We examined mitochondrial DNA control region sequences of 101 individuals collected from 7 localities that cover the complete distributional range of this species. Haplotype frequencies showed a significant population

differentiation whereas the spatial distribution NVP-AUY922 datasheet of haplotypes suggests moderate geographical structure. Genetic differentiation was not consistent with a simple model of isolation by distance and several independent estimates suggest that the observed phylogeographical pattern is the consequence of a complex demographic scenario. Our data suggest both reduction and population expansion events. Both kinds of demographic events were associated to major climatic changes that affected the study area during the Late Pleistocene and the Holocene. In particular, a relationship between historical changes in the degree of vegetation cover and population size for this rodent was inferred. We propose that the decrease in aridity of the Pampean region that started in the Pleistocene–Holocene boundary could have promoted a major decline in the effective population size of this species. “
“In long-term studies of wild animals, individuals are often caught initially as adults, and so their age is unknown. To better understand age structure, cohort effects and life-history traits, it is desirable to ascribe approximate ages

to individuals. Tooth wear has been used as a proxy for age in many mammals, including click here the Eurasian badger Meles meles. We used tooth-wear data derived from serial captures of over 2000 badgers of known age to calibrate the learn more relationship between tooth wear and age and produce a predictive model. As badgers were recaptured throughout

their lifetime, we used all observations of tooth wear from each individual of unknown age to estimate its year of birth. By taking into account repeated observations of tooth wear, we generated more accurate and internally consistent predictions. Spatial variations in the rates of tooth wear are likely to relate to differences in the diet and more rapid rates of wear among male badgers may be linked to higher levels of food intake. The performance of the optimum model at accurately predicting badger age from tooth wear was assessed using data from known-age animals. The reliability of predictions declined with age but for our study population, there was an 88% probability of being accurate to within 1 year. The model performed less well at predicting age from a single observation (71% accuracy to within 1 year) than from repeated observations of tooth wear. Individuals of unknown age are likely to be encountered in most studies of free-living animal populations, and in many cases, there will be physiological indicators (such as tooth wear in mammals) that can be used to approximate age.

We examined mitochondrial DNA control region sequences of 101 individuals collected from 7 localities that cover the complete distributional range of this species. Haplotype frequencies showed a significant population

differentiation whereas the spatial distribution Fulvestrant of haplotypes suggests moderate geographical structure. Genetic differentiation was not consistent with a simple model of isolation by distance and several independent estimates suggest that the observed phylogeographical pattern is the consequence of a complex demographic scenario. Our data suggest both reduction and population expansion events. Both kinds of demographic events were associated to major climatic changes that affected the study area during the Late Pleistocene and the Holocene. In particular, a relationship between historical changes in the degree of vegetation cover and population size for this rodent was inferred. We propose that the decrease in aridity of the Pampean region that started in the Pleistocene–Holocene boundary could have promoted a major decline in the effective population size of this species. “
“In long-term studies of wild animals, individuals are often caught initially as adults, and so their age is unknown. To better understand age structure, cohort effects and life-history traits, it is desirable to ascribe approximate ages

to individuals. Tooth wear has been used as a proxy for age in many mammals, including see more the Eurasian badger Meles meles. We used tooth-wear data derived from serial captures of over 2000 badgers of known age to calibrate the selleck relationship between tooth wear and age and produce a predictive model. As badgers were recaptured throughout

their lifetime, we used all observations of tooth wear from each individual of unknown age to estimate its year of birth. By taking into account repeated observations of tooth wear, we generated more accurate and internally consistent predictions. Spatial variations in the rates of tooth wear are likely to relate to differences in the diet and more rapid rates of wear among male badgers may be linked to higher levels of food intake. The performance of the optimum model at accurately predicting badger age from tooth wear was assessed using data from known-age animals. The reliability of predictions declined with age but for our study population, there was an 88% probability of being accurate to within 1 year. The model performed less well at predicting age from a single observation (71% accuracy to within 1 year) than from repeated observations of tooth wear. Individuals of unknown age are likely to be encountered in most studies of free-living animal populations, and in many cases, there will be physiological indicators (such as tooth wear in mammals) that can be used to approximate age.

We examined mitochondrial DNA control region sequences of 101 individuals collected from 7 localities that cover the complete distributional range of this species. Haplotype frequencies showed a significant population

differentiation whereas the spatial distribution CDK inhibitor of haplotypes suggests moderate geographical structure. Genetic differentiation was not consistent with a simple model of isolation by distance and several independent estimates suggest that the observed phylogeographical pattern is the consequence of a complex demographic scenario. Our data suggest both reduction and population expansion events. Both kinds of demographic events were associated to major climatic changes that affected the study area during the Late Pleistocene and the Holocene. In particular, a relationship between historical changes in the degree of vegetation cover and population size for this rodent was inferred. We propose that the decrease in aridity of the Pampean region that started in the Pleistocene–Holocene boundary could have promoted a major decline in the effective population size of this species. “
“In long-term studies of wild animals, individuals are often caught initially as adults, and so their age is unknown. To better understand age structure, cohort effects and life-history traits, it is desirable to ascribe approximate ages

to individuals. Tooth wear has been used as a proxy for age in many mammals, including BTK inhibitor the Eurasian badger Meles meles. We used tooth-wear data derived from serial captures of over 2000 badgers of known age to calibrate the this website relationship between tooth wear and age and produce a predictive model. As badgers were recaptured throughout

their lifetime, we used all observations of tooth wear from each individual of unknown age to estimate its year of birth. By taking into account repeated observations of tooth wear, we generated more accurate and internally consistent predictions. Spatial variations in the rates of tooth wear are likely to relate to differences in the diet and more rapid rates of wear among male badgers may be linked to higher levels of food intake. The performance of the optimum model at accurately predicting badger age from tooth wear was assessed using data from known-age animals. The reliability of predictions declined with age but for our study population, there was an 88% probability of being accurate to within 1 year. The model performed less well at predicting age from a single observation (71% accuracy to within 1 year) than from repeated observations of tooth wear. Individuals of unknown age are likely to be encountered in most studies of free-living animal populations, and in many cases, there will be physiological indicators (such as tooth wear in mammals) that can be used to approximate age.

We therefore used ≥25 m as the final water depth category. Flow tides indicated tidal condition before high tides and ebb tides after high tides. The Moreton Bay dugongs made

frequent excursions between two very different habitats: shallow seagrass meadows on the Eastern Banks and deeper offshore waters, east of Moreton and North Stradbroke Islands (Fig. 1; Phinn et al. 2008, Lyons et al. 2012). We expected diving patterns in these habitats to be different, because feeding individuals spend more time submerged to excavate or crop seagrasses than when offshore and not feeding (Marsh et al. 2011). We therefore compared the dugong’s availability for detection in each of these habitat types for the Moreton Bay dugongs only. We used logistic regression via generalized linear mixed models (GLMMs). The response Dabrafenib variable was binary, and this statistical method can accommodate random components from individual dugongs (Breslow and Clayton 1993). We used Gaussian Hermite Quadrature (GHQ) estimation with lme4 (Bates et al. 2012). The GHQ is based on a restricted maximum likelihood. The GHQ provides estimations that are more accurate than alternative methods, such as Penalized Quasi-likelihood or Laplace approximation (Agresti et al. 2000, Bolker et al. 2009). To compare GSI-IX ic50 models, we used Akaike Information Criterion (AIC) and Chi-square tests. Diagnostic plots were used to check the performance

of individual models. Dive data comprised a time-series of depth records separated by 1 or 2 s and were strongly autocorrelated. Visual inspection of dive profiles indicated that successive dives tended to be similar. To ensure independent samples, we treated 10 min as a sampling unit (the subsampled period around a GPS or QFP fix). The 10 min interval ensured that at least one complete dive was included in a sample. Longer intervals were not appropriate because the location

of the dugong could change and the estimated water depth needed to remain constant during a sampling unit. A saturated model was first examined using individual dugong as a random factor and water depth, tidal condition, selleck chemicals llc and habitat types as categorical fixed factors. The model was reduced by removing the tidal variable because some water depth and tide combinations had few observations, and because no tidal effects were identified during exploratory data analysis. We estimated the probabilities of dugongs being in the detection zones using GLMM linear predictor estimates. The 95% confidence intervals for the predicted values were also calculated based on fixed factors. Data manipulations and statistical analyses were executed using SPlus version 8 (TIBCO Software 2007) and R 2.15.1 (R Development Core Team 2011). We estimated and compared the number of dugongs that were not detected during previous aerial surveys of Hervey Bay conducted in 2001, 2005, and 2011 (Lawler 2002, Marsh and Lawler 2006, Sobtzick et al.

Disclosures: Fabien Zoulim – Advisory Committees or Review Panels: Janssen, Gilead,

Novira, Abbvie, Tykmera, Transgene; Consulting: selleck chemical Roche; Grant/Research Support: Novartis, Gilead, Scynexis, Roche, Novira; Speaking and Teaching: Bristol Myers Squibb, Gilead Maciej S. Jablkowski – Advisory Committees or Review Panels: Gilead, Abbvie; Consulting: BMS, Gilead, Roche, MSD; Speaking and Teaching: BMS, Roche, MSD, Janssen-Cilag, Novartis Joerg Petersen – Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/ Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck Patrick Marcellin – Consulting: Roche,

Gilead, BMS, Vertex, Novartis, Janssen, MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer, Abbvie Aleksandra Kedzierska – Employment: Bristol-Myers Squibb Krzysztof. Simon – Advisory Committees or Review Panels: BMS, MSD, Roche, GIlead Harry L. Janssen – Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: selleck screening library Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris The following people have nothing to disclose: Mircea. Diculescu, Soumaya Bendahmane Background/Aims: It is not clear whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) combination therapy shows superior antiviral efficacy over tenofovir monotherapy in patients who harbor ETV-resistant hepatitis B virus (HBV). Methods: In this multicenter open-label trial, patients who had HBV with genotypic resistance

mutations to ETV and serum HBV DNA concentration >60 IU/mL were randomized to TDF (300 mg/day) monotherapy (TDF group, n = 45) or to TDF and ETV (1 mg/day) combination therapy (TDF+ETV group, n = 45), and were included in the intention-to-treat analyses. Patients who had adefovir-resistant selleck HBV (rtA181V/T and/or rtN236T) were excluded. Results: At baseline, mean HBV DNA level was 4.28 +/− 1.60 log10 IU/mL. All 90 patients had at least one ETV-resistance mutations; rtT184 (n = 49), rtS202 (n = 43), or rtM250 (n = 7). All also had rtM204V/I +/− rtL180M mutations. One patient in the TDF group withdrew the consent at week 2. At week 48, the number of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was 32 (71%) and 33 (73%) in the TDF and TDF+ETV groups, respectively (P=0.81). Mean reduction in HBV DNA levels from baseline was −3.65 +/− 1.64 log10 IU/mL and −3.77 +/− 1.30 log10 IU/mL in the TDF and TDF+ETV groups, respectively (P=0.69). Virological breakthrough was observed in a patient in the TDF group at 48 weeks, which was attributed to documented non-adherence to study drug.

Disclosures: Fabien Zoulim – Advisory Committees or Review Panels: Janssen, Gilead,

Novira, Abbvie, Tykmera, Transgene; Consulting: Selleck PD0332991 Roche; Grant/Research Support: Novartis, Gilead, Scynexis, Roche, Novira; Speaking and Teaching: Bristol Myers Squibb, Gilead Maciej S. Jablkowski – Advisory Committees or Review Panels: Gilead, Abbvie; Consulting: BMS, Gilead, Roche, MSD; Speaking and Teaching: BMS, Roche, MSD, Janssen-Cilag, Novartis Joerg Petersen – Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/ Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck Patrick Marcellin – Consulting: Roche,

Gilead, BMS, Vertex, Novartis, Janssen, MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer, Abbvie Aleksandra Kedzierska – Employment: Bristol-Myers Squibb Krzysztof. Simon – Advisory Committees or Review Panels: BMS, MSD, Roche, GIlead Harry L. Janssen – Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Trametinib solubility dmso Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris The following people have nothing to disclose: Mircea. Diculescu, Soumaya Bendahmane Background/Aims: It is not clear whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) combination therapy shows superior antiviral efficacy over tenofovir monotherapy in patients who harbor ETV-resistant hepatitis B virus (HBV). Methods: In this multicenter open-label trial, patients who had HBV with genotypic resistance

mutations to ETV and serum HBV DNA concentration >60 IU/mL were randomized to TDF (300 mg/day) monotherapy (TDF group, n = 45) or to TDF and ETV (1 mg/day) combination therapy (TDF+ETV group, n = 45), and were included in the intention-to-treat analyses. Patients who had adefovir-resistant see more HBV (rtA181V/T and/or rtN236T) were excluded. Results: At baseline, mean HBV DNA level was 4.28 +/− 1.60 log10 IU/mL. All 90 patients had at least one ETV-resistance mutations; rtT184 (n = 49), rtS202 (n = 43), or rtM250 (n = 7). All also had rtM204V/I +/− rtL180M mutations. One patient in the TDF group withdrew the consent at week 2. At week 48, the number of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was 32 (71%) and 33 (73%) in the TDF and TDF+ETV groups, respectively (P=0.81). Mean reduction in HBV DNA levels from baseline was −3.65 +/− 1.64 log10 IU/mL and −3.77 +/− 1.30 log10 IU/mL in the TDF and TDF+ETV groups, respectively (P=0.69). Virological breakthrough was observed in a patient in the TDF group at 48 weeks, which was attributed to documented non-adherence to study drug.

Disclosures: Fabien Zoulim – Advisory Committees or Review Panels: Janssen, Gilead,

Novira, Abbvie, Tykmera, Transgene; Consulting: FK228 research buy Roche; Grant/Research Support: Novartis, Gilead, Scynexis, Roche, Novira; Speaking and Teaching: Bristol Myers Squibb, Gilead Maciej S. Jablkowski – Advisory Committees or Review Panels: Gilead, Abbvie; Consulting: BMS, Gilead, Roche, MSD; Speaking and Teaching: BMS, Roche, MSD, Janssen-Cilag, Novartis Joerg Petersen – Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/ Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck Patrick Marcellin – Consulting: Roche,

Gilead, BMS, Vertex, Novartis, Janssen, MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer, Abbvie Aleksandra Kedzierska – Employment: Bristol-Myers Squibb Krzysztof. Simon – Advisory Committees or Review Panels: BMS, MSD, Roche, GIlead Harry L. Janssen – Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: DAPT Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris The following people have nothing to disclose: Mircea. Diculescu, Soumaya Bendahmane Background/Aims: It is not clear whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) combination therapy shows superior antiviral efficacy over tenofovir monotherapy in patients who harbor ETV-resistant hepatitis B virus (HBV). Methods: In this multicenter open-label trial, patients who had HBV with genotypic resistance

mutations to ETV and serum HBV DNA concentration >60 IU/mL were randomized to TDF (300 mg/day) monotherapy (TDF group, n = 45) or to TDF and ETV (1 mg/day) combination therapy (TDF+ETV group, n = 45), and were included in the intention-to-treat analyses. Patients who had adefovir-resistant selleck products HBV (rtA181V/T and/or rtN236T) were excluded. Results: At baseline, mean HBV DNA level was 4.28 +/− 1.60 log10 IU/mL. All 90 patients had at least one ETV-resistance mutations; rtT184 (n = 49), rtS202 (n = 43), or rtM250 (n = 7). All also had rtM204V/I +/− rtL180M mutations. One patient in the TDF group withdrew the consent at week 2. At week 48, the number of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was 32 (71%) and 33 (73%) in the TDF and TDF+ETV groups, respectively (P=0.81). Mean reduction in HBV DNA levels from baseline was −3.65 +/− 1.64 log10 IU/mL and −3.77 +/− 1.30 log10 IU/mL in the TDF and TDF+ETV groups, respectively (P=0.69). Virological breakthrough was observed in a patient in the TDF group at 48 weeks, which was attributed to documented non-adherence to study drug.

Therefore, the hepatic uptake of αMCA and DCA might be an important determining factor in the excretion of these BAs, especially for DCA, which originates from the bacterial activity in the intestine. Studies in rats indicate that rodent liver has high capacity of conversion of CDCA to βMCA, but not to αMCA.25, 26 Thus, the selective decrease of biliary excretion of αMCA, but not βMCA, is likely due to their differences in buy X-396 hepatic synthesis in Oatp1b2-null mice. For further characterization of the in vivo role of Oatp1b2 in BA transport, WT and Oatp1b2-null mice were injected with CA or T-CA (Fig. 4). The plasma concentration

of CA is approximately 3 fold higher in Oatp1b2-null mice after the intravenous administration of CA (Fig. 4). In CA-injected mice, the Vd of the central compartment

is approximately 50% smaller in Oatp1b2-null than in WT mice. The smaller Vdcentral results in a 55% lower hepatic clearance in Oatp1b2-null mice (Fig. 5). In contrast to CA, T-CA concentrations are similar in Oatp1b2-null and WT mice after intravenous administration of T-CA. This finding confirmed the key role of Oatp1b2 in the hepatic uptake of unconjugated BAs. It can be assumed that the reabsorption of BAs by the ileum is not altered in the Oatp1b2-null mice, because there are no changes in either the BA levels in small intestine content (Supporting Information Fig. LY2157299 research buy 3) or in the mRNA/protein expression of the BA transporters in the ileum (Asbt and Ostα/β, data not shown) in Oatp1b2-null mice compared with WT mice. Therefore, application of a pharmacokinetic equation after intravenous infusion ( ) is consistent with the constant high concentrations of unconjugated BAs in Oatp1b2-null mice, where Css is the steady-state concentration, DR is the dose rate (in selleckchem this case

the intestinal absorption of BAs), and Cl is clearance. In Oatp1b2-null mice, the Css is higher than in WT mice, because of the decreased hepatic clearance of unconjugated BAs. The homeostasis of hepatic BAs is regulated not only by transporters but also by the de novo biosynthesis of BAs from cholesterol. Because the disposition of unconjugated BAs is altered in Oatp1b2-null mice, the gene expression of BA synthetic enzymes was examined. Surprisingly, the mRNA expression of Cyp7a1, the rate-limiting enzyme of BA synthesis,27 is 70% lower in Oatp1b2-null mice (Fig. 7). The absence of Oatp1b2 does not influence other key enzymes either in the classical or in the alternative BA synthetic pathway (Fig. 7). The regulation of Cyp7a1 is complex. Cyp7a1 is a target gene of liver X receptor α (LXRα) in rodents.28 A high cholesterol diet increases bile acid synthesis in WT but not in LXRα-null mice, which results in high levels of cholesterol in livers of LXRα-null mice.29 Serum total cholesterol is higher in Oatp1b2-null than in WT mice.

5 versus 33.9 years; P < 0.003). Males with a truncating variant were younger (31 ± 12 years) than those with missense variant (40 ± 13 years); likewise, females with a truncating variant were younger (26 ±6 years) than those with a missense variant (40 ± 13 years) (P < 0.001). There was no significant association between truncating sequence variations and severity of either acute or chronic biliary complications (severe biliary complications defined as

acute pancreatitis, recurrent cholangitis, segmental spindle-shape dilatation of the biliary tree filled with gallstones): odds ratio (OR) = 0.8 (95% confidence interval [CI] 0.3-3.7, P = 0.8). These complications were more frequent in men (71% versus 45%, P = 0.05, OR 2.9, 95% CI 1.0-9.6), that in women, independently of age at onset of symptoms and type of variant. About half of the women who had pregnancy experienced buy Tamoxifen ICP. The frequency and severity of ICP did not differ in patients with missense (44%) and truncating variant (69%) (P = 0.2). In patients without an

ABCB4 detectable variant the clinical characteristics Selleck ICG-001 were similar to those observed in patients with gene variation. Of note, in a subset of patients the phospholipid/bile acid ratio measured in hepatic bile (ratio of control gallbladder bile >25%) did not differ between the two groups: 11%, range 4%-16% (n = 7) versus 12%, range 1.4%-16% (n = 8) in patients with and without the ABCB4 variant, respectively. In the overall cohort, biliary cirrhosis was detected in only two patients. Both patients had a missense heterozygous variant (location see more and nucleotide changes: c.523A>G and c.959C>T). Intrahepatic

cholangiocarcinoma leading to death was observed in a noncirrhosis female patient with a heterozygous splicing mutation (c.1005+5 G>A). All the patients received ursodeoxycholic acid (UDCA) (8-10 mg/kg/day) as the mainstay treatment after the diagnosis had been made. All the patients with severe chronic biliary complications had sphincterotomy. Patients with symptomatic intrahepatic bile duct dilatations filled with gallstones had repeated endoscopic procedures to remove the stones. All the patients with or without detectable variant and free of intrahepatic bile duct dilatations with gallstones became asymptomatic up to now. The only exception was a patient who did not tolerate UDCA because of bile acid-induced watery diarrhea. Among patients presenting with symptomatic cholelithiasis, three main features defined the syndromatic phenotype termed LPAC: recurrence of biliary symptoms after cholecystectomy, intrahepatic lithiasis, and age <40 years. The results of the present study may be summarized as follows: (1) half of the patients with the LPAC phenotype have detectable sequence variations of the ABCB4 gene, most of them being heterozygous missense.

5 versus 33.9 years; P < 0.003). Males with a truncating variant were younger (31 ± 12 years) than those with missense variant (40 ± 13 years); likewise, females with a truncating variant were younger (26 ±6 years) than those with a missense variant (40 ± 13 years) (P < 0.001). There was no significant association between truncating sequence variations and severity of either acute or chronic biliary complications (severe biliary complications defined as

acute pancreatitis, recurrent cholangitis, segmental spindle-shape dilatation of the biliary tree filled with gallstones): odds ratio (OR) = 0.8 (95% confidence interval [CI] 0.3-3.7, P = 0.8). These complications were more frequent in men (71% versus 45%, P = 0.05, OR 2.9, 95% CI 1.0-9.6), that in women, independently of age at onset of symptoms and type of variant. About half of the women who had pregnancy experienced check details ICP. The frequency and severity of ICP did not differ in patients with missense (44%) and truncating variant (69%) (P = 0.2). In patients without an

ABCB4 detectable variant the clinical characteristics see more were similar to those observed in patients with gene variation. Of note, in a subset of patients the phospholipid/bile acid ratio measured in hepatic bile (ratio of control gallbladder bile >25%) did not differ between the two groups: 11%, range 4%-16% (n = 7) versus 12%, range 1.4%-16% (n = 8) in patients with and without the ABCB4 variant, respectively. In the overall cohort, biliary cirrhosis was detected in only two patients. Both patients had a missense heterozygous variant (location click here and nucleotide changes: c.523A>G and c.959C>T). Intrahepatic

cholangiocarcinoma leading to death was observed in a noncirrhosis female patient with a heterozygous splicing mutation (c.1005+5 G>A). All the patients received ursodeoxycholic acid (UDCA) (8-10 mg/kg/day) as the mainstay treatment after the diagnosis had been made. All the patients with severe chronic biliary complications had sphincterotomy. Patients with symptomatic intrahepatic bile duct dilatations filled with gallstones had repeated endoscopic procedures to remove the stones. All the patients with or without detectable variant and free of intrahepatic bile duct dilatations with gallstones became asymptomatic up to now. The only exception was a patient who did not tolerate UDCA because of bile acid-induced watery diarrhea. Among patients presenting with symptomatic cholelithiasis, three main features defined the syndromatic phenotype termed LPAC: recurrence of biliary symptoms after cholecystectomy, intrahepatic lithiasis, and age <40 years. The results of the present study may be summarized as follows: (1) half of the patients with the LPAC phenotype have detectable sequence variations of the ABCB4 gene, most of them being heterozygous missense.