6 to 6.0 [23]. Hu et al. reported that CD8+ depleted PBMCs from four non-inhibitor haemophilic subjects proliferated when stimulated by FVIII or by several A2 domain peptides [25]. Reding et al. did not consistently observe proliferation of T cells from non-inhibitor haemophilic subjects in response to A3 domain peptides [26], while C2 domain peptides spanning FVIII residues 2190–2210 and 2291–2330 elicited proliferation in some subjects with and without haemophilia or inhibitors [27]. We cloned T cells from an individual with haemophilia A but no clinically

significant inhibitor (IV-2); these clones retained their antigen specificity for FVIII2194–2213 presented click here by DR0101, as demonstrated by both tetramer binding and proliferation assays. The SI values for proliferation assays utilizing six of these T-cell clones were highly significant, ranging between 62 and 248 at a low peptide concentration of 0.1 μm. To our knowledge, this study is the first to demonstrate conclusively an HLA-DR-restricted

T-cell response, validated by isolation of relevant epitope-specific T-cell clones, to a FVIII epitope in a haemophilia A subject without a clinically significant inhibitor. We isolated FVIII-responsive T cells from two haemophilia A subjects who did not have a clinically significant inhibitor, one of whom NVP-LDE225 cell line had received infusions of wild-type FVIII to achieve haemostasis. T cells from these subjects may well have different immune characteristics compared to those

from subjects with an established antibody response to FVIII. A recent study demonstrated that cytokine production by FVIII-stimulated polyclonal CD4+ T cells differs between healthy subjects, haemophilia A subjects without inhibitors, and haemophilia A subjects with inhibitors [39]. T cells from haemophilia A subjects with inhibitors produced higher levels of IFN-γ and IL-4, whereas T cells from controls and haemophilia A subjects without inhibitors secreted higher levels of TGF-β Clomifene but did not produce IL-4. We are utilizing the T-cell clones isolated from the A2201P missense substitution subjects, which are restricted by the same HLA-DR-FVIII peptide complex, to investigate additional features of T-cell immune responses to FVIII, including cytokine secretion and T-cell receptor variations. As noted above, T-cell responses to the haemophilic peptide differed in these individuals. Their T cells may also have different thresholds of responsiveness to haemophilic and/or wild-type peptides. DRB1 proteins corresponding to the second allele (DRB1*1503) of inhibitor subject IV-1 were not available, but his brother’s second allele was DRB1*0401. This subject, IV-2, did not have DR0401-restricted T cells that recognized FVIII C2 domain peptides, although he did have a pronounced DR0101-restricted T-cell response to one of these FVIII peptides.

Herein, we report, for the first time, the discovery of β-D-2′-C-methyl-4-N-hydroxycytidine

phosphoramidate nucleotides as non-toxic anti-HCV agents that upon intracellular metabolism deliver multiple nucleoside inhibitor 5′-triphosphates (NI-TP). Anti-infection Compound Library price Methods: A variety of β-D-2′-C-methyl-4-N-OH-C prodrugs were synthesized and evaluated for: 1) inhibition of HCV viral replication in Huh7 replicon cells; 2) cytotoxicity in various cell lines; 3) cellular pharmacology in both Huh7 cells and primary human hepatocytes; and 4) IC50 values for three NI-TPs were determined against the HCV NS5B polymerase (Pol). Results: The β-D-2′-C-methyl-4-N-OH-C prodrugs were pan-genotypic, effective against various HCV resistant mutants and resistant variants could not be selected in a Huh7 based replicon system. Upon cellular entry, β-D-2′-C-methyl-4-N-OH-C prodrugs were metabolized to generate three distinct NI-TPs: 2′-C-methyl-CTP, 2′-C-methyl-UTP and 2′-C-methyl-4-N-OH-CTP. The two former NI-TPs are well characterized for their anti-HCV activity, but interestingly, we found that 2′-C-methyl-4-N-OH-CTP

can be incorporated both as a cytidine and uridine analog with HCV pol. We also established that 2′-C-methyl-4-N-OH- CTP was able to effectively inhibit RNA polymerization when pre-incubated with purified HCV pol, but was outcompeted when co-incubated with natural CTP and UTP substrates. Conclusion: The discovery of these novel β-D-2′-C-methyl-4-N-OH-C prodrugs could have learn more important clinical implications based on their unique ability to deliver a cascade of three active pan-ge-notypic NI-TPs intracellularly with distinctive incorporation profiles and high barrier to resistance. Disclosures: Raymond F. Schinazi – Board Membership: RFS Pharma, LLC; Stock Shareholder: RFS Pharma, LLC Tony Whitaker – Employment: RFS Pharma, LLC Tami R. McBrayer – Employment: RFS Pharma Steven J. Coats – Employment: RFS Pharma The following people have nothing to disclose: Franck Amblard, Sijia Tao, Maryam Ehteshami, Sheida Amiralaei, Hao Li, Jadd Shelton Background A once

daily fixed-dose combination tablet (FDC) of NS5A inhibitor ledipasvir (LDV) 90 mg and NS5B inhibitor sofosbuvir Bacterial neuraminidase (SOF) 400 mg is being developed for the treatment of chronic HCV infection. Methods The drug-drug interaction (DDI) profile of FDC has been characterized using in vitro data, Phase 1 DDI results in healthy subjects and Phase 2/3 population pharmacokinetic (popPK) analyses in HCV-in-fected patients. The Phase 1 program evaluated DDIs between FDC or components, and HIV antiretrovirals (ARVs), oral contraceptives (OCs), acid-reducing agents, immunosuppressants (IST), opiates and rifampin (RIF). The effect of anticoagulants, selective serotonin reuptake inhibitors (SSRIs), calcium channel blockers (CCB), statins and diuretics on FDC PK was assessed by popPK analyses.

16, 17 Heinrichs et al. demonstrated that MIF causes an increase in AMPK phosphorylation in vitro, although this effect is weaker than

that of metformin. Thus, these findings indicate that the antifibrotic function of MIF in the liver might be mediated by the CD74/AMPK pathway in HSCs, whereas the proinflammatory action of MIF has been attributed to leukocyte recruitment processes via MIF/CXCR2 or MIF/CXCR4 in atherogenic, arthritic, and other murine models of inflammation.18, 19 The beneficial antifibrotic effect of MIF in a mouse model of liver fibrosis demonstrated in this study by Heinrichs et al.10 suggests that MIF is a novel target for treatment of chronic liver disease. Concomitant treatment of WT mice with recombinant MIF (rMIF) and CCl4 resulted in the attenuation of both HSC activation and the expression of fibrosis-associated genes. These therapeutic effects of MIF based on activating AMPK, which has a proven Selleckchem Panobinostat beneficial action on liver glucose and lipid metabolism,17 may have

an additional rationale in their antifibrogenic properties. Regarding the experimental approaches performed by Heinrichs et al., some questions still need to be answered. Because the authors investigated the role of MIF in two models of liver fibrosis using Mif−/− mice, investigating whether the expression of Mif in WT mice was altered when treated with TAA or CCl4 would be crucial to our understanding; a decrease in the expression of Mif would support the subsequent results of this BMN 673 manufacturer study. In addition, the phosphorylation of AMPK was shown to be induced by rMIF in HSCs isolated from untreated Mif−/− mice; thus, the activation status of AMPK should be determined in HSCs isolated DOK2 from the liver of TAA- or CCl4-treated Mif−/− mice. With regard to the in vitro experiments in which MIF inhibited PDGF-induced HSC migration and proliferation via the CD74/AMPK pathway, it is not clear why MIF alone did not modify these functions of HSCs, given that primary HSCs from Mif-deficient mice were used. The authors speculate that these MIF-mediated effects only occur under energy-consuming conditions. In fact,

it was reported that a common polymorphism in the human MIF promoter containing 5, 6, 7, or 8 CATT tetra-nucleotide repeat units has functional differences with respect to MIF secretion and cellular AMPK activation; furthermore, human fibroblasts with the “5 CATT” polymorphism exhibit diminished MIF release and AMPK activation during hypoxia.20 It would be appropriate to investigate further the presence of this polymorphism in the immortalized murine HSCs used in this study and to determine the subsequent effects of this polymorphism, if any. In conclusion, this study sheds light upon the novel mechanism of MIF signaling in liver fibrosis. MIF, which is believed to be a pleiotropic inflammatory cytokine, was shown for the first time to have antifibrotic properties in the liver.

Conclusions:  Complications selleck chemical are rare during EUS-guided drainage of PFC and can be managed successfully in most patients. “
“Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional

regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in Dasatinib clinical trial the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models. (HEPATOLOGY 2012;) The liver has a unique anatomical and functional niche in the body that profoundly affects its physiology and pathophysiology, including its oxygen homeostasis. Afferent blood flow to the liver derives from both highly oxygenated blood in the hepatic artery

as well as oxygen-depleted blood in the hepatic portal vein. Furthermore, the directional flow of mixed oxygenated and deoxygenated blood toward the central vein of the hepatic lobule creates a physiological oxygen gradient.1 This gradient has been reported to result in oxygen tensions from about 60-65 mmHg in periportal blood, falling to about 30-35 mmHg in perivenous portions

of the liver parenchyma; by comparison, physiological arterial oxygen concentration in most other body tissues is about 74-104 mmHg, and venous oxygen concentration is 34-46 mmHg.1 Hypoxia has profound consequences for tissues of an aerobic organism. In recent decades, our knowledge of the homeostatic response to hypoxia has increased to molecular genetic mechanisms. The hypoxia inducible factors (HIFs) are a family of heterodimeric Dichloromethane dehalogenase transcription factors that act as master regulators of a homeostatic transcriptional response to hypoxia in virtually all cells and tissues. Active HIF consists of an alpha subunit and a beta subunit. Three alpha subunits, termed HIF1α, HIF2α, and HIF3α, have been described in humans, mice, and rats; all bind to a common β subunit named, alternatively, HIF1β, or the aryl-hydrocarbon-nuclear receptor translocator [ARNT].2 Active HIF is termed by its (1)alpha subunit; hence, HIF1 is the active transcription factor consisting of HIF1α and ARNT, HIF2 is the dimer of HIF2α and ARNT, etc. HIF1 and HIF2 are the major hypoxia-inducible factors in humans, mice, and rats. Far less is known about the function of HIF3.2 Posttranslational degradation by the proteasome is a major pathway of HIF regulation.

Papillary dilation using large-bored (12–20 mm) balloon dilation catheter was performed through the percutaneous transhepatic route. We analyzed the efficacy of the stone retrieval and post-procedure complications after the procedure. Results: The success rate for the complete duct clearance was 100%. There was no patient who needs use of basket to remove the stone buy Staurosporine after PPLBD. Electrohydraulic lithotripsy was required in 2 (18.2%) patients. The median time to complete stone removal after PPLBD was 17.8 minutes. There was no any complications

occurred after PPLBD. Asymptomatic hyperamylasemia did not occur in all patients. Conclusion: The current data suggested that PPLBD is safe and effective for removal of large CBD stones. Keywords: Balloon Dilation, Choledocholithiasis N MAQBOUL,1 S GUPTA1,2 1Princess Alexandra Hospital, Brisbane, Australia, 2The Wesley Hospital, Brisbane, Australia Introduction: EUS plays an important role in the characterisation of gastro-intestinal and pancreatic lesions. EUS/FNA allows real-time sampling with minimal risk of complications. The Echotip Procore 25-gauge (Cook Medical) is a novel needle designed to obtain tissue for both cytology and histology, potentially increasing diagnostic yield with fewer needle passes. Methods: A retrospective review of all EUS performed between June 2012 and May 2013 at two tertiary referral academic

centres in Brisbane, Australia. All PF-02341066 purchase EUS were carried out by a single endoscopist. EUS/FNA procedures utilising the Echotip Procore 25-gauge needle were included for analysis. A positive result was defined GBA3 as adequate cellular yield and cytology concordant with the predicted diagnosis at the time of EUS. Assessment of tissue for histology was not routinely performed. Results: A total of 82 EUS/FNA were performed using the Echotip Procore 25-gauge needle in 49 males and 33 females. Indication for EUS/FNA was further characterisation of a pancreatic mass (67.1% of cases), gastric/duodenal lesions (13.4%), mediastinal masses/lymphadenopathy/lung

lesions (13.4%), liver lesions (4.9%) and evaluation of a rectal lesion (1.2%). On-site cytopathology service was utilised when available. Positive results were obtained in 72 of the 82 cases (87.8%); one was a second procedure in a patient with an initial negative result. Negative, or non-diagnostic, results were seen in 10 of the 82 cases (12.2%). The mean number of passes in the positive group was 3.40, compared with 3.60 in the negative group. There were no immediate complications with this technique. Conclusion: Our initial experience utilising the Echotip Procore 25-gauge needle resulted in high diagnostic yield with very few passes, and low complication rates. Given the higher cost associated with this needle in Australia, a randomised trial comparing yield against the standard 25-gauge needle would be needed to determine cost-effectiveness.

1A) and spotted necrosis (Supporting Fig. 1) in wild-type (WT) C57BL/6 mice by 16 hours postinjection. However, to our surprise, α-Galcer induced 5- to 6-fold higher serum ALT and AST levels and a larger area of necrosis in IL-4−/−IFN-γ−/− dKO mice than those in WT mice at 16 hours after α-Galcer injection (Fig. 1; Supporting Fig. 1). In addition, administration of α-Galcer induced an accumulation of inflammatory foci in the livers of BMS-907351 datasheet WT mice, with the peak effect occurring

at 72 hours postinjection (Supporting Fig. 1), and the number of inflammatory foci was also much higher in dKO mice than that in WT mice (Supporting Fig. 1). To determine the role of early production of IL-4 in α-Galcer-induced liver injury, we examined the effects in IL-4−/− and IL-4R−/− Z VAD FMK mice. As illustrated in Fig. 2A,B, α-Galcer-induced elevation of serum ALT and AST was lower in IL-4−/− and

IL-4R−/− mice than in WT controls. Liver histology analyses further revealed that IL-4−/− and IL-4R−/− mice had reduced liver necrosis and fewer inflammatory foci than WT control mice after α-Galcer administration (Figs. 2C-D). The number of myeloperoxidase (MPO)-positive neutrophils was also lower in IL-4−/− and IL-4R−/− mice than in WT mice 72 hours after α-Galcer administration (Fig. 2C,D). The above findings indicated that the number of inflammatory foci (iNKT expansion) in the liver was lower in IL-4−/− or IL-4R−/− mice than in WT mice 72 hours post-α-Galcer injection, which may have been due to IL-4-mediated promotion of iNKT proliferation, Mannose-binding protein-associated serine protease as demonstrated previously.[17] Fluorescence-activated cell sorting (FACS) analyses of liver MNCs revealed that WT and IL-4−/− mice had a similar number of iNKT cells at the early timepoints post-α-Galcer injection (data not shown), which does not explain the reduced liver injury in IL-4−/− mice. To further explore the mechanisms underlying α-Galcer-induced liver injury, we examined NK cells and neutrophils in the liver. In this case, FACS analyses revealed that the number of NK cells was not increased post-α-Galcer injection and that depletion of NK cells using an anti-ASGM1

antibody did not affect α-Galcer-induced liver injury in mice (data not shown), suggesting that NK cells are not involved in this process. In contrast, there was a striking increase in the percentage and total number of neutrophils in the liver after α-Galcer injection. As illustrated in Fig. 3A,B, the percentage of neutrophils was elevated 4-fold, whereas the total number of neutrophils was elevated 30-fold at 3 hours post-α-Galcer administration. Moreover, depletion of neutrophils markedly reduced serum ALT and AST levels (Fig. 3C), suggesting that the accumulation of neutrophils contributes to α-Galcer-induced hepatocellular damage. Figure 3D shows that the percentage and total number of hepatic neutrophils were lower in IL-4−/− mice than in WT mice at 3 hours post-α-Galcer administration. Furthermore, Fig.

(HEPATOLOGY 2011;) Hepatitis C virus (HCV) infects over 3% of the population, causing severe liver disease. Current therapy comprising pegylated interferon (IFN) and ribavirin (Rib) is inadequate, which, combined with high cost and poor patient compliance, has driven the demand for new virus-specific drugs.1 Future standard of care will replace IFN/Rib with combinations of specific inhibitors, such as seen for human immunodeficiency virus (HIV) therapy. However, extensive HCV variability raises concerns 3-deazaneplanocin A nmr over the ability of relatively few compounds to suppress resistance. Thus, great effort focuses on expanding the repertoire of HCV drug targets, expedited by the availability

of the Japanese fulminant hepatitis clone 1 (JFH-1) infectious isolate.2 HCV is the prototype member of the Hepacivirus genus within the Flaviviridae.3

It is enveloped and possesses a positive-sense single-stranded RNA genome of ∼9.6 kb. An internal ribosome entry site in the 5′ untranslated region drives translation selleck chemical of a polyprotein that is cleaved into 10 mature products. The core and envelope glycoproteins with the RNA genome comprise the virion, whereas nonstructural (NS) proteins modulate host metabolism and replication of the viral RNA. JFH-1 has permitted the study of particle production, and it has become clear that, in addition to canonical virion components, other viral proteins are required.4-13 HCV p7 forms a cation channel in vitro,14-16 and both deletions and point mutations markedly reduce the production of infectious virions in culture.4, 5 It is comprised of two trans-membrane domains separated by a cytosolic loop and forms both hexameric and heptameric complexes.14, 17, 18 We have recently shown that p7 acts as a proton channel within infected cells, which is directly required for the production PD184352 (CI-1040) of infectious virions.19 p7 is required for HCV to replicate in chimpanzees20 and small molecules block both channel function in vitro and virion production in culture, rendering it an attractive antiviral target.21, 22 Skepticism concerning

p7 inhibitors heralds from trials where p7 inhibitor monotherapy, or combinations with IFN/Rib failed to significantly improve responses.23 However, evidence from meta-analyses24, 25 and patient virus loads at early time points26, 27 supports a specific antiviral effect, and selection of specific nonsynonymous mutations occurs within patient isolate p7 sequences.28, 29 Because HCV displays genotype (GT)-dependent p7 inhibitor sensitivity,21 changes in amino acid sequence could interfere with the binding of drug molecules, making it likely that the emergence of resistant quasispecies accounts for trial outcomes. Here, we identify p7 resistance mutations specific to adamantane and IS drugs, indicative of a genuine antiviral effect that supports their inclusion in future combination therapies.

Third, risk of NAFL is undoubtedly associated with obesity and metabolic syndrome and has been traditionally associated with more affluent living standards. In the current study too, even

nonobese subjects with NAFL had worse metabolic parameters and higher income than their age-matched and sex-matched counterparts who did not have NAFL. Nevertheless, coexistence of intrauterine and neonatal malnutrition and c-Met inhibitor the development of obesity, type 2 diabetes, and related comorbidities have been confirmed in a number of studies in humans and animal models.2 Moreover, it has been shown that, in humans, the intrahepatic lipid content increase following starvation also may be due to reduced apolipoprotein B-100 production and hepatic lipid export, and/or impaired mitochondrial function;

this could have implications for exacerbations of steatohepatitis that is sometimes seen with rapid weight loss, anorexia nervosa, and parenteral nutrition.3 Therefore, in contrast to the popular view, malnutrition rather than obesity at different stages of life may well be an explanation for pathogenesis of NAFL in this predominantly poor population. Sujoy Maitra M.D., MRCP Dr.*, * Consultant Hepatologist, Columbia Small molecule library Asia Hospital Calcutta, India. “
“Background and Aim:  The aim of this study was to evaluate endoscopic band ligation plus argon plasma coagulation versus scleroligation. Methods:  Patients were randomized to: Group I, 50 patients subjected to endoscopic injection sclerotherapy; Group II, 50 patients subjected to variceal band ligation; Group III, 50 patients subjected to combined endoscopic sclerotherapy and band ligation; and Group IV, 50 patients

subjected to endoscopic band ligation plus argon plasma coagulation. Results:  A comparison of the number of therapeutic sessions showed that group III underwent significantly fewer sessions. As regards post-treatment complications, Group I showed a high incidence Ureohydrolase of transient pyrexia, transient dysphagia and/or retrosternal pain and ulceration, while in group II a higher incidence of rebleeding was demonstrated, as well as a higher incidence of esophageal varix recurrence after eradication during the follow-up period. A higher mortality incidence was detected in groups I and II. The follow-up incidence did not significantly differ between the different study groups. Conclusion:  Scleroligation allows very rapid eradication of varices, has a low recurrence rate, avoids the disadvantage of high recurrence of band ligation alone, and does not require special skills over sclerotherapy or band ligation. Also, band ligation plus argon plasma coagulation allows for very rapid eradication of varices, and a low recurrence rate, with no obvious recorded complications, but it has the disadvantage of being the most expensive technique and requires special equipment that is only available in a few endoscopic centers.

41%) were H. pylori positive. The prevalence reached a peak at the age of 30–39 years (90.82%). There was significant difference between sexes and women had a higher infection rate than men. The prevalence of

H. pylori infection was also associated with eating kipper food and fried food. No association between H. pylori prevalence and smoking or drinking was found. Compared to healthy individuals, people with dyspeptic diseases (peptic ulcer, gastroenteritis) click here presented a high prevalence of H. pylori infection. Using multivariate logistic regression analysis, age, history of peptic ulcer and gastroenteritis were the independent predictors for H. pylori infection. Conclusion: Yangzhong country, a persistent high risk area of gastric carcinoma, had a high prevalence of H. pylori infection and was related to several risk factors. The underlying mechanisms are needed to be further investigated. Key Word(s): 1. Helicobacter pylori; 2. risk factor; 3. Jiangsu province; 4. gastric cancer; Presenting Author: YIN ZHU Additional Authors: HONGSHENG WANG, YAN SUN, MING YAN, JUNGSOO JOO, JIAFANG SUN, WEIPING CHEN, CHENFENG QI, NONGHUA LV, HERBERTCARPENTER Paclitaxel manufacturer MORSE, III, WILLIAMG COLEMAN, JR Corresponding Author: HERBERTCARPENTER MORSE, III,, WILLIAMG COLEMAN, JR Affiliations: National Institutes of Health, NIDDK; the First Aiilated Hospital of NanChang Univerisity, the Department of

Gastroenterology; National Institutes of Health, NIAID; the First Affiliated Hosptial of Nanchang University,

the Department of Gastroenterology Objective: Interferon Regulatory Factor 8 (IRF8) is a transcription factor Avelestat (AZD9668) of the interferon regulatory factor (IRF) family and has many functions involved in the regulation of development, growth and host defense in hematopoietic lineage cells including innate and adaptive immune responses. However, expression and function of IRF8 in non-hematopoietic cells remain poorly understood. Methods: We used microarray analysis to monitor host responses to Helicobacter pylori (H. pylori) infection. The expression of IRF8 was detected by quantitative PCR and western blot in the gastric epithelial cell line (GSM06) and macrophage cell line (RAW264.7) infected by H. pylori. We generated an IRF8-EGFP fusion protein reporter mice (IRF8-EGFP mice) to monitor IRF8 expression during H. pylori infection using immunofluorescence and qPCR. Results: The results of microarray analysis showed that the IRF8 gene was up-regulated (fold changes > 2, p < 0.0001). Both IRF8 mRNA expression and IRF8 protein level increased in GSM06 and RAW264.7 after infected by H. pylori. The protein of IRF8 expressed in gastric epithelial cells from IRF8-EGFP mouse stomach, mostly localized in the nucleus. The fluorescence of IRF8 increased on gastric epithelial cells with the extension of H. pylori infection. IRF8 mRNA expression of stomach tissues increased significantly in IRF8-EGFP mice infected by H. pylori, compared with wild type control mice (p < 0.05).

Thus, there is a significant unmet need in terms of effective available treatments and this unmet need may be overcome by adopting alternate therapeutic strategies such as (1) employing different agents to improve insulin resistance (e.g., GLP-1 agonists) and oxidative stress (betaine, SAMe); (2) exploring agents affecting different targets such as apoptosis (e.g., GS 9450) and FXR (e.g., obeticholic acid), or stellate cell activation (losartan); or (3) investigating a combination buy PD-0332991 of agents affecting different targets/pathways. In this issue of HEPATOLOGY, Harrison’s

group6 report the results of their randomized controlled trial that investigated two different combination therapies to treat NASH. Angiotensin II receptors have been identified on hepatic stellate cells (HSC) and their activation leads Alisertib cell line to HSC proliferation. Angiotensin II receptor knockout

mice when challenged with carbon-tetrachloride had significantly reduced hepatic fibrosis when compared to wildtype mice, suggesting angiotensin receptor II is a novel target to improve hepatic fibrosis.7 Losartan, an angiotensin II receptor blocker (ARB), has been shown in mice models to have beneficial effects on liver fibrosis,8, 9 and in a small study consisting of seven patients with NASH, Yokohama et al.10 suggested that losartan may improve necroinflammation and fibrosis. Torres et al.6 randomized 137 subjects with biopsy-proven NASH to a 48-week course of rosiglitazone

4 mg twice daily alone, or in combination with either metformin 500 mg twice daily or losartan 50 mg daily. The primary endpoint was change in hepatic histology as evidenced by at least one point improvement in steatosis, inflammation, and fibrosis. Steatosis, inflammation, and oxyclozanide fibrosis improved between baseline and the end of treatment within each treatment arm, but the changes in liver histology were statistically not different between the three treatment groups.6 Randomized controlled trials of NASH with histological endpoints are expensive and difficult to conduct, and thus Harrison’s group must be applauded for undertaking this study and for their other important contributions to the field. However, we suggest caution in interpreting the results of this study because of some of its limitations. This study was prematurely stopped due to severe restrictions imposed by the Food and Drug Administration on rosiglitazone use in the United States, leading to an underpowered sample size. The presence of fibrosis was not a prerequisite at baseline and yet its improvement was required to achieve the primary outcome.