DCA is formed after bacterial 7 alpha dehydroxylation of CA in the colon and is a potent natural TGR5 agonist20, 21 and a ligand activating FXR.22-24 Using mouse 3T3 cells as adipocytes, the authors could further demonstrate

that both TGR5 and FXR activation was able to induce adiponectin expression. However, it must be kept in mind that the presence of FXR in adipose tissue may be questionable25 and that in addition to adipocytes also inflammatory cells could significantly contribute to TGR5 expression within fat.21 Since TGR5 and FXR have different affinities selleck chemical for DCA, the absolute serum concentrations would have been of interest in order to estimate which receptor may be most likely involved. Moreover, the possibility to activate TGR5 and FXR in vivo by specific ligands

and using specific knockout mice should help to decipher in the near future which receptor plays a key role in regulation of adiponectin expression. Whether such agonists regulate adiponectin in humans could be addressed in ongoing and future clinical trials with FXR and TGR5 activators. On the other hand, it is important to consider that high adiponectin levels are associated with increased cardiovascular mortality despite improved inflammatory, atherogenic, and insulin-sensitizing effects,26 which might result from adiponectin BGB324 purchase resistance.27 It is known that DCA represses

endogenous BA synthesis MCE公司 by way of Cyp7a1, but without suppressing cholesterol synthesis, in contrast to CDCA.28 Increased hepatic cholesterol synthesis promotes progression of NAFLD.29 Therefore, a DCA increase in patients with advanced burnt-out NASH might also contribute to deterioration of the liver condition by failing to repress the endogenous cholesterol synthesis (Fig. 1). In addition, a high fat diet is known to increase DCA levels in mouse, which in turn increases the intestinal permeability and thus propagates inflammation.30 It is therefore possible that a fat-enriched diet in human favors ectopic fat storage in the liver and DCA formation, which then keeps endogenous cholesterol synthesis at a high level and promotes intestinal leakage by enhancing bacterial translocation promoting inflammation and fatty liver development. The identification of DCA as an important BA in NASH patients in the current study could also indicate a potential role of the gut flora. In the gut, FXR maintains epithelial barrier integrity by induction of multiple genes involved in intestinal mucosal defense against inflammation and microbes, which, together with direct antibacterial detergent actions, help to control the gut microbiota.

DCA is formed after bacterial 7 alpha dehydroxylation of CA in the colon and is a potent natural TGR5 agonist20, 21 and a ligand activating FXR.22-24 Using mouse 3T3 cells as adipocytes, the authors could further demonstrate

that both TGR5 and FXR activation was able to induce adiponectin expression. However, it must be kept in mind that the presence of FXR in adipose tissue may be questionable25 and that in addition to adipocytes also inflammatory cells could significantly contribute to TGR5 expression within fat.21 Since TGR5 and FXR have different affinities Belnacasan for DCA, the absolute serum concentrations would have been of interest in order to estimate which receptor may be most likely involved. Moreover, the possibility to activate TGR5 and FXR in vivo by specific ligands

and using specific knockout mice should help to decipher in the near future which receptor plays a key role in regulation of adiponectin expression. Whether such agonists regulate adiponectin in humans could be addressed in ongoing and future clinical trials with FXR and TGR5 activators. On the other hand, it is important to consider that high adiponectin levels are associated with increased cardiovascular mortality despite improved inflammatory, atherogenic, and insulin-sensitizing effects,26 which might result from adiponectin MK-8669 clinical trial resistance.27 It is known that DCA represses

endogenous BA synthesis 上海皓元 by way of Cyp7a1, but without suppressing cholesterol synthesis, in contrast to CDCA.28 Increased hepatic cholesterol synthesis promotes progression of NAFLD.29 Therefore, a DCA increase in patients with advanced burnt-out NASH might also contribute to deterioration of the liver condition by failing to repress the endogenous cholesterol synthesis (Fig. 1). In addition, a high fat diet is known to increase DCA levels in mouse, which in turn increases the intestinal permeability and thus propagates inflammation.30 It is therefore possible that a fat-enriched diet in human favors ectopic fat storage in the liver and DCA formation, which then keeps endogenous cholesterol synthesis at a high level and promotes intestinal leakage by enhancing bacterial translocation promoting inflammation and fatty liver development. The identification of DCA as an important BA in NASH patients in the current study could also indicate a potential role of the gut flora. In the gut, FXR maintains epithelial barrier integrity by induction of multiple genes involved in intestinal mucosal defense against inflammation and microbes, which, together with direct antibacterial detergent actions, help to control the gut microbiota.

We thank Maria Bond for technical assistance with manuscript preparation. Additional Supporting Information may be found in the online version of this article. “
“Systemic inflammation and susceptibility to developing sepsis is common in acute liver failure (ALF) resulting in tissue damage and http://www.selleckchem.com/products/ink128.html organ failure. This study characterized the function of circulating neutrophils in 25 patients with ALF and subacute liver failure (SALF). ALF (n = 15) / SALF (n = 10) patients were prospectively studied and compared with 11 healthy (HC) and 6 septic controls (SC). Neutrophils were isolated on admission to intensive care

and every 3-4 days until death / liver transplantation / recovery. Neutrophil phenotype was determined using fluorochrome-labeled antibodies to CD16 and CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) was determined using fluorescein isothiocyanate-labeled opsonized Escherichia coli and oxidative burst (OB) was determined by the percentage of neutrophils producing reactive oxygen species (ROS) at rest and after stimulation with opsonized E. coli. Physiological variables, biochemistry, arterial ammonia, microbiology, and outcomes were collected. Plasma pro- and antiinflammatory DNA Damage inhibitor cytokine profiles were performed by enzyme-linked immunosorbent assay. Neutrophil

expression of CD16 which recognizes the FcγRIII region of immunoglobulin G was significantly reduced in the ALF cohort (P < 0.001) on day 1 compared to HC. 上海皓元医药股份有限公司 NPA was significantly impaired in the SALF cohort compared to HC (P < 0.01). Impaired NPA in the ALF and SALF cohorts on admission predicted nonsurvival without liver transplantation (P = 0.01). Spontaneous neutrophil production of ROS was not significantly increased in any of the cohorts. E. coli-stimulated OB was preserved in ALF/SALF cohorts but was significantly impaired in the SC group (P < 0.05). Conclusion: Circulating neutrophils in ALF/SALF have impaired bacteriocidal function similar

to that seen in severe sepsis. Neutrophil function indices are important biomarkers in ALF and may be implicated in the development of organ dysfunction and the increased susceptibility to developing sepsis. (HEPATOLOGY 2013) Acute liver failure (ALF) is a rare but frequently catastrophic consequence of an acute primary hepatic injury arising from a wide variety of insults. It is characterized by coagulopathy and encephalopathy, with a variable dynamic of progression to multiple organ dysfunction syndrome (MODS) and death.1 Liver transplantation (LT) remains the only curative option for advanced ALF with poor prognostic criteria and contributes to ∼10% of LT in the Western world.2 Neutrophils are a major innate immune cell subset involved in the first line of defense against infection.

When the cut-off was lowered and set at Al=1.0, anti-HCV Core reactivity increased up to 8.6% (18/210) including 6/65 (9.2%) patients with virological markers of occult HCV infection. Conclusions: The anti-HCV Core High Sensitivity® ELISA shows an enhanced sensitivity among dialysis patients at risk of occult HCV infection compared with commercial anti-HCV screening assays. Anti-HCV Core testing shows diagnostic usefulness in the management of the dialysis setting because identifies potentially infectious cases without serological

or virological markers of HCV infection. Disclosures: The following people Acalabrutinib order have nothing to disclose: Juan A. Quiroga, Guillermina Barril, Dolores Arenas, Mario Espinosa, Nuria Garcia Fernandez, Secundino Cigarran, Jose Herrero, Gloria del Peso, Pilar Caro, Rebeca Garcia, Yesica Amezquita, Ana Blanco, Pilar Martinez, Jose M. Alcazar, Emilio González-Parra, Jose C. Dίaz-Bailón, Adoración Martin, Inmaculada Castillo, Javier Bartolomé, Vicente Carreno Objective: Insulin resistance (IR) increases during the early stages of hepatitis C virus (HCV)-related chronic liver disease and is a sign of poor

MG-132 cost prognosis as well as a risk factor for hepatic fibrosis and hepatocellular carcinoma. In liver cirrhosis (LC) patients, the levels of branched-chain amino acids (BCAAs) decrease, whereas levels of aromatic amino acids such as tyrosine (Tyr) and phenylalanine increase. In addition, serum Tyr level has been founded to predict occurrence of diabetes mellitus. However, no clinical studies have examined the relationship between serum Tyr levels and IR in HCV-related chronic liver disease. We aimed to determine the factors affecting IR in HCVrelated chronic liver disease. Patients and Method: We retrospectively examined 71 patients with HCV-related chronic liver disease (chronic hepatitis, 31; LC, 40) and analyzed various parameters, including amino acids, as possible predictors of IR. IR was assessed using the homeostatic model assessment of IR (HOMA-IR). Amino acids were assayed as BCAAs, Tyr level, and

the ratio of BCAAs to Tyr level (BTR). Results: There was a significant correlation between HOMA-IR and body mass index (r = 0.40); platelet count (r = -0.29); BTR (r = -0.46, P = 0.0001); prothrombin time (r = -0.36); and levels of hemoglobin (r = -0.26), total bilirubin MCE公司 (r = 0.38), total protein (r = 0.25), albumin (r = -0.53), total cholesterol (r = -0.32), fasting glucose (r = 0.35), and Tyr (r = 0.55, P < 0.0001). However, BCAAs were not significantly correlated with HOMA-IR (r =0.21, P = 0.082). In multivariate analysis, total cholesterol (odds ratio [OR], 6.511; [95% confidence interval (95% Cl), 1.554-27.284; P = 0.010]) and Tyr level (OR, 4.839; 95% Cl, 1.087-21.549; P = 0. 039) were identified as independent parameters contributing to a HOMA-IR of >2.5. Conclusions: Serum Tyr level may be a biomarker of IR in patients with HCVrelated chronic liver disease.

54 It could be a consequence of altered blood-brain barrier, decreased expression

of LEPRb, or decreased LEPRb signaling via Jak-2-Stat3 due to an imbalance between expression of negative regulators of leptin sensitivity (suppressors of cytokine signaling [SOCS] proteins, protein tyrosine phosphatase 1B [PTP1B] and SH domain phoshatase 2), and of cellular adaptor molecules, such as SH2B1, which facilitates leptin signaling (Fig. 3).54 Another possibility has recently come to light—requirement of Bardet-Biedl proteins for LEPR signaling, inferring a possible BMN673 role of receptor scaffold assembly on neuronal primary cilia.55 Neurons express a primary cilium, on which is assembled a range of receptors involved in development (e.g. Hedgehog), neurohormonal regulation (somatostatin receptor 3) and appetite (melanin-concentrating hormone receptor 1 [MC-1R], and LEPRb).55–59 KU-57788 clinical trial Primary cilia are found on many cells, but not hepatocytes. They may act as sensory

‘cell antennae’, coordinating inter-cellular communications via receptor clustering and signalling.56–58 Bardet-Biedl syndrome (BBS) is the archetypical example of a ciliopathy with profound appetite dysregulation.59 Like children with leptin deficiency or LEPRb mutations,50–53 BBS children are unable to resist the drive to eat, becoming massively obese at an early age, and about half develop T2D and metabolic syndrome.59,60 Multiple mutations of the BBS gene have been described;55,59 in mice, at least four genotypes are associated with defective LEPRb signaling.55,59 Another childhood obesity syndrome that may be ascribed to a ciliopathy is Alström syndrome.61,62 In addition to their respective specific features (skeletal, retinal, renal and hepatobiliary fibrocystic abnormalities, hearing defects and male infertility), BBS and Alström syndrome are both associated with hyperphagic obesity, early onset of insulin resistance, T2D and (best described for Alström syndrome) severe fatty liver disease leading to cirrhosis.63 An animal model of Alström syndrome,

上海皓元 the foz/foz mouse (which carries a mutation of the gene for basal body protein, Alms1), develops NAFLD.64 Further, environmental factors affect expression of liver pathology, so that mice fed chow develop only steatosis, whereas those fed a high fat diet develop NASH with fibrosis.64,65 An additional exciting finding is that pre-adipocytes also express primary cilia,66,67 and these play a role in their capacity to differentiate and form triglyceride-storing adipocytes and secrete adiponectin. Further studies should explore whether the problem of restricted adipose expansion in metabolic syndrome and NASH (discussed later) could actually be due to innate properties of pre-adipocytes/adipocyte differentiation rather than ‘adipose exhaustion’.

54 It could be a consequence of altered blood-brain barrier, decreased expression

of LEPRb, or decreased LEPRb signaling via Jak-2-Stat3 due to an imbalance between expression of negative regulators of leptin sensitivity (suppressors of cytokine signaling [SOCS] proteins, protein tyrosine phosphatase 1B [PTP1B] and SH domain phoshatase 2), and of cellular adaptor molecules, such as SH2B1, which facilitates leptin signaling (Fig. 3).54 Another possibility has recently come to light—requirement of Bardet-Biedl proteins for LEPR signaling, inferring a possible this website role of receptor scaffold assembly on neuronal primary cilia.55 Neurons express a primary cilium, on which is assembled a range of receptors involved in development (e.g. Hedgehog), neurohormonal regulation (somatostatin receptor 3) and appetite (melanin-concentrating hormone receptor 1 [MC-1R], and LEPRb).55–59 Ivacaftor molecular weight Primary cilia are found on many cells, but not hepatocytes. They may act as sensory

‘cell antennae’, coordinating inter-cellular communications via receptor clustering and signalling.56–58 Bardet-Biedl syndrome (BBS) is the archetypical example of a ciliopathy with profound appetite dysregulation.59 Like children with leptin deficiency or LEPRb mutations,50–53 BBS children are unable to resist the drive to eat, becoming massively obese at an early age, and about half develop T2D and metabolic syndrome.59,60 Multiple mutations of the BBS gene have been described;55,59 in mice, at least four genotypes are associated with defective LEPRb signaling.55,59 Another childhood obesity syndrome that may be ascribed to a ciliopathy is Alström syndrome.61,62 In addition to their respective specific features (skeletal, retinal, renal and hepatobiliary fibrocystic abnormalities, hearing defects and male infertility), BBS and Alström syndrome are both associated with hyperphagic obesity, early onset of insulin resistance, T2D and (best described for Alström syndrome) severe fatty liver disease leading to cirrhosis.63 An animal model of Alström syndrome,

medchemexpress the foz/foz mouse (which carries a mutation of the gene for basal body protein, Alms1), develops NAFLD.64 Further, environmental factors affect expression of liver pathology, so that mice fed chow develop only steatosis, whereas those fed a high fat diet develop NASH with fibrosis.64,65 An additional exciting finding is that pre-adipocytes also express primary cilia,66,67 and these play a role in their capacity to differentiate and form triglyceride-storing adipocytes and secrete adiponectin. Further studies should explore whether the problem of restricted adipose expansion in metabolic syndrome and NASH (discussed later) could actually be due to innate properties of pre-adipocytes/adipocyte differentiation rather than ‘adipose exhaustion’.

54 It could be a consequence of altered blood-brain barrier, decreased expression

of LEPRb, or decreased LEPRb signaling via Jak-2-Stat3 due to an imbalance between expression of negative regulators of leptin sensitivity (suppressors of cytokine signaling [SOCS] proteins, protein tyrosine phosphatase 1B [PTP1B] and SH domain phoshatase 2), and of cellular adaptor molecules, such as SH2B1, which facilitates leptin signaling (Fig. 3).54 Another possibility has recently come to light—requirement of Bardet-Biedl proteins for LEPR signaling, inferring a possible BYL719 mouse role of receptor scaffold assembly on neuronal primary cilia.55 Neurons express a primary cilium, on which is assembled a range of receptors involved in development (e.g. Hedgehog), neurohormonal regulation (somatostatin receptor 3) and appetite (melanin-concentrating hormone receptor 1 [MC-1R], and LEPRb).55–59 Wnt inhibitor Primary cilia are found on many cells, but not hepatocytes. They may act as sensory

‘cell antennae’, coordinating inter-cellular communications via receptor clustering and signalling.56–58 Bardet-Biedl syndrome (BBS) is the archetypical example of a ciliopathy with profound appetite dysregulation.59 Like children with leptin deficiency or LEPRb mutations,50–53 BBS children are unable to resist the drive to eat, becoming massively obese at an early age, and about half develop T2D and metabolic syndrome.59,60 Multiple mutations of the BBS gene have been described;55,59 in mice, at least four genotypes are associated with defective LEPRb signaling.55,59 Another childhood obesity syndrome that may be ascribed to a ciliopathy is Alström syndrome.61,62 In addition to their respective specific features (skeletal, retinal, renal and hepatobiliary fibrocystic abnormalities, hearing defects and male infertility), BBS and Alström syndrome are both associated with hyperphagic obesity, early onset of insulin resistance, T2D and (best described for Alström syndrome) severe fatty liver disease leading to cirrhosis.63 An animal model of Alström syndrome,

上海皓元医药股份有限公司 the foz/foz mouse (which carries a mutation of the gene for basal body protein, Alms1), develops NAFLD.64 Further, environmental factors affect expression of liver pathology, so that mice fed chow develop only steatosis, whereas those fed a high fat diet develop NASH with fibrosis.64,65 An additional exciting finding is that pre-adipocytes also express primary cilia,66,67 and these play a role in their capacity to differentiate and form triglyceride-storing adipocytes and secrete adiponectin. Further studies should explore whether the problem of restricted adipose expansion in metabolic syndrome and NASH (discussed later) could actually be due to innate properties of pre-adipocytes/adipocyte differentiation rather than ‘adipose exhaustion’.

In adults with chronic GT1 hepatitis C virus (HCV) infection, similar SVR12 rates (97.1% vs. 95.9%) were observed in patients >65 vs. <65 years of age in phase 3 trials of co-formulated ABT-450/r/ombitasvir and dasabuvir

(3D regimen) with or without ribavirin (RBV). We evaluated safety in patients >65 years of age across phase 2 and 3 trials of 3D±RBV. Methods: HCV GT1 infected treatment-naïve, treatment-experienced, cirrhotic and non-cirrhotic patients were enrolled in phase 3 trials (SAP- PHIRE-I or -II, PEARL-II, -III, or -IV, TURQUOISE-II) or phase 2 (AVIATOR, M14-103) trials of 3D±RBV and received at least one dose of study drug at the following or higher dosages: ABT-450 150mg once daily, ritonavir 100mg once daily, selleck chemicals ombitasvir 25mg QD, and dasabuvir 250mg twice daily, with or without weight-based RBV. Patients from placebo groups in the SAPPHIRE trials were also

included. The incidence of treatment-emergent adverse events (AEs) and treatment discontinuation rates was this website determined for patients <65 and ≥65 years of age. Results: In the active treatment groups, there were 214 patients who were ≥65 year old at the time of treatment initiation; 49 (22.9%) had compensated cirrhosis compared with 331 (13.7%) of the <65 group. There was no significant

interaction between treatment and age across the frequent safety outcomes, regardless of inclusion of RBV (Table), with the exception of higher rates of anemia and RBV dose modification in the elderly group compared with the younger group. The overall rate of discontinuation due to an AE was low for patients in both age categories receiving active drug; placebo results are also provided. Conclusions: The interferon-free combination of ABT-450/ombitasvir and medchemexpress dasabuvir with or without ribavirin was safe and effective in patients ≥65 years of age, including those with cirrhosis. Disclosures: Steven L. Flamm – Advisory Committees or Review Panels: Gilead, Bristol Myers Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and Teaching: Salix Edward J. Gane – Advisory Committees or Review Panels: Novira, AbbVie, Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag Jean-Francois J.

In adults with chronic GT1 hepatitis C virus (HCV) infection, similar SVR12 rates (97.1% vs. 95.9%) were observed in patients >65 vs. <65 years of age in phase 3 trials of co-formulated ABT-450/r/ombitasvir and dasabuvir

(3D regimen) with or without ribavirin (RBV). We evaluated safety in patients >65 years of age across phase 2 and 3 trials of 3D±RBV. Methods: HCV GT1 infected treatment-naïve, treatment-experienced, cirrhotic and non-cirrhotic patients were enrolled in phase 3 trials (SAP- PHIRE-I or -II, PEARL-II, -III, or -IV, TURQUOISE-II) or phase 2 (AVIATOR, M14-103) trials of 3D±RBV and received at least one dose of study drug at the following or higher dosages: ABT-450 150mg once daily, ritonavir 100mg once daily, PLX-4720 concentration ombitasvir 25mg QD, and dasabuvir 250mg twice daily, with or without weight-based RBV. Patients from placebo groups in the SAPPHIRE trials were also

included. The incidence of treatment-emergent adverse events (AEs) and treatment discontinuation rates was www.selleckchem.com/products/pf-562271.html determined for patients <65 and ≥65 years of age. Results: In the active treatment groups, there were 214 patients who were ≥65 year old at the time of treatment initiation; 49 (22.9%) had compensated cirrhosis compared with 331 (13.7%) of the <65 group. There was no significant

interaction between treatment and age across the frequent safety outcomes, regardless of inclusion of RBV (Table), with the exception of higher rates of anemia and RBV dose modification in the elderly group compared with the younger group. The overall rate of discontinuation due to an AE was low for patients in both age categories receiving active drug; placebo results are also provided. Conclusions: The interferon-free combination of ABT-450/ombitasvir and MCE dasabuvir with or without ribavirin was safe and effective in patients ≥65 years of age, including those with cirrhosis. Disclosures: Steven L. Flamm – Advisory Committees or Review Panels: Gilead, Bristol Myers Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and Teaching: Salix Edward J. Gane – Advisory Committees or Review Panels: Novira, AbbVie, Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag Jean-Francois J.

In adults with chronic GT1 hepatitis C virus (HCV) infection, similar SVR12 rates (97.1% vs. 95.9%) were observed in patients >65 vs. <65 years of age in phase 3 trials of co-formulated ABT-450/r/ombitasvir and dasabuvir

(3D regimen) with or without ribavirin (RBV). We evaluated safety in patients >65 years of age across phase 2 and 3 trials of 3D±RBV. Methods: HCV GT1 infected treatment-naïve, treatment-experienced, cirrhotic and non-cirrhotic patients were enrolled in phase 3 trials (SAP- PHIRE-I or -II, PEARL-II, -III, or -IV, TURQUOISE-II) or phase 2 (AVIATOR, M14-103) trials of 3D±RBV and received at least one dose of study drug at the following or higher dosages: ABT-450 150mg once daily, ritonavir 100mg once daily, selleck products ombitasvir 25mg QD, and dasabuvir 250mg twice daily, with or without weight-based RBV. Patients from placebo groups in the SAPPHIRE trials were also

included. The incidence of treatment-emergent adverse events (AEs) and treatment discontinuation rates was CHIR-99021 supplier determined for patients <65 and ≥65 years of age. Results: In the active treatment groups, there were 214 patients who were ≥65 year old at the time of treatment initiation; 49 (22.9%) had compensated cirrhosis compared with 331 (13.7%) of the <65 group. There was no significant

interaction between treatment and age across the frequent safety outcomes, regardless of inclusion of RBV (Table), with the exception of higher rates of anemia and RBV dose modification in the elderly group compared with the younger group. The overall rate of discontinuation due to an AE was low for patients in both age categories receiving active drug; placebo results are also provided. Conclusions: The interferon-free combination of ABT-450/ombitasvir and medchemexpress dasabuvir with or without ribavirin was safe and effective in patients ≥65 years of age, including those with cirrhosis. Disclosures: Steven L. Flamm – Advisory Committees or Review Panels: Gilead, Bristol Myers Squibb, AbbVie, Janssen, Salix; Consulting: Merck, Janseen, Bristol Myers Squibb, AbbVie, Salix, Gilead; Grant/Research Support: Janssen, Bristol Myers Squibb, Merck, Vertex, Gilead, AbbVie, Boehringer Ingelheim; Speaking and Teaching: Salix Edward J. Gane – Advisory Committees or Review Panels: Novira, AbbVie, Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-nix; Speaking and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag Jean-Francois J.