New management options such as prophylaxis have been introduced and new treatment choices in the form of longer acting factor concentrates are on the horizon. In the current clinical environment, inhibitor formation continues to be a major complication in the treatment of patients with haemophilia. Prevention and eradication have therefore become a major focus of clinical and scientific investigation. This supplement is based on an international haemophilia meeting held on 21 September 2013 in Barcelona, Spain, and sponsored by Grifols

S.A. The meeting brought together leading haemophilia and bleeding disorder experts from around the world to discuss advances in RG7204 in vitro inhibitor prevention and optimization of immune tolerance induction (ITI) therapy in patients with haemophilia AZD1208 A and inhibitors. The meeting consisted of three main sessions: The first session featured novel investigations which reinforce the protective role of factor VIII (FVIII)/von Willebrand factor complex in inhibitor development, with presentations by P.M. Mannucci (Milan, Italy), Q. Shi (Milwaukee, WI, USA), S. Bonanad (Valencia, Spain) and R. Klamroth (Berlin, Germany). The second session covered choice of ITI therapy for optimal management of inhibitor patients from both a clinical and pharmacoeconomic perspective, and featured discussions by J.

Oldenburg (Bonn, Germany), S. Austin (London, UK), and C. Kessler (Washington DC, USA). In the final session of the meeting, new predictive approaches for ITI management were discussed by G. Di Minno (Naples, Italy), E. Santagostino (Milan, Italy), K. Pratt (Bethesda, MD, USA) and C. Königs aminophylline (Frankfurt, Germany). These latter two contributors

presented novel investigators that assist in understanding the immunological response in ITI, a topic that has gained significance in recent years and an area that is anticipated to provide the basis for more targeted and individualized therapy in the future. The author received an honorarium from Grifols S.A. for participating in the international meeting and production of the article. The author thanks Content Ed Net for providing editorial assistance in the preparation of the article, with funding from Grifols S.A. “
“Measurement of the activity of factor VIII (FVIII:C) is a central component of haemophilia care and is used in the diagnosis of and monitoring following treatment with clotting factor concentrate or desmopressin. Although three different assays (the one and two stage clotting and chromogenic assays) have been available for many years, in practice the one-stage clotting assay predominates worldwide. The dominance of the one-stage assay is the result of the international drive for simplicity, automation and cost control.

DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1–2.6), B*5701 (PR=2.0; 95% CI = 1.0–3.1), B*5703 (PR = 1.7; 95% CI = 1.0–2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0–3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), PI3K Inhibitor Library solubility dmso whereas DRB1*0301 (PR = 0.4; 95% CI = 0.2–0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2–11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles

with HCV infection (serostatus) in women at high risk of HCV from injection drug use (N = 838), but no significant relationships were observed. Conclusion: HLA genotype influences the host capacity to clear HCV viremia. The specific HLA

associations observed in the current study are unlikely to be due to chance because they were a priori hypothesized. (HEPATOLOGY 2010.) More than 4 million women and men in the United States and 150 million people worldwide are estimated to be hepatitis C virus (HCV) seropositive.1, 2 Most of these individuals are chronically infected with the virus and are at high risk of cirrhosis, hepatocellular carcinoma, and liver-related death. The natural history of HCV infection, however, is highly variable. Some individuals do not become HCV infected despite high levels of exposure.3 Other individuals may clear HCV RNA following Nivolumab cost acute infection, and whereas some individuals with long-term HCV viremia remain clinically asymptomatic, others have progressive disease.4 Indeed, marked variability in natural history is seen even among groups of individuals with single-source exposure to HCV, as occurred in a population of Irish women exposed to HCV-contaminated anti-D immune globulin.5 Together these observations suggest that host factors, particularly host immune response, play a key role in the regulation of HCV pathogenesis. Human leukocyte antigen (HLA) genes are critical to the regulation of both cellular and innate immunity and are among the most polymorphic in the human genome.

HLA genes are clustered together on the short arm of chromosome 6 and encode HLA molecules that form stable complexes when bound to foreign peptides. These complexes are presented on cell surfaces where they are recognized Urease and bound by T cells initiating a cascade of immune responses capable of clearing foreign material. The diversity of HLA variants, or alleles, is a critical factor in the ability of HLA to bind a wide variety of antigens and for the immune system to respond to a wide variety of pathogens. Several strong associations between HLA alleles and infectious agents have been reported and recent genome-wide association studies of HIV disease progression have provided further evidence of the importance of HLA polymorphism in host control of viral infections.

21 (95% CI = 1.66-10.7),

P = 0.0024], portal fibrosis [grade > 2; HR = 14.1 (95% CI = 5.47-36.5), P < .0001], and pericellular fibrosis [grade > 2; HR = 4.86 (95% CI = 1.73-13.7), P = 0.0027] on the liver biopsy samples were all associated with LRM. Additionally, histologic documentation of advanced fibrosis grade ≥ 2 [HR = 20.4 (95% CI = 5.9-70.5), P < 0.0001] or any cirrhosis [HR = 10.6 (95% CI = 4.19-26.7), P < 0.0001] was also associated with LRM. In these univariate analyses, the grades of steatosis and lobular inflammation were not associated with LRM. buy Sunitinib Using multivariate analyses, we further tested these pathologic features as independent predictors of LRM. As a result, using these binary parameters in the Cox proportional hazards model, we found that portal fibrosis graded as ≥3 (with the current study’s fibrosis grading, this included all patients with bridging fibrosis and cirrhosis) remained independently associated with LRM [aHR = 5.68 (95% CI = 1.50-21.45)]. Similarly, when we tested pathologic features graded with NAS, advanced fibrosis (stage 4) was independently associated with LRM [aHR = 5.62 (95% CI = 1.92-6.46)]. The LRM survival curves for individuals with different grades of fibrosis graded according ABT-263 to the current study’s criteria (Fig. 1A) and the NAS criteria (Fig. 1B) are shown. This is the first study providing the interprotocol agreement and predictability

values for LRM of four sets of pathologic criteria for diagnosing NASH. This study used a well-defined cohort of NAFLD patients for whom clinical data, liver biopsy slides, and long-term mortality data were available. We have confirmed the findings of previous studies2, 6-18 reporting that, regardless of the specific pathologic criteria for

NASH, patients with a histologic diagnosis of NASH have higher LRM. Our study is the first study to assess interprotocol agreement between different pathologic criteria for NASH. Our data show that diagnoses of NASH by the original criteria for NAFLD subtypes15 and diagnoses of NASH by the current study’s NASH criteria18 were in almost perfect agreement. On the other hand, diagnoses of NASH made by NAS threshold of17 showed only moderate agreement with diagnoses of NASH made by the other pathologic criteria for NASH. Nevertheless, NAS threshold of 5 returned an almost 100% positive predictive value for NASH as a cause OSBPL9 of liver-related death. However, this NAS threshold, missed every third NAFLD patient who would ultimately die of liver-related causes, whereas the other NASH pathologic criteria used in this study successfully predicted 90% to 100% of cases dying from liver-related causes. These findings are consistent with the conclusions of a recent article by the authors of NAS that discusses the role of NAS thresholds.21 In fact, our data indicate that a NAS value ≥5 seems to be a strict criterion that could potentially lead to underdiagnosis of NAFLD in patients who will ultimately die of liver-related causes.

Liver steatosis is strongly associated with poor graft function after liver transplantation. Liver with more than 40–50% macrosteatosis should not be used. However, at present the quantity of fatty livers lack accepted standards. The computerized image analysis programs should be used to automate the determination of fat content in liver biopsy specimens. Liver grafts from anti-HBc positive donors can be safely used, preferentially in hepatitis B surface antigen (HBsAg) positive or anti-HBc/anti-HBs positive recipients. HCV positive allografts free from fibrosis or severe inflammation are a safe option for HCV positive recipients. The procurement team should consider liver biopsy to evaluate

these HCV positive allografts. Donor serum sodium over 150 mm may predict a higher rate of graft primary non-functions. Recently, however, some investigators reported the sodium level likely has little Fluorouracil cell line clinical impact on post-transplant liver function. The incidence of hepatic artery variations has been reported to be approximately

Selleckchem RG7204 30%. To avoid injuries, it is very important to know and identify these variations with precision at the time of organ procurement. THE SUCCESSFUL RESULTS of liver transplantation (LT) have been followed by an increased number of patients on waiting lists. Organ shortage is a major problem in LT. The current era of organ shortage has promoted attempts to expand the donor pool, including the use of expanded criteria donors (ECD). ECD are currently defined as tumor, drug abuse, meningitis, hepatitis B or C, donor age greater than 65 years, intensive care unit stay greater than 7 days, high body mass index, steatosis, hypernatremia and high levels of liver enzymes or bilirubin. If any of these parameters apply, a donor is considered an ECD.[1] Use of ECD is an alternative to overcome the organ shortage. However, patients receiving ECD are at higher risk of impaired

graft function or increased early mortality after LT.[2] Therefore, to assess the quality of an organ is of critical importance for the outcome of the transplantations. In order to predict outcome after LT, Feng et al.[3] developed a quantitative donor risk index (DRI). They used data from adult deceased donor liver transplants in the USA to identify factors associated PJ34 HCl with allograft failure. The original report identified that seven donor characteristics – including donor age (>40 years), donation after cardiac death, split/partial grafts, African-American race, less height, cerebrovascular accident and “other” causes of brain death, and cold ischemic time – were significantly associated with liver allograft failure. As the DRI increased from the baseline risk index group (0.0–1.0) to the highest risk index group listed (2.0), the frequency that the graft would be discarded was significantly higher, rising from 3.1% to 12.5%. After that, several studies have been performed by using risk models based on donor and transplant factors.

METHODS: Patients who achieved SVR in

two NIAID open-label, phase 2 clinical trials of treatment with sofosbuvir/ ribavirin for 24 weeks (n=38), sofosbuvir/ledipasvir for 12 weeks (n=20), sofosbuvir/ledipasvir + GS-9669 for 6 weeks (n=19) or sofosbuvir/ledipasvir + GS-9451 for 6 weeks (n=19) were followed. HCV viral loads were measured with find more Abbott M2000 RealTime HCV assay with a limit of quantification of <12 IU/mL. RESULTS: Ninety-six patients with chronic hepatitis C genotype 1 infection [F/M: 36/60; GT-1A/1B: 68/28; median age: 55 years (range: 21-79 years); IL28B genotype CC/(CT/TT): 18/78; Black race/other races: 82/14; Fibrosis stage pre-treatment 3-4/0-2: 22/74] achieving SVR after IFN-free DAA therapy were followed for a median of 8.3 (0 to 22.6) months. No cases of late relapses were observed. All 96 patients

have maintained HCV viral loads at <12 IU/ mL beyond SVR 12 in follow up (Table 1). At the time of the follow up period, ALT, AST, and bilirubin levels remained normal in 96%, 91%, and 99% respectively. CONCLUSIONS: This study suggests that HCV eradication after IFN-free DAA therapy remains durable in long-term follow up. Follow up liver biopsies may be indicated to demonstrate whether prolonged SVR will lead to reversal of liver fibrosis. Table 1: Durability of response SVR in weeks Disclosures: The following people have nothing to disclose: Sara Jones, Miriam Marti, Zayani Sims, Anita Kohli, Sarah Kattakuzhy, Tess L. Petersen, Rachel Silk, Michael A. Polis, Henry Masur, Shyam Kottilil, Anu Osinusi Purpose: Interferon (IFN) can exacerbate underlying depression or bipolar disease; check details thus, many patients with this history are poor candidates for IFN-based therapies. Adults with chronic GT1 hepatitis C virus infection, including those with compensated cirrhosis, achieved SVR12 rates of 90%-100% in phase 3 trials of the interferon-free

3D regimen of ABT-450 (dosed with ritonavir, ABT-450/r), ombitasvir (ABT-267), and dasabuvir (ABT-333) with or without ribavirin (RBV). We evaluated safety and efficacy of 3D ±RBV in patients with a history of depression G protein-coupled receptor kinase or bipolar disorder (DEP/BPD). Methods: In phase 3 trials, treatment-naïve or -experienced cirrhotic and non-cirrhotic patients received at least one dose of 3D ±RBV (co-formulated ombitasvir/ABT- 450/r, 25mg/150mg/100mg once daily, dasabuvir 250mg twice daily, ± weight-based RBV.) SVR12 rates, incidence of adverse events (AEs) and treatment discontinuation due to AE were determined for patients with and without a history of DEP/BPD at enrollment. Results: A greater percentage of patients with a history of DEP/BPD (357/2052, 17.4%) were female and treatment-experienced versus those without history of DEP/BPD. SVR12 rates were similar for both subgroups (>94.5%); virologic failure occurred in 1 (0.4%) patient with DEP/BPD history. The incidence of any AEs was higher for patients with DEP/BPD history compared to patients without DEP/BPO history; most AEs were mild.

GW4064 was provided by the University of Kansas (Kansas City, KS). Other reagents, unless mentioned, were obtained from Sigma-Aldrich (St. Louis, MO). Whole body (WB) Fxr knockout (KO) mice (Fxr WB KO) were reported on and were on a pure C57BL/6J genetic Dabrafenib molecular weight background.16, 17 The generation of tissue-specific Fxr KO mice on a mixed genetic background has been described previously using loxP/Cre technology with specific disruption of the Nr1h4 gene in hepatocytes (Fxr Liv KO) or in enterocytes (Fxr Int KO).18 Specifically, Fxr Liv KO and Fxr Int KO mice were generated by cross-breeding Fxr floxed/floxed mice with albumin cre (+) or villin cre (+) mice. But, these mice were on a mixed genetic background with variable

basal expression of bile-acid synthetic genes. So, in the current study, congenic Fxr Liv KO and Fxr Int KO mice in the C57BL/6J genetic background were produced. Shp KO mice and hepatocyte-specific Shp transgenic (Tg) mice (albumin promoter derived, Shp Tg) have been reported on.19, 20 Fxr WB KO mice with hepatocyte-specific Shp overexpression (Fxr WB KO/Shp Tg) were generated by crossing Fxr RO4929097 supplier WB KO mice with Shp Tg mice, with all three strains on the pure C57BL/6J genetic background. Fgfr4 KO mice on a mixed C57/129SvJ background were provided by Dr. Curtis Klaassen (University of Kansas Medical Center). Fgfr4/Shp double-KO (Fgfr4/Shp DKO) mice were generated

by cross-breeding Fgfr4 KO and Shp KO mice. Egr1 KO mice on a C57BL/6 genetic background were obtained from Taconic (Hudson, NY). C57BL/6J mice bred in the same animal

facility were used as wild-type (WT) controls for KO mice on the C57BL/6J background. If KO mice were on a mixed genetic background (Fgfr4 KO and Fgfr4/Shp DKO), littermates were used as controls. Mice were bred and maintained in the laboratory animal research facility at the University of Kansas Medical Center in rooms under a 12-hour light-dark cycle. All protocols were approved by the institutional animal care and use committee. All experiments used 10-16-week-old male mice, and all mice were sacrificed within a 30-minute period in the morning. In addition, all treatments were repeated twice. The activation of Fxr in vivo was achieved by treatment with an Fxr synthetic PRKD3 agonist (GW4064) at 150 mg/kg. GW4064 or vehicle was administered by oral gavage at 6 p.m., followed by a second administration at 8 a.m. the next morning. Two hours later, the liver and ileum were harvested. The generation of purified Fgf15 has been reported on previously.15 Fgf15 protein was injected into mice through the tail vein at a dosage of 10 μg/kg. Two hours or at indicated time points (for time-course study) after injection, livers were collected. Total bile-acid pool size was determined by measuring bile acids of the small intestine, gallbladder, liver, and their contents. Ten 16-week-old mice were fed a chow diet with 2% cholestyramine for 10 days.

T cell–derived MPs may give rise to their exploitation as

novel diagnostic markers and potential antifibrotic agents. LX-2 HSCs were kindly donated by Scott L. Friedman. We thank Gunda Millonig (Beth Israel Deaconess Medical Center) and Veronika Lukacs-Kornek (Dana-Farber Cancer Institute) for help with initial FACS experiments and Franck Grall (Beth Israel Deaconess Medical Idasanutlin Center) for help with mass spectroscopy. Additional Supporting Information may be found in the online version of this article. “
“Acetaminophen (APAP) is one of the most commonly used drugs for treating pain and fever. Although it is safe at therapeutic dosage levels, overdose of APAP causes severe liver injury (APAP-induced liver injury; AILI), with the potential to progress to liver failure. Up to 40% of patients who suffer from liver failure will die (or undergo liver transplant).1 Data combined from 22 specialty medical centers in the United States revealed that AILI accounts for approximately half of acute liver failure cases and results in more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths each year.1 AILI, APAP-induced liver injury; APAP, acetaminophen; ATP, adenosine triphosphate; DAMP, damage-associated molecular pattern; FPR1, formyl peptide receptor 1; IL, interleukin; mtDNA, mitrochondrial

DNA; NAPQI, N-acetyl-p-benzoquinone Ulixertinib imine; TLR-9, Toll-like receptor 9. APAP hepatotoxicity is initiated by the generation of a chemically reactive metabolite (N-acetyl-p-benzoquinone imine; NAPQI). NAPQI depletes liver glutathione and covalently binds to cellular proteins, thereby causing mitochondrial dysfunction.2-6 Studies using rodent models in the last four decades have Tenofovir demonstrated that mitochondrial disruption is the key underlying mechanism of AILI (Fig. 1FIG1)). Covalent binding to mitrochondrial

proteins by NAPQI causes oxidative stress and mitochondrial membrane permeability transition pore opening, which triggers the collapse of membrane potential, cessation of adenosine triphosphate (ATP) production, and the release of apoptosis-inducing factor and endonuclease G.7-11 Together, the mitochondrial dysfunction, energy crisis, and nuclear DNA damage result in hepatocyte necrosis. In recent years, there has been a growing interest to investigate whether downstream events of early hepatocyte necrosis contribute to the aggravation and progression of AILI. Necrotic cells release a number of damage-associated molecular pattern (DAMP) molecules, such as high-mobility group box-1, heat-shock proteins, hyaluronan, fibronectin, cardiolipin, and DNA fragments. Upon activation by DAMP molecules, innate immune cells infiltrate the damaged area and release cytokines and cheomokines, thereby causing tissue sterile inflammation.12-22 The soluble products of innate immune cells can exacerbate tissue damage, as well as promote wound healing (Fig. 1).

Methods:  The subjects were selected from an epidemiological survey in the Guangdong province of southern China. In each polymorphism study, 50–117 subjects who met the diagnostic criteria of NAFLD and had typical clinical and ultrasonographic findings were placed into the case group. Using a nested case–control design, the same numbers of matched people without NAFLD were included as controls. Single nucleotide polymorphisms (SNP) at nine positions in seven candidate genes were tested. These SNP were found to be associated with

the pathogenesis of metabolic syndrome. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. Polymerase chain reaction–restriction fragment length polymorphism was applied to detect SNP. Results:  Most candidate genes’ SNP were associated

with susceptibility Metformin cell line to NAFLD. Some showed positive relationships (increased risk): tumor necrosis factor-α-238, adiponectin-45, leptin-2548, peroxisome proliferator-activated receptors-161 and phosphatidyletha-nolamine N-methyltransferase-175. Other SNP demonstrated a negative association (decreased risk): adiponectin-276 and hepatic lipase-514. Only two were not associated: selleck chemicals tumor necrosis factor-α-380 and peroxisome proliferator-activated receptors-γ co-activator-1α-482. Conclusion:  Most candidate genes’ SNP examined in metabolic syndrome patients were associated with susceptibility to NAFLD. Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome with fatty deformation of hepatic parenchymal cells as the pathological feature. It refers to a spectrum of histological findings ranging from simple steatosis, to steatohepatitis (NASH) and to NASH-related cirrhosis. The latter can develop into hepatocellular carcinoma (HCC). NAFLD represents the hepatic manifestation of metabolic syndrome, which is characterized by obesity, type 2 diabetes mellitus, dyslipidemia and hypertension with insulin resistance (IR) as the main mechanisms. Histology remains the gold standard for the diagnosis of NAFLD. In practice, however, the diagnosis is usually made by Fludarabine chemical structure clinical and ultrasonographic (US) findings after ruling out

other liver diseases, in particular alcoholic liver disease.1,2 NAFLD has become a common problem both in developed and developing countries. It is estimated that the prevalence of NAFLD ranges from 3% to 24%, with most countries’ prevalence between 6% and 14%.3,4 In recent years, due to alterations of lifestyle and dietary habits, the incidence of NAFLD has increased dramatically in China.5 In our previous survey in Guangdong, a southern province of China, we found a prevalence of 15% in the population.6 Studies suggest that both environmental and genetic factors are required for the development and progression of NAFLD. The pathogenesis of NAFLD remains unclear. A so-called ‘two-hit’ model has been proposed for the development of NAFLD.

pylori eradication therapy could reduce the incidence of metachronous gastric cancers after endoscopic resection for early gastric cancer [29]. In this study, no difference was noted in the incidence of metachronous gastric tumors between gastric tumor patients in group A’ and non-A.

Although group A is generally regarded as low-risk group for gastric cancer, patients in group A’ may have a high risk of subsequent gastric tumor development. Because we clarified that most of the gastric tumor patients in group A were those with previous H. pylori infection, this result may indicate that H. pylori eradication therapy cannot always reduce the incidence of gastric tumor. Many of patients in group A’ had severe atrophic gastritis. Therefore, the incidence of gastric tumor in group A’ http://www.selleckchem.com/products/BIBW2992.html might be relatively high. Patients with a history of gastric tumors have

a high risk of subsequent gastric tumor development [8, 29] and evaluating cancer risk using ABC system is not suitable for these patients. Use of the ABC system to classify people into low-, intermediate-, and high-risk groups for gastric cancer is very effective, but U0126 clinical trial the inclusion of high-risk individuals as well as patients after H. pylori eradication therapy in group A is a key problem. To resolve this problem, new methods such as the discriminant function using serum markers for identifying patients are needed. No author has conflicts of interest or financial arrangements that could potentially influence the described research. Competing interests: the authors have no competing interests. “
“Recent studies have shown that patients with inflammatory bowel disease (IBD) are less likely to be infected with Helicobacter pylori compared with non-IBD patients. We aimed to study the prevalence of H. pylori-positive and H. pylori-negative gastritis in newly diagnosed children with IBD in comparison to those with non-IBD in Greece. All children who underwent first esophagogastroduodenal endoscopy between 2002 and 2011 were retrospectively Cepharanthine included. Four groups were studied: patients with Crohn’s disease (CD), ulcerative colitis (UC), IBD unclassified (IBDU), and non-IBD individuals (non-IBD).

Helicobacter pylori infection was defined by positive culture or by positive histology and CLO test. Those children with negative or not available culture and only one positive test (histology or CLO) were further evaluated by urea breath test, and the positives were also included in the infected group. We studied 159 patients with IBD (66 CD, 34 UC, and 59 IBDU) and 1209 patients in non-IBD individuals. Helicobacter pylori gastritis was less frequent in the IBD group (3.8% vs 13.2% in the control group, p < .001), whereas IBD patients were significantly older than non-IBD children (p < .001). Children with H. pylori-negative gastritis were 3.3 times more likely to belong in the IBD group compared with H. pylori-positive patients (p = .006). Occurrence of H.

Further studies which precise and determine the molecular mechanism involved in the regulation of TH development and drug therapy in order to design therapeutic options that become applicable to improve the prognostic in these patients. Disclosures: The following people have nothing to disclose: Jorge A. López-Velázquez, Varenka J. Barbero-Becerra,

Vicente Sánchez- Valle, Ylse Gutiérrez-Grobe, Norberto C. Chavez-Tapia, José M. Ramírez-Jaramillo, Fredy Chablé-Montero, Misael N. Uribe-Esquivel, Nahum Méndez-Sanchéz “
“We used concanavalin A (Con A)-induced liver injury to study the role of galectin-3 (Gal-3) in the induction of inflammatory pathology and hepatocellular damage. We tested susceptibility to Con A–induced hepatitis in galectin-3-deficient (Gal-3−/−) mice and analyzed the effects of pretreatment with a selective inhibitor of Gal-3 (TD139) in wild-type (WT) C57BL/6 mice, as evaluated by a liver enzyme test, quantitative histology, mononuclear cell (MNC) infiltration, cytokine production, intracellular staining of immune

cells, and percentage of apoptotic MNCs in the liver. Gal-3−/− mice were less sensitive to Con A–induced hepatitis and had a significantly lower number of activated lymphoid and dendritic cells (DCs) in the liver. The level of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin (IL)-17 and -4 in the Sirolimus manufacturer sera and the number of TNFα-, IFNγ-, and IL-17- and -4-producing cluster of differentiation (CD)4+ cells as well as IL-12-producing CD11c+ DCs were lower, whereas the number of IL-10-producing CD4+ T cells and F4/80+ macrophages were significantly higher in livers of Gal-3−/− mice. Significantly higher percentages of late apoptotic Annexin V+ propidium-idodide+ liver-infiltrating MNCs and splenocytes were observed in Gal-3−/− mice, compared to WT mice. Pretreatment of WT C57BL/6 mice with TD139 led to the attenuation of liver injury and milder infiltration of IFNγ- and IL-17- and -4-producing CD4+ T cells, as well as an increase in the total number of IL-10-producing CD4+ T cells

and F4/80+ CD206+ alternatively activated macrophages and prevented the apoptosis of liver-infiltrating MNCs. Conclusions: Gal-3 plays an important proinflammatory role in Con A–induced hepatitis by promoting the activation of T lymphocytes and natural killer T cells, maturation of DCs, secretion of proinflammatory cytokines, down-regulation of M2 macrophage polarization, and apoptosis of MNCs in the liver. (HEPATOLOGY 2012;55:1954–1964) Concanavalin A (Con A)-induced liver injury is a well-established murine model of LEE011 chemical structure T-cell-mediated hepatitis. Intravenous (IV) injection of Con A induces acute liver injury and systemic immune activation in mice that resembles the pathology of immune-mediated hepatitis in humans.1 Activated T cells have a critical role in Con A–induced liver damage.