38 Thus, a CAC score of zero is associated with a very low risk

38 Thus, a CAC score of zero is associated with a very low risk

of subsequent coronary events,38, 39 whereas an elevated CAC score is related to a stepwise increase in the risk of subsequent coronary events.11, 38 CAC scores have been shown to be highly predictive of future cardiovascular events independent of traditional risk AUY-922 chemical structure factors.11, 40, 41 Thus, in this study, we used the CAC score as an outcome variable to predict future coronary heart disease in individuals with NAFLD. Currently, three published papers address the relationship between NAFLD and CAC. But, these results conflict with each other. As part of the Diabetes Heart Study, McKimmie et al.42 suggested that hepatic steatosis is less likely to be a direct mediator of cardiovascular disease and may be described as an epiphenomenon. The preponderance of diabetes (82.8%) and the nature of the Diabetes Heart Study as a family study, however, may limit the generalizability of these BMS-777607 ic50 results. On the contrary, Chen et al.43 reported a significant relationship between NAFLD and CAC in Taiwan, but the possibility of selection bias was raised because of the exclusion of a large number of subjects without hepatic imaging. Jung et al.44 also suggested that hepatic steatosis and increased ALT are associated with CAC. They used less stringent

criteria to define ALT elevation for women and only a single cutoff point of CAC (>100). Importantly, Beta adrenergic receptor kinase two studies did not include VAT data in multivariate analysis. Although the pathogeneses that relate NAFLD and coronary artery disease

have not been thoroughly investigated, several possible explanations have been offered. A low-grade systemic and hepatic inflammatory milieu may link NAFLD to atherosclerosis, which increases the risk of coronary artery disease.45, 46 In NAFLD, reactive oxygen radicals may induce the production of cytokines, such as tumor necrosis factor-α and interleukin-6,47 and add further atherogenic stimuli to the already high oxidative and proinflammatory status that is closely related to metabolic syndrome.48, 49 In addition, such conditions favor the up-regulation of hepatic C-reactive protein levels, which may link NAFLD to coronary atherosclerosis.45, 50 Furthermore, subjects with NAFLD have reduced serum adiponectin levels, which are inversely related to the severity of NAFLD histology.3, 51 Low serum adiponectin levels may also play an important role in the pathogenesis between NAFLD and subclinical coronary atherosclerosis. The strengths of our study are the use of CAC scores, CT-measured VAT, with a high degree of validity and reproducibility, high-quality data collected by trained personnel with a systematic protocol, a wealth of metabolic variables, and a large number of subjects. In addition, we simultaneously measured CAC, hepatic ultrasonography, and VAT on the same day.

38 Thus, a CAC score of zero is associated with a very low risk

38 Thus, a CAC score of zero is associated with a very low risk

of subsequent coronary events,38, 39 whereas an elevated CAC score is related to a stepwise increase in the risk of subsequent coronary events.11, 38 CAC scores have been shown to be highly predictive of future cardiovascular events independent of traditional risk BMN673 factors.11, 40, 41 Thus, in this study, we used the CAC score as an outcome variable to predict future coronary heart disease in individuals with NAFLD. Currently, three published papers address the relationship between NAFLD and CAC. But, these results conflict with each other. As part of the Diabetes Heart Study, McKimmie et al.42 suggested that hepatic steatosis is less likely to be a direct mediator of cardiovascular disease and may be described as an epiphenomenon. The preponderance of diabetes (82.8%) and the nature of the Diabetes Heart Study as a family study, however, may limit the generalizability of these Doxorubicin cost results. On the contrary, Chen et al.43 reported a significant relationship between NAFLD and CAC in Taiwan, but the possibility of selection bias was raised because of the exclusion of a large number of subjects without hepatic imaging. Jung et al.44 also suggested that hepatic steatosis and increased ALT are associated with CAC. They used less stringent

criteria to define ALT elevation for women and only a single cutoff point of CAC (>100). Importantly, Ixazomib two studies did not include VAT data in multivariate analysis. Although the pathogeneses that relate NAFLD and coronary artery disease

have not been thoroughly investigated, several possible explanations have been offered. A low-grade systemic and hepatic inflammatory milieu may link NAFLD to atherosclerosis, which increases the risk of coronary artery disease.45, 46 In NAFLD, reactive oxygen radicals may induce the production of cytokines, such as tumor necrosis factor-α and interleukin-6,47 and add further atherogenic stimuli to the already high oxidative and proinflammatory status that is closely related to metabolic syndrome.48, 49 In addition, such conditions favor the up-regulation of hepatic C-reactive protein levels, which may link NAFLD to coronary atherosclerosis.45, 50 Furthermore, subjects with NAFLD have reduced serum adiponectin levels, which are inversely related to the severity of NAFLD histology.3, 51 Low serum adiponectin levels may also play an important role in the pathogenesis between NAFLD and subclinical coronary atherosclerosis. The strengths of our study are the use of CAC scores, CT-measured VAT, with a high degree of validity and reproducibility, high-quality data collected by trained personnel with a systematic protocol, a wealth of metabolic variables, and a large number of subjects. In addition, we simultaneously measured CAC, hepatic ultrasonography, and VAT on the same day.

38 Thus, a CAC score of zero is associated with a very low risk

38 Thus, a CAC score of zero is associated with a very low risk

of subsequent coronary events,38, 39 whereas an elevated CAC score is related to a stepwise increase in the risk of subsequent coronary events.11, 38 CAC scores have been shown to be highly predictive of future cardiovascular events independent of traditional risk http://www.selleckchem.com/products/PD-0325901.html factors.11, 40, 41 Thus, in this study, we used the CAC score as an outcome variable to predict future coronary heart disease in individuals with NAFLD. Currently, three published papers address the relationship between NAFLD and CAC. But, these results conflict with each other. As part of the Diabetes Heart Study, McKimmie et al.42 suggested that hepatic steatosis is less likely to be a direct mediator of cardiovascular disease and may be described as an epiphenomenon. The preponderance of diabetes (82.8%) and the nature of the Diabetes Heart Study as a family study, however, may limit the generalizability of these Tipifarnib order results. On the contrary, Chen et al.43 reported a significant relationship between NAFLD and CAC in Taiwan, but the possibility of selection bias was raised because of the exclusion of a large number of subjects without hepatic imaging. Jung et al.44 also suggested that hepatic steatosis and increased ALT are associated with CAC. They used less stringent

criteria to define ALT elevation for women and only a single cutoff point of CAC (>100). Importantly, Montelukast Sodium two studies did not include VAT data in multivariate analysis. Although the pathogeneses that relate NAFLD and coronary artery disease

have not been thoroughly investigated, several possible explanations have been offered. A low-grade systemic and hepatic inflammatory milieu may link NAFLD to atherosclerosis, which increases the risk of coronary artery disease.45, 46 In NAFLD, reactive oxygen radicals may induce the production of cytokines, such as tumor necrosis factor-α and interleukin-6,47 and add further atherogenic stimuli to the already high oxidative and proinflammatory status that is closely related to metabolic syndrome.48, 49 In addition, such conditions favor the up-regulation of hepatic C-reactive protein levels, which may link NAFLD to coronary atherosclerosis.45, 50 Furthermore, subjects with NAFLD have reduced serum adiponectin levels, which are inversely related to the severity of NAFLD histology.3, 51 Low serum adiponectin levels may also play an important role in the pathogenesis between NAFLD and subclinical coronary atherosclerosis. The strengths of our study are the use of CAC scores, CT-measured VAT, with a high degree of validity and reproducibility, high-quality data collected by trained personnel with a systematic protocol, a wealth of metabolic variables, and a large number of subjects. In addition, we simultaneously measured CAC, hepatic ultrasonography, and VAT on the same day.

13 Sleep may alter physiological mechanisms responsible for norma

13 Sleep may alter physiological mechanisms responsible for normal esophageal clearance, resulting in increased esophageal acid exposure. Rate of swallowing

is reduced during sleep leading to decrease in primary peristalsis, a pivotal defense mechanism that is responsible for volume clearance of a refluxate from the esophagus.14,15 The latter results in decrease in acid clearance and thus increase in acid mucosal contact time.16 Diminished salivary production during sleep as well as reduced delivery of saliva to the distal esophagus due to decreased primary peristalsis delays alkalization and thus normalization of esophageal pH after acid reflux has occurred. The upper esophageal sphincter basal pressure, but not the lower esophageal sphincter, progressively declines with deeper sleep stages, resulting in an increased risk for aspiration in GERD patients. selleck chemicals Moreover, there is less conscious awareness of gastroesophageal reflux during sleep, resulting in reduction in symptom perception and thus alteration in conscious-dependent defensive

Erastin manufacturer behavior against gastroesophageal reflux (e.g. antacid consumption, assuming the upright position, initiating a swallow).17 Early studies have suggested that acid reflux was significantly more frequent during the first half of the supine period as compared with the second half.18 Dickman et al. demonstrated that esophageal acid exposure was the highest during the first 2 h of sleep.19 This was further triclocarban accentuated in patients with Barrett’s esophagus as compared to those with erosive esophagitis or non-erosive reflux disease with abnormal pH test. Patients with Barrett’s esophagus had the highest esophageal acid exposure parameters throughout the sleep period. Surprisingly, there was no difference in esophageal acid exposure parameters between patients with erosive esophagitis and those with non-erosive reflux disease and abnormal pH test. The increase in esophageal acid exposure during the first hours

of sleep is likely to be driven amongst others by short dinner-to-bed time. It has been shown that dinner-to-bed time less than 3 h significantly increased the risk of subjects to experience gastroesophageal reflux regardless of their phenotypic presentation of GERD (erosive esophagitis or non-erosive reflux disease).20 A recent article by Piesman et al. demonstrated that a meal consumed 2 h before going to bed was significantly more associated with supine reflux as compared to a meal consumed 6 h prior to bedtime.21 The presence of hiatal hernia, higher body mass index, and having erosive esophagitis increased the likelihood of developing supine reflux. Other factors like alcohol and/or carbonated beverage consumption, use of benzodiazepines at bedtime have all been shown to increase the risk for reported heartburn during sleep time.11,22 Dickman et al.

pylori-positive than -negative subjects21 In various human and i

pylori-positive than -negative subjects.21 In various human and in animal model systems, RAS components are expressed by different gastric mucosal cell types, such as endocrine, glandular epithelial, beta-catenin mutation mesenchymal, lamina propria and vascular endothelial.21,24 Inflammatory cell migration and activation

enhances mucosal inflammation in response to the locally produced proinflammatory cytokines.25 In a gerbil model, levels of gastric mucosal AT1R show a particular correlation with those of gastric mucosal interleukin (IL)-17 mRNA, but not with levels of IL-1β, IL-11, IL-18 or tumor necrosis factor (TNF)-α. It is this association with IL-17 mRNA which ultimately influences the outcome of H. pylori-associated disease (Fig. 3b).23 In humans, the infection initially presents as an antral-predominant gastritis, followed by the extension of inflammation into the corpus gastritis and eventually leading to atrophic gastritis with metaplasia, gastric ulcers and, rarely, even gastric cancer.6 It is therefore important to clarify the molecule profile of RAS components in the acute and chronic phases of H. pylori infection. Differential expression pattern may play different roles in gastric mucosal pathogenesis

and in the development of atrophic gastritis, peptic ulcers and gastric cancer. In a Mongolian gerbil model, AT1R and AT2R mRNA levels gradually increase with time after H. pylori infection (Figs 2,4),23 and antral AT1R mRNA Rucaparib manufacturer level dominated over that in the body mucosa in the acute phase (Fig. 4)23 but were significantly higher

than those in the antrum in the chronic phase. The fact that AT1R levels in the body are significantly higher in the chronic phase of H. pylori infection may mean that AT1R expression plays a role in gastric mucosal inflammatory cell infiltration and the development of atrophy, with greater potential for the development of gastric cancer. However, only one report has described these time course findings Methocarbamol after H. pylori infection,23 and further research using animal models is required. The presence and differential activities of H. pylori virulence factors correlate with the severity of gastric mucosal injury and inflammation, and thus with the risk of developing different gastroduodenal diseases.26–28 Among putative H. pylori virulence genes, the outer inflammatory protein (OipA) functions as an adhesion which is involved in inducing the pro-inflammatory response27 and is associated with high H. pylori cell density and severe inflammatory cell infiltrations.29 In Mongolian gerbils, oipA-negative H. pylori strains exhibit diminished ability to induce gastric inflammation and disease relative to decreased H. pylori density.30 The status of oipA needs to be functional for it to enhance gastric ATR levels.

044∼0000) The AUCs (area under receiver operating characteristi

044∼0.000). The AUCs (area under receiver operating characteristic curve) were 0.657∼1.000 (7 indicators >0.8); sensitivities, specificities and accuracies for PHC diagnosis were 61.8∼100.0% (4 indicators >80%), 61.1∼100.0% (6 indicators >80%) and 64.3∼100.0% (6 indicators >80%), respectively. These results indicate the method we developed is a valuable approach for aptamer application in diagnosis. Conclusion: A simple method was developed for aptamer application in diagnosis of primary hepatic carcinoma based on polyacrylamide gel electrophoresis and gray analysis. Key Word(s): 1. Aptamer; 2. Diagnosis;

3. PAGE; 4. Heptoma; Presenting Author: MEI-DI HU Inhibitor Library Additional Authors: TING WANG, KUN-HE ZHANG, WEN-XUE CHEN, GUO-FENG XU, CHAO-ZHU HE,

XUAN ZHU, NONG-HUA LV Corresponding Author: KUN-HE ZHANG Affiliations: the First Affiliated Hospital of Nanchang University; Jiangxi Institute of Gastroenterology & Hepatology Objective: Aptamers are oligonucleotide sequences capable of binding to their targets with high specificity and affinity. We previously generated a group of aptamers against the serum of patients with primary hepatic carcinoma (PHC), and some of them were valuable in the diagnosis of PHC. Here we present the preliminary results of the capture and analysis of target proteins of the aptamers in the serum of patients with PHC for discovering new serum biomarkers of PHC. Methods: The biotinylated aptamers were incubated with pooled PHC serum and pooled normal serum to allow the binding CCR antagonist of aptamers to their target proteins, followed by adding streptavidin-coated magnetic beads. The beads were magnetically separated and the bound proteins were eluted

and analyzed by mass spectrometry. The spectrum of captured proteins from Protein kinase N1 PHC serum was compared with that from normal serum to identify the specific targets of PHC. Results: We captured 61 proteins that expressed in PHC serum but not in normal serum, in which 7 proteins related to the human tumors according to previous reports. They might be potential serum biomarkers of PHC. The capture and analysis of aptamer targets is a new strategy to discover novel tumor biomarkers. It has been reported that aptamer-based identification of serum biomarkers of lung cancer was highly valuable in the diagnosis of lung cancer. Because the aptamers could be selected “blindly”, the strategy is powerful in the study of tumor diagnosis. Conclusion: With aptamer-based strategy, potential serum biomarkers of PHC were captured from the PHC serum. Key Word(s): 1. Aptamer; 2. Hepatoma; 3. Serum; 4. Biomarker; Presenting Author: TING WANG Additional Authors: GUO-FENG XU, KUN-HE ZHANG, WEN-XUE CHEN, MEI-DI HU, XUAN ZHU, NONG-HUA LV Corresponding Author: KUN-HE ZHANG Affiliations: the First Affiliated Hospital of Nanchang University; Jiangxi Institute of Gastroenterology & Hepatology Objective: Aptamers are artificial nucleic acid ligands capable of binding to targets with high specificity and affinity.

The UK has conducted three such contracts to date and has been su

The UK has conducted three such contracts to date and has been successful in containing the overall costs of haemophilia therapy by using accurate data on the consumption of concentrates and the distribution of patients, and through the ability to monitor the adherence to any new contracts. This may be an attractive option for other registries to explore as financial constraints continue to be imposed on healthcare in many countries. At registration, medicines have to be shown to be efficacious and safe. Mandated

regulatory studies, however, tend to be small and are likely to identify only frequent adverse events. No other patient community has suffered as much as that of haemophilia patients in terms of treatment adverse events. Before 1985, a single exposure to selleck chemicals clotting factor concentrate had an almost 100% chance of transmitting the hepatitis C virus (HCV) to the recipient. It is obvious,

therefore, that effective pharmacovigilance is C59 wnt order critical to this community. Systems for reporting adverse events are available in many countries but, unfortunately, they are often not used for many reasons including lack of time to undertake reporting, belief that the event is already well known, uncertainty about the relationship of the event to treatment, and delaying until the treating clinician has published their own report on the case(s). EUHASS is a simple prospective adverse event reporting system set up in Europe with support from the European Commission and the pharmaceutical industry selleck chemicals llc [9]. The system started on 1 October 2008, and 75 sentinel haemophilia centres

from 26 European countries participated in the first 4 years of the project. The adverse events reported by the centres are as follows: Allergic or acute reactions Transfusion transmitted infections Inhibitors Thromboses New malignancies Deaths Unexpected poor efficacy (since 2012) Any other possible adverse event (since 2012). The EUHASS system is a secure web based system and patient details are reported anonymously. Events are reported at the time they occur or, at a minimum, at the end of each 3 month period. Centres not having any events to report still have to confirm this by signing off each quarter. Participating centres also have to provide, annually, the number of patients with bleeding disorders registered in their centre and how many of these received treatment with clotting factor concentrate or platelet transfusions (for inherited platelet disorders), in the preceding 12 month period. Furthermore, annually, centres provide information on how many patients in their centre received each clotting factor concentrate and how many of these individuals had a severe bleeding disorder.

Given the expanding appreciation of MYH9 function in different ce

Given the expanding appreciation of MYH9 function in different cell types,6 it may therefore be of interest to examine the role of MYH9 genetic variation in individuals with abnormal liver-enzyme results

but without other known etiologies. Rémi Favier buy CH5424802 M.D.*, Analisa DiFeo Ph.D.†, Nathalie Hezard M.D., Ph.D.‡, Monique Fabre M.D.§, Pierre Bedossa M.D., Ph.D.¶, John A. Martignetti M.D., Ph.D.**, * Assistance Publique Hopitaux de Paris, Armand Trousseau Children’s Hospital, French Reference Center for Inherited Platelet, Disorders and Inserm U1009, Villejuif, France, † Case Comprehensive Cancer Center, Case Western Reserve University 2103 Cornell Road, Wolstein Research Building, 2-127 Cleveland OH, USA, ‡ Laboratoire d’Hematologie, Hopital Robert Debre, CHU Reims, France, § Service d’anatomo Pathologie, Institut Gustave Roussy, 94805 Villejuif, France, ¶ Assistance Publique-Hopitaux de Paris, Departement de Pathologie, Hopital Beaujon, 92118 CLICHY, France, ** Departments of Genetics and Genomic Sciences and Pediatrics, Adriamycin manufacturer Mount Sinai School of Medicine, 1425 Madison Ave., Box 1498, New York, NY 10029, USA. “
“Use of proton pump

inhibitors (PPI) after endoscopic hemostatic treatment of bleeding peptic ulcers is a standard therapy for preventing early re-bleeding.1 However, controversy continues regarding the optimal dose and route of administration of PPI.2 While both i.v. and oral PPI are effective in preventing early re-bleeding, meta-analysis of randomized trials found that i.v. infusion of high-dose PPI is superior to low-dose (i.e. oral or repeated i.v. injections) PPI in terms of the need for surgery.1 Oral PPI have

two major limitations: a slow onset of action and failure to maintain a stably high intragastric pH. One attempt to overcome next the limitations of conventional oral PPI is the development of immediate-release (IR) formulations. In this issue, Banerjee et al.3 shows that healthy volunteers who received buffered IR esomeprazole 40 mg p.o. had superior intragastric pH profile compared to those who received i.v. pantoprazole 40 mg every 12 h for 24 h. After the first dose of buffered IR esomeprazole, the intragastric pH was rapidly raised to 6 in a median time of 2 min whereas it took 80 min for i.v. pantoprazole to achieve this level of intragastric pH. Furthermore, the mean percentage time to an intragastric pH of more than 6.0 was 91% in the buffered IR esomeprazole group compared to 20% in the i.v. pantoprazole group in a 24-h period. While many readers would agree that the intragastric pH profile achieved by buffered IR esomeprazole was close to perfection, was the result too good to be true? The rapid rise in intragastric pH with buffered IR esomeprazole was not unexpected because the bicarbonate content of the formulation would neutralize gastric acid.

Therefore, primary cholangiocytes from the double-transgenic mice

Therefore, primary cholangiocytes from the double-transgenic mice are capable of adopting a myofibroblast phenotype in vitro, as has been reported for mouse and human cholangiocytes by others.7, 34, 35 To determine whether EMT occurs in vivo, we induced liver fibrosis click here in Alfp-Cre × Rosa26-YFP mice by BDL. Sirius Red staining demonstrated progressively increasing hepatic fibrosis at 2, 4, and 8 weeks post-BDL (Fig. 3; Supporting Information Fig. 2). At these timepoints (Figs. 4, 5; Supporting Information Fig. 3), there was no evidence of YFP colocalization with the mesenchymal markers S100A4, vimentin, α-SMA, or procollagen 1α2,

despite significant peribiliary staining for these markers compared with untreated controls (Supporting Information Figs. 1C, 5). Occasional YFP-negative, S100A4-positive cells appeared to infiltrate bile ducts (Fig. 5D); these may be lymphocytes or monocytes, which are known to express S100A4.36-38 Despite significant hepatic stellate cell accumulation by 8 weeks post-BDL, no YFP colocalization with the HSC marker desmin was noted (Fig. 7). These data indicate that EMT does not occur at these timepoints in the mouse BDL model. To corroborate these findings, we exposed mice to CCl4, a hepatotoxin that induces hepatic (though nonbiliary-specific) fibrosis. Although

progenitor cell proliferation has been described in this model, the phenotype depends mostly on hyperplasia of mature cholangiocytes.39, 40 After 3 weeks of Trametinib manufacturer treatment the increase in fibrosis compared to controls was modest but statistically significant (Supporting Information Fig. 2). There was no evidence of YFP costaining with mesenchymal markers noted in any of the animals despite significant peribiliary staining (Fig. 7; Supporting Information Figs. 4, 5). Neither the CCl4 model nor the BDL model produced evidence of marker colocalization in YFP-labeled hepatocytes, consistent with a recent study suggesting that hepatocyte EMT does not occur.8 BDL is the most widely used rodent model of biliary

fibrosis, although it is an imperfect model for many human diseases because the phenotype results from marked proliferation Amoxicillin of mature cholangiocytes (primarily from the large bile ducts) rather than a ductular reaction, which is proposed to involve activation of bipotential progenitor cell populations (oval cells).39, 41, 42 The ductular reaction is a dominant feature of several fibrosing biliary diseases, including biliary atresia.43, 44 To assess the possibility that EMT occurs in cholangiocyte precursors, before the expression of K19, we used the DDC dietary model, which results in an oval cell response with a marked ductular reaction and sclerosing cholangitis.45, 46 Mice fed the DDC diet for 2 weeks developed moderate fibrosis (data not shown) compared to mice fed normal chow. At 3 weeks of treatment, fibrosis was more marked and roughly equivalent by Sirius Red staining to mice 2 weeks post-BDL (Fig. 3).

Therefore, primary cholangiocytes from the double-transgenic mice

Therefore, primary cholangiocytes from the double-transgenic mice are capable of adopting a myofibroblast phenotype in vitro, as has been reported for mouse and human cholangiocytes by others.7, 34, 35 To determine whether EMT occurs in vivo, we induced liver fibrosis CHIR-99021 ic50 in Alfp-Cre × Rosa26-YFP mice by BDL. Sirius Red staining demonstrated progressively increasing hepatic fibrosis at 2, 4, and 8 weeks post-BDL (Fig. 3; Supporting Information Fig. 2). At these timepoints (Figs. 4, 5; Supporting Information Fig. 3), there was no evidence of YFP colocalization with the mesenchymal markers S100A4, vimentin, α-SMA, or procollagen 1α2,

despite significant peribiliary staining for these markers compared with untreated controls (Supporting Information Figs. 1C, 5). Occasional YFP-negative, S100A4-positive cells appeared to infiltrate bile ducts (Fig. 5D); these may be lymphocytes or monocytes, which are known to express S100A4.36-38 Despite significant hepatic stellate cell accumulation by 8 weeks post-BDL, no YFP colocalization with the HSC marker desmin was noted (Fig. 7). These data indicate that EMT does not occur at these timepoints in the mouse BDL model. To corroborate these findings, we exposed mice to CCl4, a hepatotoxin that induces hepatic (though nonbiliary-specific) fibrosis. Although

progenitor cell proliferation has been described in this model, the phenotype depends mostly on hyperplasia of mature cholangiocytes.39, 40 After 3 weeks of Z-VAD-FMK datasheet treatment the increase in fibrosis compared to controls was modest but statistically significant (Supporting Information Fig. 2). There was no evidence of YFP costaining with mesenchymal markers noted in any of the animals despite significant peribiliary staining (Fig. 7; Supporting Information Figs. 4, 5). Neither the CCl4 model nor the BDL model produced evidence of marker colocalization in YFP-labeled hepatocytes, consistent with a recent study suggesting that hepatocyte EMT does not occur.8 BDL is the most widely used rodent model of biliary

fibrosis, although it is an imperfect model for many human diseases because the phenotype results from marked proliferation Tangeritin of mature cholangiocytes (primarily from the large bile ducts) rather than a ductular reaction, which is proposed to involve activation of bipotential progenitor cell populations (oval cells).39, 41, 42 The ductular reaction is a dominant feature of several fibrosing biliary diseases, including biliary atresia.43, 44 To assess the possibility that EMT occurs in cholangiocyte precursors, before the expression of K19, we used the DDC dietary model, which results in an oval cell response with a marked ductular reaction and sclerosing cholangitis.45, 46 Mice fed the DDC diet for 2 weeks developed moderate fibrosis (data not shown) compared to mice fed normal chow. At 3 weeks of treatment, fibrosis was more marked and roughly equivalent by Sirius Red staining to mice 2 weeks post-BDL (Fig. 3).