown in cirrhosis,3 which could worsen further hepatic impairment. However, the effects of changing gut flora on liver function in patients with cirrhosis remain unclear. Treatment with synbiotics improved the Child-Pugh class as a result of significant improvements in serum bilirubin and albumin levels and in prothrombin activity.4 Additionally, probiotics reduced endotoxemia and improved the Child-Pugh score, although not significantly, in patients with compensated cirrhosis.5 Finally, treatment with paromomycin and neomycin for 3-6

months significantly improved serum albumin levels6 and the Child-Pugh score, mainly because of a decreased incidence of ascites and encephalopathy,7 respectively. Herein, we present preliminary data on the SAHA HDAC effects of rifaximin, a virtually unabsorbable antibiotic with broad-spectrum www.selleckchem.com/products/ink128.html antimicrobial activity and an excellent safety profile8 on endotoxemia

and liver function and disease severity in 9 liver transplant candidates with alcoholic cirrhosis (male, n = 7; mean age = 56 ± 6 years; Child-Pugh class B/C: 5/4). All patients abstained from alcohol for at least 1 year before inclusion. Plasma endotoxin levels were detected by the Limulus amebocyte lysate chromogenic selleck chemical endpoint assay (Hycult Biotech, Uden, The Netherlands). Clinical infection, upper gastrointestinal bleeding, and use of antibiotics or prebiotics 6 weeks before or during the

study were exclusion criteria. Patients were evaluated after an 8-week observational period and after an 8-week course of rifaximin (1,200 mg/day). All measures remained unchanged during the observational period. Rifaximin significantly reduced plasma endotoxin levels, together with a significant increase in serum albumin levels and significant decreases in serum total bilirubin levels and international normalized ratio. Child-Pugh and model for end-stage liver disease scores decreased significantly after treatment (Table 1). In conclusion, intestinal decontamination by rifaximin could be a feasible, safe approach to prevent endotoxin-induced liver injury and improve liver function and disease severity in patients with decompenstaed cirrhosis. The present findings should be confirmed in a placebo-controlled trial. Georgios N. Kalambokis M.D.*, Epameinondas V. Tsianos M.D., Ph.D., F.E.B.G., A.G.A.F.*, * 1st Division of Internal Medicine and Hepato-Gastroenterology Unit University Hospital, Ioannina, Greece. “
“On April 2, 2012, Nelson Fausto, Professor and former Chairman of the Department of Pathology at Washington University School of Medicine, died at the age of 75.