Despite their striking diversity, the songs of rattling cisticola

Despite their striking diversity, the songs of rattling cisticolas have traits that are a characteristic of the species across a wide geographic range. Song form has likely evolved as a result of multiple evolutionary pressures, including stabilizing selection on some elements for species identification and selection for diversity on the form and frequency characteristics of other elements. In a previous study (Benedict & Bowie, 2009), we found that a congener, the red-faced cisticola, also showed diverse song forms with some species-specific elements, supporting Daporinad the idea that song form is generated by multiple evolutionary pressures (Seddon, 2005). In both cisticola

species, song structure and a few characteristic syllable forms are fixed, but birds of the two species generate song diversity differently. Red-faced cisticolas mix up the ordering Tyrosine Kinase Inhibitor Library of syllables and vary song duration, whereas rattling cisticolas have relatively fixed song durations and ordering, but generate highly variable end-phrase forms (Benedict & Bowie, 2009). These two data points illustrate the potential for song variation to arise through many different avenues. Fixed features can take many forms, potentially allowing all 40 plus species of the morphologically

conserved cisticola warblers to signal species identity with song. These studies illustrate the importance of phenotypic features beyond morphology for species identification. They also emphasize the value of library resources Vasopressin Receptor for evaluating phenotypic features of problematic groups. Many forms of information, including sound archives with wide geographic sampling, are available to researchers wishing to examine current patterns of diversity and the resulting indicators of evolutionary processes. We thank the Wildlife Division of the British Library, the Macaulay Library of Natural Sounds and the Ditsong Museum of Natural History (Transvaal Museum) for providing song samples, as well as all of the authors who contributed to these valuable sound

depositories. This paper was improved by comments from Jay McEntee, Alex Kirschel, Tim Parker, Tereza Petruskova and an anonymous reviewer. Thanks are due to Kim Hoke for statistical advice. Funding to conduct this study was provided by the Museum of Vertebrate Zoology Alexander Fund. “
“Little is known about how season influences burrowing activity, burrow structure or reproductive behaviour in subterranean mammals. We excavated burrow systems of male and female Georychus capensis, a solitary, subterranean rodent, in winter (wet season) and summer (dry season) to investigate whether, if any, seasonal differences were due to putative mate-seeking behaviour of males. Burrow structure differed between seasons but not between sexes.

Thief pigeons are worth further study The second example of prom

Thief pigeons are worth further study. The second example of promiscuity was one Darwin (1871) cited in Descent. The information came from his cousin

William Darwin Fox and involved the two species of geese he kept. In one season, a male Chinese goose seduced a white domestic goose, causing her to abandon her domestic gander: when the female’s clutch hatched, it was immediately evident from the appearance of the goslings that both the Chinese gander and the white gander had fathered offspring: promiscuity and multiple paternity in a single, striking example. With such clear evidence in front of him, it is easy (with the benefit of hindsight) to ask how Darwin could have overlooked the potential for promiscuity and sperm competition. In this instance, I think Victorian prudery won out over science (Birkhead, 1997), but Smith (1998) MAPK inhibitor Selleck KU-57788 offers

some other possibilities. He suggests that Darwin (and many of his successors) were psychologically predisposed to presume that females are monogamous. If so, the few explicit examples of female promiscuity that Darwin was aware of were then viewed as exceptions and could be ignored. Darwin may also have assumed pre-copulatory choice to preclude the necessity of female promiscuity. Finally, Smith (1998) suggests that during Darwin’s lifetime, knowledge of sexual reproduction was both amorphous and confused, creating an intellectual barrier that prevented Darwin from considering the implications of female promiscuity. As far as I am aware, there is no synthesis of what Darwin understood or did not understand about sexual reproduction in animals. He wrote extensively about the process of fertilization in plants, and so it is almost inconceivable that he did not have an interest in animal reproduction, and yet our understanding of Darwin’s knowledge of sexual reproduction remains Astemizole unclear. He knew a great deal about the reproductive anatomy of the barnacles

he spent so long dissecting. We also know from his notebooks (Barrett et al., 1987) that he had read Spallanzani’s (1769) ingenious study from the late 1700s that erroneously concluded that spermatozoa had no role in fertilization. As Smith (1998) points out, Spallazani’s account of fertilization must have confused Darwin, and continues: ‘Perhaps it was this confusion that pressed Darwin to his own fuzzy “gemmule” theory of inheritance [pangenesis], which despite its own vagaries at least restored a heritable male contribution to reproduction’. Smith then says: ‘Ideas about fertilisation and heredity remained extremely amorphous through the eighteenth and most of the nineteenth centuries …’. While it is certainly true that ideas about heredity remained amorphous, it is less clear why Darwin should have remained confused about sexual reproduction.

The comparison between patients with or without steatosis are sho

The comparison between patients with or without steatosis are shown in Table 2. By univariate analysis, ALT (P = 0.0004), AST (P = 0.0005), HOMA-IR (P = 0.0043), GGT (P = 0.0044), BMI (P = 0.0049), fasting insulin (P = 0.0050) and age (P = 0.0379) were significantly associated with liver steatosis. By multivariate analysis, L/S ratio (P = 0.012; OR, 0.501; CI, 0.29–0.86), AST (P = 0.022; OR, 1.253; CI, 1.03–1.52), and HOMA-IR (P = 0.041; OR, 1.335; CI, 1.01–1.76) were significantly associated with liver steatosis (Table 3). The percentage of steatosis was calculated by using Dynamic cell

count BZ-H1C Selleck Y27632 software after measuring the real steatotic area of liver specimens by BIOREVO BZ-9000 microscope. Figure 2 (a) shows the relationship between steatotic grades and percentage of steatosis. Percentage of steatosis was significantly correlated with the steatotic grade (r = 0.86, P = 1.85 × 10−18). L/S ratios were: S0, 1.16 ± 0.20 (mean ± SD); S1, 0.88 ± 0.28; S2, 0.76 ± 0.20; and S3, 0.40 ± 0.18, respectively (Fig. 2a). L/S ratio was negatively

correlated with steatotic grade (r = −0.77, P = 7.94 × 10−13) (Fig. 2b). Because the percentage of steatosis was evaluated from the liver specimens, this was expected to show the real fat deposition in the liver. Therefore, the relationship between the percentage of steatosis and L/S ratio was compared Urease (Fig. 3), and showed the significant negative correlation. Based on this curve, L/S ratio could Apitolisib manufacturer be expected by the formula: (−0.6356 × [log percentage of steatosis] + 1.2964). The AUROC for the diagnosis of steatosis was 0.886 for L/S ratio (Fig. 4). The optimum cut-off value for L/S ratio to exclude steatosis was 1.1 which produced sensitivity and specificity values of 83.3% and 93.3%, respectively, as well as a positive predictive value of 97.6% and a negative predictive value of 63.3%. THIS STUDY ATTEMPTED to elucidate

the accuracy of histological diagnosis of fatty deposition by pathologists and also to demonstrate the optimal cut-off value for the diagnosis of fatty liver on CT. As a result, evaluation by histological findings and steatotic grades assessed by a pathologist were comparatively accurate compared with imaging modalities such as CT in this case. That is, steatotic grades diagnosed by a pathologist were significantly correlated with the percentage of steatosis and L/S ratio. From the point of laboratory findings, patients with steatosis were younger, had higher BMI, and increased AST, ALT, GGT and HOMA-IR. By multivariate logistic regression analysis, AST and HOMA-IR were independently associated with steatosis. For the non-invasive assessment of liver steatosis, imaging analyses and histological findings were compared to elucidate the utility of L/S ratio on CT.

Conclusions: Silencing NGF may have a beneficial, anti-inflammato

Conclusions: Silencing NGF may have a beneficial, anti-inflammatory and protective effect in acute hepatotoxicity models. The following people have nothing to disclose: Rafael Bruck, Einav Hubel, Isabel Zvibel Aim: The goal

of this study was to investigate the relationship between inflammation-related microRNAs and NAFLD patho-genesis in a rodent model with metabolic syndrome. Methods: Leptin receptor deficient (Leprdb/db) mice were fed a high fat diet or standard chow for 5 or 10 weeks. Liver histology was scored for steatosis, ballooning, inflammation, fibrosis and NAFLD activity score (NAS) by a hepatopathologist; and classified Autophagy Compound Library cell line into DM (diabetes mellitus), NAFL (nonalcoholic fatty liver) and NASH (nonalcoholic steatohepatitis) groups. Serum were analyzed for metabolic changes, and hepatic microRNA (miR-122, −146a, −155, and −223) levels were determined. Results: Greater find more than half of the mice fed high-fat diet developed NASH compared to controls. Mice with NAFL and NASH had elevated hepatic triglycerides,

serum aminotransferases, inflammatory cytokines (IL-6 and TNF-α), glucose and insulin levels. Expression of miR-155 and −223 (p<0.01 for both] were increased in NAFL and NASH mice, while miR-122 was decreased, relative to DM. Expression of miR-146a were also increased in the livers of NAFL and NASH mice compared to DM mice (p<0.03), though the extent of increase was smaller compared to miR155 and 223. Increased levels of miR155 correlated with upregulation of its transactivator and target, NF-KB, in NASH livers, indicated by increased phosphoryla-tion of the p65 subunit of NF-KB, and increased expression of MCP-1, an NF-KB regulated chemokine and CCR2, its cognate receptor. http://www.selleck.co.jp/products/carfilzomib-pr-171.html Consistent with the upregulation of miR-155 (and down-regulation of miR-122), we observed increased infiltration of macrophages in NASH livers indicated by increased F480 and Mac-2 staining; and elevated CD68, F480 and CD11b gene expression levels in the NASH livers, relative to DM. Also consistently,

T cell markers such as CD3gamma, IFN-gamma, MHCII and CD8 were upregulated in NASH livers. Regression analysis revealed that correlating miR-155 versus miR-223 gave a Pearson r of 0.91. These miRs were strongly associated with %mass increase (r=0.61, p<0.0001 for both), ALT & AST (r>0.56, p<0.001 for all), adiponectin (r<-0.50 for both, p<0.001), and NAS (Spearman r=0.50, p<0.001 for both). Conclusions: MicroRNAs associated with inflammation, especially miR155 and its known targets, were significantly altered in this mouse model of NASH, suggesting their involvement in cytokine/chemokine induction and immune cell recruitment and activation. The significant Pearson’s correlation between MiR-155 and miR-223 indicated that these microRNAs are involved in similar inflammatory cascades in NASH progression. These studies emphasize a key role for these microRNAs in NASH pathogenesis. Kris V.

Conclusions: Silencing NGF may have a beneficial, anti-inflammato

Conclusions: Silencing NGF may have a beneficial, anti-inflammatory and protective effect in acute hepatotoxicity models. The following people have nothing to disclose: Rafael Bruck, Einav Hubel, Isabel Zvibel Aim: The goal

of this study was to investigate the relationship between inflammation-related microRNAs and NAFLD patho-genesis in a rodent model with metabolic syndrome. Methods: Leptin receptor deficient (Leprdb/db) mice were fed a high fat diet or standard chow for 5 or 10 weeks. Liver histology was scored for steatosis, ballooning, inflammation, fibrosis and NAFLD activity score (NAS) by a hepatopathologist; and classified Forskolin nmr into DM (diabetes mellitus), NAFL (nonalcoholic fatty liver) and NASH (nonalcoholic steatohepatitis) groups. Serum were analyzed for metabolic changes, and hepatic microRNA (miR-122, −146a, −155, and −223) levels were determined. Results: Greater CB-839 order than half of the mice fed high-fat diet developed NASH compared to controls. Mice with NAFL and NASH had elevated hepatic triglycerides,

serum aminotransferases, inflammatory cytokines (IL-6 and TNF-α), glucose and insulin levels. Expression of miR-155 and −223 (p<0.01 for both] were increased in NAFL and NASH mice, while miR-122 was decreased, relative to DM. Expression of miR-146a were also increased in the livers of NAFL and NASH mice compared to DM mice (p<0.03), though the extent of increase was smaller compared to miR155 and 223. Increased levels of miR155 correlated with upregulation of its transactivator and target, NF-KB, in NASH livers, indicated by increased phosphoryla-tion of the p65 subunit of NF-KB, and increased expression of MCP-1, an NF-KB regulated chemokine and CCR2, its cognate receptor. DNA ligase Consistent with the upregulation of miR-155 (and down-regulation of miR-122), we observed increased infiltration of macrophages in NASH livers indicated by increased F480 and Mac-2 staining; and elevated CD68, F480 and CD11b gene expression levels in the NASH livers, relative to DM. Also consistently,

T cell markers such as CD3gamma, IFN-gamma, MHCII and CD8 were upregulated in NASH livers. Regression analysis revealed that correlating miR-155 versus miR-223 gave a Pearson r of 0.91. These miRs were strongly associated with %mass increase (r=0.61, p<0.0001 for both), ALT & AST (r>0.56, p<0.001 for all), adiponectin (r<-0.50 for both, p<0.001), and NAS (Spearman r=0.50, p<0.001 for both). Conclusions: MicroRNAs associated with inflammation, especially miR155 and its known targets, were significantly altered in this mouse model of NASH, suggesting their involvement in cytokine/chemokine induction and immune cell recruitment and activation. The significant Pearson’s correlation between MiR-155 and miR-223 indicated that these microRNAs are involved in similar inflammatory cascades in NASH progression. These studies emphasize a key role for these microRNAs in NASH pathogenesis. Kris V.

The latest of several such candidates for use in BE surveillance

The latest of several such candidates for use in BE surveillance is a small peptide sequence which has been

shown to bind specifically to the surface of dysplastic mucosa ex vivo; this bound peptide can be detected endoscopically by use of a fluorescent HKI-272 mw tag.39 Rigorous assessments of the clinical utility of molecular probes for BE surveillance should appear in the next few years. A possible major limitation of using a highly specific probe is the considerable diversity of genetic changes seen in EA4. The demonstrated ability of endoscopic confocal microscopy to display mucosal histology is an impressive and provocative technical development. The most recent evaluations of its accuracy suggest that variability of diagnoses among observers is

a significant issue,40,41 which is no surprise, given the practical issues of interpretation of traditional biopsies discussed below. Another important limitation of this technique is that it may not provide sufficient opportunity for later review of histologic interpretations by another “pathologist” which, as discussed below, is so important to good management of BE. Considerably more research needs to be done before endoscopic confocal microscopy might be proven as a valid, routine diagnostic approach for mucosal assessment in BE. Pech and colleagues have used a Japanese AZD6244 cell line surface topographic classification (originally designed to aid recognition of early gastric cancers suitable for endoscopic mucosal resection), to reliably subdivide 380 early EAs into five topographic types. Most BE centers have adopted this classification, but early data suggest that it is not sufficiently sensitive for use as a primary method for defining the clinically crucial depth of penetration

of early EA.42 High frequency endoscopic ultrasound is a theoretically attractive option for staging early EA,42 but unfortunately this method has an unacceptably low (less than 30%) sensitivity for detection of submucosal penetration by early, mainly surveillance-detected EA, Anacetrapib when histopathologic examination of endoscopically resected EA is used as the gold standard.43,44 These data relegate endoscopic ultrasound to a secondary role for staging apparently early EA. Endoscopic resection presents the pathologist with an extensive “surgical” specimen which gives a highly accurate measure of the extent of EA, both into the depth and along the length of the esophagus. The determination whether EA is confined to the mucosa is the crucial variable, since if this is so, there is only a low risk of metastatic spread: by contrast, penetration of EA into the submucosa to any degree not only makes complete local removal by endoscopic therapy difficult to achieve, but is also associated with a much higher risk of lymph node metastases irrespective of the depth of submucosal penetration.

For neutralization of endogenous IL-17A or IL-23, 02 mg of neutr

For neutralization of endogenous IL-17A or IL-23, 0.2 mg of neutralizing rabbit antimouse IL-17A (Clone TC11-18H10.1, BioLegend, USA) or neutralizing rabbit antimouse IL-123p19 (Clone G23-8, eBioscience, USA) was administered intravenously at the time of acetaminophen treatment. Control rabbit IgG was used as an isotype control. For deletion of γδ T cells, NK1.1+ cells, or CD4+ cells, the mice were injected intravenously with 0.5 mg of an anti-γδ TCR mAb (clone TIB-207, ATCC, Manassas, VA), anti-NK1.1

mAb (clone HB191, ATCC), or anti-CD4 mAb (clone TIB-207, ATCC), respectively, 48 hours before acetaminophen treatment. For inhibition of macrophages, mice were injected intravenously with GdCl3 at 20 mg/kg (body weight, Sigma-Aldrich) GSI-IX research buy at 24 hours before acetaminophen treatment. For inhibition of HMGB1, mice were treated with glycyrrhizin (TCI, Shanghai, China) at 5 mg/mouse 1 hour before acetaminophen

treatment. Acute liver injury was evaluated by serum levels of ALT and total bilirubin. They were measured using diagnostic kits (Rongsheng, Shanghai, China). Total RNA was isolated from frozen liver tissue using total RNA purification solutions (Invitrogen, USA). Two μg of total RNA was reverse-transcribed at 25°C for 15 minutes, 42°C for 50 minutes, and 70°C for 10 minutes using reverse transcription kits (Sangon Biotech, Shanghai, China). Complementary DNA (cDNA) fragments were amplified using the following gene-specific primers: IL-17A (sense 5-GCTCCAGA AGGCCCTCAG-3; antisense 5-CTTTCCCTCGCA oxyclozanide Selleckchem Y 27632 TTGACA-3); IL-23p19 (sense 5-AGCGGGACATAT GAATCTACTAAGAGA-3; antisense 5-TCCTAGT AGG GAGGTGTGAAGTTG-3); IL-23p40 (sense 5-TCCACCAAACTCCCCAGACA-3; antisense 5-CTG TGCATGCTCTTTGGTTGAT-3); and β-actin (sense 5-TGGAATCCTGTGGCATCCATGAAA-3; antisense 5-TAAAACGCAGCTCAGTAACAGTCC-3).

Quantitative RT-PCR was performed to measure the messenger RNA (mRNA) expression of IL-17A, IL-23p19, and IL-23p40 using commercially available SYBR Premix Ex Taq (TaKaRa Biotechnology, Dalian, China) and specific primers in a reaction with an optimal number of cycles at 95°C for 10 seconds, then 60°C for 30 seconds in a Corbett Rotor-Gene 3000 real-time PCR system (Corbett Research). The gene expression levels were calculated relative to the housekeeping gene β-actin. Liver specimens from mice exposed to different treatments were fixed in 4% paraformaldehyde, dehydrated with a graded series of alcohol, and embedded in paraffin. Six-micron tissue sections were prepared and stained with H&E. At each indicated timepoint, sera were harvested for measurement of IL-17A, IL-23, IL-23p40, and HMGB1. Hepatic mononuclear cells were stimulated in vitro with IL-1β (50 ng/mL, PeproTech, USA), IL-23 (50 ng/mL, Miltenyi Biotec, USA) or the combination for 48 hours.

[15] In these studies, groups of PPAR-α-expressing WD-fed hApoE2

[15] In these studies, groups of PPAR-α-expressing WD-fed hApoE2 KI mice were included for comparison. Treatment of PPAR-α-expressing

hApoE2 KI mice with GFT505 significantly reduced plasma total cholesterol, triglycerides (TGs), and free fatty acids (FFAs) and strongly increased high-density lipoprotein (HDL) cholesterol levels (Fig. 1A-D). In hApoE2 KI/PPAR-α KO mice, GFT505 failed to influence plasma TGs (Fig. 1A). However, in this strain of mice, GFT505 still decreased plasma FFAs and total cholesterol and increased HDL cholesterol, albeit to a lesser extent (Fig. 1B-D). These data suggest that GFT505 selleckchem may have favorable effects on plasma lipids that are independent of activation of PPAR-α. In contrast, in a similar study, the PPAR-α reference agonist, fenofibrate (100 mg/kg/day), did not show any lipid-modulating effects in hApoE2 KI/PPAR-α KO mice (Supporting Fig. 2A-D). As expected in rodents exposed to a PPAR-α agonist,[11] GFT505 significantly

increased liver weight in hApoE2 KI mice, but not in hApoE2 KI/PPAR-α KO mice (Fig. GSK2126458 1E), illustrating the hyperresponsiveness of rodents to PPAR-α-induced peroxisomal proliferation and hepatomegaly. Similar findings were observed with fenofibrate (data not shown). Microscopic examination of livers revealed both macro- and microsteatosis in WD-fed hApoE2 KI/PPAR-α KO mice, whereas PPAR-α-expressing hApoE2 KI mice were relatively resistant to WD-induced steatosis (Fig. 2A-C). In hApoE2 KI/PPAR-α KO mice, GFT505 administration reduced both diet-induced macro- and microsteatosis Osimertinib ic50 (Fig. 2A-C) and significantly reduced circulating

levels of the liver dysfunction markers, aspartate aminotransferase (AST) and ALT (data not shown). Interestingly, GFT505 reduced WD-induced increased cellularity in sinusoids (KCs) in both hApoE2 KI and hApoE2 KI/PPAR-α KO mice (Fig. 2D). In contrast, fenofibrate had no effect on cellularity of sinusoids in ApoE2 KI/PPAR-α KO mice (Supporting Fig. 2E,F). These results suggested that GFT505 has liver-protective effects through combined PPAR-α-dependent and -independent mechanisms. In hApoE2 KI mice, GFT505 provoked a significant reduction in hepatic expression of proinflammatory genes, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), the macrophage marker, F4/80, and the fibrosis genes, transforming growth factor beta (TGF-β) and tissue inhibitor of metalloproteinase (TIMP)−2 (Supporting Table 2). In hApoE2 KI/PPAR-α KO mice, these genes were also reduced by GFT505, with significant down-regulation of additional profibrosis markers, such as collagens (Supporting Table 2). In contrast, fenofibrate significantly reduced the expression of proinflammatory and profibrotic genes in hApoE2 KI mice, but had little effect in hApoE2 KI/PPAR-α KO mice. In keeping with PPAR-α agonist-induced hepatomegaly in rodents (Fig.

The major limitations

The major limitations Vismodegib research buy in recruiting patients into trials were the requirement of liver biopsy

and the need of drug substitution. A liver biopsy was obtained in 98% of study participants, but in only 59% of SOC patients. Among biopsied patients, advanced fibrosis was more common in SOC patients (40%) than in study patients (21%). This may be an underestimate, because patients in the SOC group may have been cirrhotic, but did not undergo biopsy, because they had obvious clinical, laboratory, or radiographic features of cirrhosis. Most studies excluded patients on drug-substitution therapy, representing a substantial proportion of patients in “real life.” In SOC patients on drug-substitution therapy lost to follow-up, the rate was 56%, but only 9% Stem Cell Compound Library in study patients. The limitations of this study were its retrospective nature and the variations within each treatment protocol. A direct comparison of the SVR rates in SOC and study patients was not possible. SOC patients represent an inhomogeneous group consisting of persons not willing or not being able (because of stringent timelines for recruitment or the presence of exclusion criteria) to participate in randomized, controlled trials. Furthermore, most SOC patients were treated by a response-guided treatment concept. Treatment extension may have slightly improved outcome on peg-IFN/RBV-based

treatment in our SOC cohort. Also, the design of the DAA studies varied considerably and did not allow a comparison between different regimes. Except for one study, DAA trials included a placebo arm; the PROVE-2 trial9 also evaluated patients not receiving RBV. Because

all phase II and III studies with telaprevir were published,9, 11, 14 we could analyze the outcome of patients treated with telaprevir (Table 4; Fig. 2). All other studies are as yet unpublished and their results cannot be presented Levetiracetam separately because of confidentially issues. The balapiravir study was prematurely stopped because of severe side effects,20 and therefore, patients participating in that trial were not included for further SVR analysis. In unblinded studies, the outcome of the DAA or placebo groups could be compared. The improved SVR rates on DAA became only detectable in the ITT analysis. Similarly, ITT-SVR rates in patients receiving peg-IFN/RBV within a study setting (63%) with stringent inclusion and exclusion criteria were higher than in SOC patients (46%; P < 0.02), reinforcing the role of adherence to optimize treatment outcome. Overall, participation in well-controlled, prospective trials may increase adherence by a strict visit schedule and also allows an early treatment of side effects, resulting in lower drop-out rates. In addition, study patients are, in general, better informed, having detailed discussion about study design, treatment procedures, and potential side effects before signing informed consent.

400)] and 3% at month 30 [27 IU/ml (12-1040)] Transient virolog

400)] and 3% at month 30 [27 IU/ml (12-1.040)]. Transient virological breakthroughs were observed in few patients only, no resistance to TDF was observed. Serum

creatinine and phosphorus blood levels remained unchanged over time (0.90 mg/dl; 3.3 mg/dl) while eGFR declined from 84 to 80 ml/min. The proportion of patients with eGFR<50 and <60 ml/min (MDRD) increased from 2% to 3% (year 4) and from 7% to 1 1 % (year 4), respectively. The proportion of patients with blood phosphate below 2.3 mg/dl increased from 2%(baseline) to 5.1%(year 4), while 1% of the patients had phosphate <2.0 throughout the study period. Due to renal events, TDF dose was adjusted Z-VAD-FMK in vitro in 19 (5%) patients (eGFR decline in 17; low phosphate in 2) and discontinued in additional 7 (2%) patients who were switched to ETV (Overall, renal events in 26 patients,7%). Nine additional patients

withdrew from TDF and switched to ETV because of nonrenal related side effects. HCC developed in 1 0 compensated cirrhotics (4-year cumulative probability: 1 7%, 4.2%/year) and in 6 non cirrhotics (4-year cumulative probability: 4%, 1 %/year) while no cirrhotics clinically decom-pensated. Overall, 3.7% of patients died (7 for HCC, 1 liver failure, 4 extrahepatic, 2 unknown) and 1.6% underwent liver transplantation (4 buy PD0325901 RAS p21 protein activator 1 with HCC, 2 with baseline decompensated disease). In conclusion, 4 years of TDF suppressed HBV replication in most treatment-naïve field practice European patients with CHB without any major renal safety signal but failed to prevent HCC independently of liver disease severity Disclosures: Pietro Lampertico – Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline,

Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead Cihan Yurdaydin – Advisory Committees or Review Panels: Janssen, Roche, Merck, Gilead George V. Papatheodoridis – Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD Maria Buti – Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis Rafael Esteban – Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo, MSD, BMS, Novartis, Gilead, Glaxo, Janssen Serena Zaltron – Speaking and Teaching: BMS, MSD Mauro Viganò – Consulting: Roche; Speaking and Teaching: Gilead Sciences, BMS Maria G.