For PCR amplification and sequencing of the ITS1/5.8S/-ITS2 and LSU D1/D2 regions, the forward and reverse primers of Adachi et al. (1994) and Scholin et al. (1994) H 89 concentration were used. Each of the purified amplicons was directly sequenced in both directions on either an Applied Biosystems ABI3130XL Genetic Analyzer (16-capillaries) or ABI3730 DNA Analyzer (48-capillaries; Applied Biosystems, Carlsbad, CA, USA). For both instruments, the Applied Biosystems in BigDye® Terminator v3.1 Cycle Sequencing Kit (Part No. 4336921) protocol was followed in conjunction with a subsequent purification step utilizing a Biomek® NXP Laboratory Automation Workstation and

the Agencourt® CleanSEQ kit protocol (Beckman Coulter, Brea, CA, USA). A phylogenetic analysis was undertaken to determine if the ITS1 through D1-D2 Ivacaftor concentration LSU sequences fell into distinct groups corresponding to the morphologically defined species of the A. ostenfeldii/A. peruvinaum complex and to reveal the genetic relationships among the isolates. Prior to the phylogenetic analysis, the 37 ITS1 through D1-D2 LSU sequences (1,256 bp) obtained for each of the algal isolates were aligned using MAFFT (Multiple Alignment with Fast Fourier Transform; Katoh et al. 2009)

as implemented in SeaView (Gouy et al. 2010). The default MAFFT settings were employed. Minor manual adjustments to the final alignment were performed using Chromas Pro (Version 1.5.). A. minutum and A. insuetum were used as outgroups. The resulting alignment is available upon request. An alternative RNA alignment was performed using the Multiple Alignment of RNAs tool (Smith et al. 2010) and representative ITS through D2 LSU sequences for A. affine, A. andersoni, click here A. fundyense, A. insuetum, A. lusitanicum, A. minutum, A. peruvianum, A. ostenfeldii, and A. tamarense from GenBank were used to guide the final alignment of the 37 combined ITS/D1-D2 LSU sequences. Bayesian inference

(BI) was performed using the software MrBayes v3.2 (Ronquist and Huelsenbeck 2003) with the GTR+G substitution model (Rodríguez et al. 1990), selected under the Bayesian Information Criterion (BIC) with jModelTest 0.1.1. (Posada 2008). For priors, we assumed no prior knowledge on the data. Two runs of four chains (three heated and one cold) were executed for 10,150 generations, sampling every 500 trees. In each run, the first 25% of samples were discarded as the burn-in phase. The stability of model parameters and the convergence of the two runs were confirmed using Tracer v1.5 (Rambaut and Drummond 2007). Additionally, a maximum likelihood (ML) phylogenetic tree based on the concatenated alignment was calculated in GARLI 2.0 (Zwickl 2006) with parameters estimated from the data, using an evolutionary model GTR+G, selected under the Akaike Information Criterion (AIC) with jModelTest 0.1.1. (Posada 2008). Tree topology was supported with bootstrap values calculated with 1,000 replicates.

16 Genotoxic and other stressful stimuli not only induce an accumulation of p53, but also the phosphorylation of mdm2, thereby enhancing p53′s nuclear localization, ubiquitination and subsequent degradation.17 Of note, mdm2 is overexpressed in many tumors and effectively impairs p53 function by http://www.selleckchem.com/products/ink128.html binding

directly to p53; this promotes its ubiquitination and targeting to the 26S proteasome for protein degradation.17 Protein–protein interactions have long been considered challenging targets for therapeutic intervention, because their opposing surfaces are often too large or flat for effective disruption by small molecules. The more successful chemical antagonists take advantage of specific interactions

within well-defined pockets on the surfaces PF 01367338 of one or both protein partners.18 The discovery that p53-mdm2 binding was dependent on only three p53 amino acid residues interacting with a discrete mdm2 pocket stimulated efforts to identify potential small molecule inhibitors.19 The first potent and selective antagonists of p53-mdm2 were the Nutlins.20 They represent a class of cis-imidazole analogues that bind to the p53 pocket on the surface of mdm2 in an enantiomer-specific manner. The three reported Nutlins, -1, -2 and -3, show potency against p53-mdm2 binding in the 100–300 nmol range with 150- to 200-fold range in affinity between enantiomers. They inhibit the p53-mdm2 selleck kinase inhibitor axis by mimicking the interaction of the three critical amino acid residues with the hydrophobic activity of mdm2.20 In addition to their high potency in vitro, they penetrate cell membranes, activate p53 and inhibit cell proliferation at a range of 1–3 µmol. Released from its negative control in the presence of Nutlin (Fig. 1b), p53 is stabilized and accumulates in cells leading to the activation of target genes; for example, p21 and mdm2. This effect, however, is dependent on the presence of wt p53, because cells in

which p53 is deleted or mutated do not respond to Nutlin treatment.20 In addition to parenteral routes, Nutlins can also be given orally, which is highly desirable for their applicability in animal models and in the clinic.20 In this issue of the Journal, Wang et al.21 utilized Nutlin-3 against three human HCC cell lines with wt (HepG2), mutant (Hep3B) and null p53 (Huh7). This selective mdm2 antagonist induced growth arrest in all three cell types in vitro with significant abrogation of the pro-proliferative genes, cyclin D1/cdk4, cyclin E/cdk2 and E2F transcription factor. Cell cycle arrest was mediated by upregulation of p21 only in p53-intact HepG2 cells, whereas p27, another downstream target of p53, was expressed by all three tumor cell lines. Regardless of p53 status, Nutlin-3 treatment triggered increased apoptosis in all tumor cells, as well as increased expression of Bax, Noxa and PUMA.

16 Genotoxic and other stressful stimuli not only induce an accumulation of p53, but also the phosphorylation of mdm2, thereby enhancing p53′s nuclear localization, ubiquitination and subsequent degradation.17 Of note, mdm2 is overexpressed in many tumors and effectively impairs p53 function by see more binding

directly to p53; this promotes its ubiquitination and targeting to the 26S proteasome for protein degradation.17 Protein–protein interactions have long been considered challenging targets for therapeutic intervention, because their opposing surfaces are often too large or flat for effective disruption by small molecules. The more successful chemical antagonists take advantage of specific interactions

within well-defined pockets on the surfaces selleck inhibitor of one or both protein partners.18 The discovery that p53-mdm2 binding was dependent on only three p53 amino acid residues interacting with a discrete mdm2 pocket stimulated efforts to identify potential small molecule inhibitors.19 The first potent and selective antagonists of p53-mdm2 were the Nutlins.20 They represent a class of cis-imidazole analogues that bind to the p53 pocket on the surface of mdm2 in an enantiomer-specific manner. The three reported Nutlins, -1, -2 and -3, show potency against p53-mdm2 binding in the 100–300 nmol range with 150- to 200-fold range in affinity between enantiomers. They inhibit the p53-mdm2 learn more axis by mimicking the interaction of the three critical amino acid residues with the hydrophobic activity of mdm2.20 In addition to their high potency in vitro, they penetrate cell membranes, activate p53 and inhibit cell proliferation at a range of 1–3 µmol. Released from its negative control in the presence of Nutlin (Fig. 1b), p53 is stabilized and accumulates in cells leading to the activation of target genes; for example, p21 and mdm2. This effect, however, is dependent on the presence of wt p53, because cells in

which p53 is deleted or mutated do not respond to Nutlin treatment.20 In addition to parenteral routes, Nutlins can also be given orally, which is highly desirable for their applicability in animal models and in the clinic.20 In this issue of the Journal, Wang et al.21 utilized Nutlin-3 against three human HCC cell lines with wt (HepG2), mutant (Hep3B) and null p53 (Huh7). This selective mdm2 antagonist induced growth arrest in all three cell types in vitro with significant abrogation of the pro-proliferative genes, cyclin D1/cdk4, cyclin E/cdk2 and E2F transcription factor. Cell cycle arrest was mediated by upregulation of p21 only in p53-intact HepG2 cells, whereas p27, another downstream target of p53, was expressed by all three tumor cell lines. Regardless of p53 status, Nutlin-3 treatment triggered increased apoptosis in all tumor cells, as well as increased expression of Bax, Noxa and PUMA.

16 Genotoxic and other stressful stimuli not only induce an accumulation of p53, but also the phosphorylation of mdm2, thereby enhancing p53′s nuclear localization, ubiquitination and subsequent degradation.17 Of note, mdm2 is overexpressed in many tumors and effectively impairs p53 function by selleck chemical binding

directly to p53; this promotes its ubiquitination and targeting to the 26S proteasome for protein degradation.17 Protein–protein interactions have long been considered challenging targets for therapeutic intervention, because their opposing surfaces are often too large or flat for effective disruption by small molecules. The more successful chemical antagonists take advantage of specific interactions

within well-defined pockets on the surfaces find protocol of one or both protein partners.18 The discovery that p53-mdm2 binding was dependent on only three p53 amino acid residues interacting with a discrete mdm2 pocket stimulated efforts to identify potential small molecule inhibitors.19 The first potent and selective antagonists of p53-mdm2 were the Nutlins.20 They represent a class of cis-imidazole analogues that bind to the p53 pocket on the surface of mdm2 in an enantiomer-specific manner. The three reported Nutlins, -1, -2 and -3, show potency against p53-mdm2 binding in the 100–300 nmol range with 150- to 200-fold range in affinity between enantiomers. They inhibit the p53-mdm2 click here axis by mimicking the interaction of the three critical amino acid residues with the hydrophobic activity of mdm2.20 In addition to their high potency in vitro, they penetrate cell membranes, activate p53 and inhibit cell proliferation at a range of 1–3 µmol. Released from its negative control in the presence of Nutlin (Fig. 1b), p53 is stabilized and accumulates in cells leading to the activation of target genes; for example, p21 and mdm2. This effect, however, is dependent on the presence of wt p53, because cells in

which p53 is deleted or mutated do not respond to Nutlin treatment.20 In addition to parenteral routes, Nutlins can also be given orally, which is highly desirable for their applicability in animal models and in the clinic.20 In this issue of the Journal, Wang et al.21 utilized Nutlin-3 against three human HCC cell lines with wt (HepG2), mutant (Hep3B) and null p53 (Huh7). This selective mdm2 antagonist induced growth arrest in all three cell types in vitro with significant abrogation of the pro-proliferative genes, cyclin D1/cdk4, cyclin E/cdk2 and E2F transcription factor. Cell cycle arrest was mediated by upregulation of p21 only in p53-intact HepG2 cells, whereas p27, another downstream target of p53, was expressed by all three tumor cell lines. Regardless of p53 status, Nutlin-3 treatment triggered increased apoptosis in all tumor cells, as well as increased expression of Bax, Noxa and PUMA.

0001). A similar pattern emerged for plasma

FFA concentration (Fig. 1B). Fasting FFA levels were comparable between lean and MHO patients (406 ± 47 versus 324 ± 25 μmol/L, respectively; P = 0.36). Despite increasing plasma http://www.selleckchem.com/products/epz-6438.html insulin concentration, there was a progressive increase in fasting plasma FFA concentration from Q1 to Q4 (436 ± 28 μmol/L [36% increase] to 718 ± 29 μmol/L [220% increase]; Q4 versus MHO; P < 0.0001). Postprandial FFA suppression during the OGTT was only slightly and nonsignificantly lower (i.e., worse) in MHO versus lean subjects (84% ± 2% versus 74% ± 5%, respectively; nonsignificant). Consistent with the fasting state, resistance to insulin's inhibitory effect on lipolysis was also evident in the postprandial state in Q1-Q4, being only 62% ± 3% in Q4 versus 74% ± 5% in MHO patients (P < 0.0001). Plasma AST (Fig. 2A) and ALT (Fig. 2B) were similar among lean

and MHO patients, but significantly higher in patients with NAFLD. They rapidly increased in Q1 by ∼1.5- to 2.0-fold (P < 0.05 versus lean and MHO). The percentage of patients with normal (arbitrarily <40 IU/L) aminotransferases decreased with worsening adipose tissue IR. Though all lean and MHO patients had normal AST/ALT, patients with normal AST/ALT decreased from 81/47% in Q1 to 51/16% in AZD2014 Q4 (Q4; P < 0.0001 versus MHO). Lean and obese insulin-sensitive subjects had a similar plasma lipid profile (Table 1; Fig. 3). Dysfunctional adipose tissue had no effect on total cholesterol (Fig. 3A) or LDL-C (Fig. 3B). However, HDL-C (Fig. 3C) decreased significantly by 20% in Q1 versus MHO patients (P < 0.01) and was most pronounced at Q4: 34 ± 1 (P < 0.001 versus MHO). Plasma TG increased in a similar pattern, even with mild click here adipose tissue IR (Q1 versus MHO: 92 ± 10 versus 158 ± 19; P = 0.05), and paralleled the worsening of adipose tissue IR (P < 0.001 versus MHO). MHO versus lean subjects showed a trend for decreased liver (Fig. 4A) and muscle (Fig. 4B) insulin sensitivity, although this

difference did not reach statistical significance (Table 1). There was ∼40%-50% worsening of HIRi between lean and MHO subjects versus Q1 and Q2 (P = 0.11), suggesting that hepatic IR develops even with a mild (Q1) to moderate (Q2) deterioration in adipose tissue insulin sensitivity (Fig. 4A). This was even more evident for Q3 and Q4, although liver fat remained constant (Q3) or was only slightly higher (Q4). As for skeletal muscle (Fig. 4B), there was an abrupt early-on decline in insulin action (Q1-Q3: −40%-50%; P < 0.001), with a further reduction to 62% in Q4 patients (P < 0.0001 versus MHO). There was a close relationship between adipose tissue, liver, and skeletal muscle IR. The liver had the strongest correlation with adipose tissue IR (r = 0.59, P < 0.0001; Fig. 5A), indicative of the deleterious effect of dysfunctional fat on hepatic metabolism. Skeletal muscle was also significantly affected (Fig.

0001). A similar pattern emerged for plasma

FFA concentration (Fig. 1B). Fasting FFA levels were comparable between lean and MHO patients (406 ± 47 versus 324 ± 25 μmol/L, respectively; P = 0.36). Despite increasing plasma CDK inhibitor review insulin concentration, there was a progressive increase in fasting plasma FFA concentration from Q1 to Q4 (436 ± 28 μmol/L [36% increase] to 718 ± 29 μmol/L [220% increase]; Q4 versus MHO; P < 0.0001). Postprandial FFA suppression during the OGTT was only slightly and nonsignificantly lower (i.e., worse) in MHO versus lean subjects (84% ± 2% versus 74% ± 5%, respectively; nonsignificant). Consistent with the fasting state, resistance to insulin's inhibitory effect on lipolysis was also evident in the postprandial state in Q1-Q4, being only 62% ± 3% in Q4 versus 74% ± 5% in MHO patients (P < 0.0001). Plasma AST (Fig. 2A) and ALT (Fig. 2B) were similar among lean

and MHO patients, but significantly higher in patients with NAFLD. They rapidly increased in Q1 by ∼1.5- to 2.0-fold (P < 0.05 versus lean and MHO). The percentage of patients with normal (arbitrarily <40 IU/L) aminotransferases decreased with worsening adipose tissue IR. Though all lean and MHO patients had normal AST/ALT, patients with normal AST/ALT decreased from 81/47% in Q1 to 51/16% in selleck screening library Q4 (Q4; P < 0.0001 versus MHO). Lean and obese insulin-sensitive subjects had a similar plasma lipid profile (Table 1; Fig. 3). Dysfunctional adipose tissue had no effect on total cholesterol (Fig. 3A) or LDL-C (Fig. 3B). However, HDL-C (Fig. 3C) decreased significantly by 20% in Q1 versus MHO patients (P < 0.01) and was most pronounced at Q4: 34 ± 1 (P < 0.001 versus MHO). Plasma TG increased in a similar pattern, even with mild click here adipose tissue IR (Q1 versus MHO: 92 ± 10 versus 158 ± 19; P = 0.05), and paralleled the worsening of adipose tissue IR (P < 0.001 versus MHO). MHO versus lean subjects showed a trend for decreased liver (Fig. 4A) and muscle (Fig. 4B) insulin sensitivity, although this

difference did not reach statistical significance (Table 1). There was ∼40%-50% worsening of HIRi between lean and MHO subjects versus Q1 and Q2 (P = 0.11), suggesting that hepatic IR develops even with a mild (Q1) to moderate (Q2) deterioration in adipose tissue insulin sensitivity (Fig. 4A). This was even more evident for Q3 and Q4, although liver fat remained constant (Q3) or was only slightly higher (Q4). As for skeletal muscle (Fig. 4B), there was an abrupt early-on decline in insulin action (Q1-Q3: −40%-50%; P < 0.001), with a further reduction to 62% in Q4 patients (P < 0.0001 versus MHO). There was a close relationship between adipose tissue, liver, and skeletal muscle IR. The liver had the strongest correlation with adipose tissue IR (r = 0.59, P < 0.0001; Fig. 5A), indicative of the deleterious effect of dysfunctional fat on hepatic metabolism. Skeletal muscle was also significantly affected (Fig.

Increase in mean diffusivity indicates the presence of interstitial brain edema. Mean diffusivity values increase as the grade of HE increases, suggesting that brain edema present in patients with HE may contribute to its pathogenesis.59 Mean diffusivity values decreased significantly and there was a corresponding improvement in neuropsychological test scores in patients with MHE after three weeks of lactulose therapy.59 MR imaging techniques therefore complement neuropsychological evaluation of MHE. 31 MRS, diffusion-weighted BMN 673 cell line imaging, magnetization transfer imaging and diffusion tensor

imaging show abnormalities in cirrhotic patients with or without HE. (1b) By definition, patients with MHE have a normal neurological examination; however they may still be symptomatic. Symptoms relate to disturbances in sleep, memory, attention, concentration and other areas of cognition.60,61 Sleep disturbance is a classic sign of HE. On a sleep questionnaire, disturbance is seen in 47% of cirrhotics and 38% of patients with chronic renal failure compared to 4.5% of controls.60 Studies using HRQOL

questionnaires have confirmed a higher frequency of sleep disturbance in cirrhotic patients with MHE as well.3,14 However, sleep disturbance in cirrhosis is not associated with cognitive impairment; thus it may not truly be an MHE symptom. Unsatisfactory sleep is associated with higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance. Disturbances in cirrhotics may also be related to abnormalities of circadian rhythm. Defective memory has also been shown to be a feature find more of MHE. Weissenborn et al.61 have shown that patients with MHE have impaired short- and long-term memory. This impairment was predominantly related to deficits in attention and visual perception. Memory deficit of MHE seems to comprise short-term but not long-term memory impairment. This can be described as an encoding defect, in which memory recall (or retrieval) is intact.

Several cognitive statements (i.e. complaints), have predictive value for MHE, including impaired psychomotor performance selleck (‘I have difficulty doing handwork; I am not working at all’); impaired sleep or rest (‘I spend much of the day lying down in order to rest’); decreased attention (‘I am confused and start several actions at a time’); and poor memory (‘I forget a lot; for example, things that happened recently, where I put things, etc.’).14 It has been shown conclusively that cognitive functions improve with therapy for MHE.3,62–67 Such therapy may improve HRQOL of patients with MHE3,67 and delay the development of HE.68 Hence all patients with liver cirrhosis should be subjected to testing for MHE. Special attention should be given to those who have cognitive symptoms and high-risk groups such as active drivers, patients handling heavy machines or reporting decline in work performance.

Increase in mean diffusivity indicates the presence of interstitial brain edema. Mean diffusivity values increase as the grade of HE increases, suggesting that brain edema present in patients with HE may contribute to its pathogenesis.59 Mean diffusivity values decreased significantly and there was a corresponding improvement in neuropsychological test scores in patients with MHE after three weeks of lactulose therapy.59 MR imaging techniques therefore complement neuropsychological evaluation of MHE. 31 MRS, diffusion-weighted Talazoparib concentration imaging, magnetization transfer imaging and diffusion tensor

imaging show abnormalities in cirrhotic patients with or without HE. (1b) By definition, patients with MHE have a normal neurological examination; however they may still be symptomatic. Symptoms relate to disturbances in sleep, memory, attention, concentration and other areas of cognition.60,61 Sleep disturbance is a classic sign of HE. On a sleep questionnaire, disturbance is seen in 47% of cirrhotics and 38% of patients with chronic renal failure compared to 4.5% of controls.60 Studies using HRQOL

questionnaires have confirmed a higher frequency of sleep disturbance in cirrhotic patients with MHE as well.3,14 However, sleep disturbance in cirrhosis is not associated with cognitive impairment; thus it may not truly be an MHE symptom. Unsatisfactory sleep is associated with higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance. Disturbances in cirrhotics may also be related to abnormalities of circadian rhythm. Defective memory has also been shown to be a feature Proteases inhibitor of MHE. Weissenborn et al.61 have shown that patients with MHE have impaired short- and long-term memory. This impairment was predominantly related to deficits in attention and visual perception. Memory deficit of MHE seems to comprise short-term but not long-term memory impairment. This can be described as an encoding defect, in which memory recall (or retrieval) is intact.

Several cognitive statements (i.e. complaints), have predictive value for MHE, including impaired psychomotor performance selleck screening library (‘I have difficulty doing handwork; I am not working at all’); impaired sleep or rest (‘I spend much of the day lying down in order to rest’); decreased attention (‘I am confused and start several actions at a time’); and poor memory (‘I forget a lot; for example, things that happened recently, where I put things, etc.’).14 It has been shown conclusively that cognitive functions improve with therapy for MHE.3,62–67 Such therapy may improve HRQOL of patients with MHE3,67 and delay the development of HE.68 Hence all patients with liver cirrhosis should be subjected to testing for MHE. Special attention should be given to those who have cognitive symptoms and high-risk groups such as active drivers, patients handling heavy machines or reporting decline in work performance.

Results: Gallbladder was enlarged in 35 patients (89 [86-106] mL) and within normal

range in 42 (41 [35-47] mL). Patients with enlarged gallbladders did not significantly differ from others regarding gender (65% vs. 66% males), median age (43 vs. 42 years), time from diagnosis (5 vs. 5.5 years), body mass index (21.6 vs. 23.7), associated inflammatory bowel disease (71% vs. 50%), UDCA treatment (89% vs. 90%), other MRI features including cystic abnormalities (8.5% vs. 12%), clinical or histological parameters of liver disease (Mayo risk score of −0.18 [−0.45-0.27] vs. −0.005 [−0.63-0.56]). Notably, malignancy was less frequent in the group with enlarged gallbladder, occurring in 2 (5.7%) vs. 11 (26.2%) patients with normal gallbladder size (P=0.029). Colorectal cancer in particular was 6.7-fold less frequent, occurring in 1 (2.8%) BGB324 nmr vs. 8 (19%) patients (P=0.037, OR=6.7 [0.9- 354])). In patients with enlarged gallbladder, the serum concentrations of secondary bile acids were lower than in other patients (1.6 [1.3-1.9] vs. 2.5 [2-3.1]

μmol/L, P=0.0004). This was true for deoxycholic acid (0.7 [0.5-1] vs. 2.2 [1-6-3] μmol/L, P=0.0001), a secondary bile acid known to promote colon carcinogenesis. Patients in this group also had higher concentrations of primary bile acids (10.5 [6.6-16.7] vs. 4.3 [3.5-5.3] μmol/L, P=0.0001) Chk inhibitor and of UDCA (44.0 [29.4-52] vs. 27.2 [14.6-31.1] μmol/L, P=0.001). Furthermore, they had higher serum concentrations of the gallbladder-relaxing hormone FGF19 (211.6 [168.6-234.6] vs. 88.6 [72.7-121.6] pg/mL, P=0.0001), learn more which concentration was correlated with gallbladder volume (R2=0.46, P=0.001) Conclusion: Gallbladder is enlarged in approximately half of PSC patients, which can be caused by increased FGF19 levels, and which is associated with a lack of secondary bile acids, enhanced UDCA enrichment and a lower prevalence of colorectal cancer, consistent with protective properties of gallbladder enlargement in PSC. Disclosures: Olivier Chazouillères – Consulting: APTALIS, MAYOLY-SPINDLER The following

people have nothing to disclose: Mourad Aissou, Lionel Arrivé, Dominique Rainteau, Sara Lemoinne, Astrid Donald D. Kemgang Fankem, Delphine Firrincieli, Nicolas Chignard, Christophe Corpechot, Chantal Housset [Background and Aims] Although it is well established that treatment with ursodeoxycholic acid (UDCA) improves long-term outcome in patients with primary biliary cirrhosis (PBC), it is still uncertain whether “early” PBC, with normal or low ALP levels and at early histological stages, would benefit from UDCA treatment. In Japan nationwide surveys for PBC have been performed every three year since 1980, and so far clinical data of 7,376 cases have been accumulated. In the current study we examined the long-term outcome of asymptomatic PBC patients with normal or low ALP and at early histological stages in whom UDCA treatment was not initiated.

Results: Gallbladder was enlarged in 35 patients (89 [86-106] mL) and within normal

range in 42 (41 [35-47] mL). Patients with enlarged gallbladders did not significantly differ from others regarding gender (65% vs. 66% males), median age (43 vs. 42 years), time from diagnosis (5 vs. 5.5 years), body mass index (21.6 vs. 23.7), associated inflammatory bowel disease (71% vs. 50%), UDCA treatment (89% vs. 90%), other MRI features including cystic abnormalities (8.5% vs. 12%), clinical or histological parameters of liver disease (Mayo risk score of −0.18 [−0.45-0.27] vs. −0.005 [−0.63-0.56]). Notably, malignancy was less frequent in the group with enlarged gallbladder, occurring in 2 (5.7%) vs. 11 (26.2%) patients with normal gallbladder size (P=0.029). Colorectal cancer in particular was 6.7-fold less frequent, occurring in 1 (2.8%) EPZ-6438 mouse vs. 8 (19%) patients (P=0.037, OR=6.7 [0.9- 354])). In patients with enlarged gallbladder, the serum concentrations of secondary bile acids were lower than in other patients (1.6 [1.3-1.9] vs. 2.5 [2-3.1]

μmol/L, P=0.0004). This was true for deoxycholic acid (0.7 [0.5-1] vs. 2.2 [1-6-3] μmol/L, P=0.0001), a secondary bile acid known to promote colon carcinogenesis. Patients in this group also had higher concentrations of primary bile acids (10.5 [6.6-16.7] vs. 4.3 [3.5-5.3] μmol/L, P=0.0001) AZD2014 in vitro and of UDCA (44.0 [29.4-52] vs. 27.2 [14.6-31.1] μmol/L, P=0.001). Furthermore, they had higher serum concentrations of the gallbladder-relaxing hormone FGF19 (211.6 [168.6-234.6] vs. 88.6 [72.7-121.6] pg/mL, P=0.0001), selleckchem which concentration was correlated with gallbladder volume (R2=0.46, P=0.001) Conclusion: Gallbladder is enlarged in approximately half of PSC patients, which can be caused by increased FGF19 levels, and which is associated with a lack of secondary bile acids, enhanced UDCA enrichment and a lower prevalence of colorectal cancer, consistent with protective properties of gallbladder enlargement in PSC. Disclosures: Olivier Chazouillères – Consulting: APTALIS, MAYOLY-SPINDLER The following

people have nothing to disclose: Mourad Aissou, Lionel Arrivé, Dominique Rainteau, Sara Lemoinne, Astrid Donald D. Kemgang Fankem, Delphine Firrincieli, Nicolas Chignard, Christophe Corpechot, Chantal Housset [Background and Aims] Although it is well established that treatment with ursodeoxycholic acid (UDCA) improves long-term outcome in patients with primary biliary cirrhosis (PBC), it is still uncertain whether “early” PBC, with normal or low ALP levels and at early histological stages, would benefit from UDCA treatment. In Japan nationwide surveys for PBC have been performed every three year since 1980, and so far clinical data of 7,376 cases have been accumulated. In the current study we examined the long-term outcome of asymptomatic PBC patients with normal or low ALP and at early histological stages in whom UDCA treatment was not initiated.