It has been suggested that most hepatotoxic drugs are administered at ≥100 mg/day, while few are

administered at <10 mg/day.8, 11 Therefore, we defined three dose groups: daily doses <10 mg, 10-100 mg, and ≥100 mg. A drug's lipophilicity is measured by an octanol-water partition coefficient (i.e., logP), which was calculated from the atomic-based prediction of AlogP using quantitative buy PXD101 structure-property relationship algorithms in Pipeline Pilot (version 8.0; Accelrys Inc, San Diego, CA). Waring13 reviewed the relevant literatures and recommended that the appropriate lipoplilicity for most drugs should be in the range of 1-3. Therefore, we defined three groups: <1, 1-3, and ≥ 3. To demonstrate clinical use of the rule-of-two, information for six DILI cases was retrieved from the National Institutes of Health LiverTox database (http://livertox.nlm.nih.gov/). These cases were chosen arbitrarily. The causality assessment was performed by a panel of independent physicians/health care professionals as described in detail at http://livertox.nlm.nih.gov/. The Cochran-Armitage test was applied to assess the relationship between logP and DILI in different daily dose groups. The odds ratio (OR) obtained from the logistic regression was used to measure

the relative risk for DILI in a specific group. A two-sided Fisher’s exact test was used to examine statistical significance of the association. The Cochran-Armitage test was performed using the “Coin” package (http://cran.r-project.org/web/packages/coin/index.html), RG7420 order and estimates for the OR and Fisher’s exact tests were obtained using R and the “Stats” package.20 First, we analyzed 164 medications of the LTKB-BD 上海皓元 database to explore the relationship between lipophilicity, daily

dose, and hepatotoxicity. As shown in Fig. 1A, at daily doses of <100 mg, no clear trend could be observed with most-DILI-concern and no-DILI-concern drugs being scattered across different logP values. In contrast, at daily doses of ≥100 mg and logP of ≥3, most-DILI-concern drugs (n = 44) were distributed into the upper right quadrant. Only two no-DILI-concern drugs appeared in this region, while no-DILI-concern drugs are associated with lower logP and daily doses, respectively. A Cochran-Armitage test9 was employed to assess the statistical significance of the relationship between logP, daily dose, and risk for DILI. Drugs were assigned into various subgroups defined by daily dose and logP. A summary of the prevalence of most-DILI-concern drugs for individual subgroups is given in Table 1. A statistically significant association between logP and risk for DILI was observed (P = 1.86E-7) for drugs given at daily doses of ≥100 mg. Here, 96%, 92%, and 65% were most-DILI-concern drugs with logP of either ≥3, 3-1, or <1, respectively. At daily doses of <100 mg, no statistically significant relationship between logP and hepatotoxicity was obtained.

It has been suggested that most hepatotoxic drugs are administered at ≥100 mg/day, while few are

administered at <10 mg/day.8, 11 Therefore, we defined three dose groups: daily doses <10 mg, 10-100 mg, and ≥100 mg. A drug's lipophilicity is measured by an octanol-water partition coefficient (i.e., logP), which was calculated from the atomic-based prediction of AlogP using quantitative Selleckchem INK 128 structure-property relationship algorithms in Pipeline Pilot (version 8.0; Accelrys Inc, San Diego, CA). Waring13 reviewed the relevant literatures and recommended that the appropriate lipoplilicity for most drugs should be in the range of 1-3. Therefore, we defined three groups: <1, 1-3, and ≥ 3. To demonstrate clinical use of the rule-of-two, information for six DILI cases was retrieved from the National Institutes of Health LiverTox database (http://livertox.nlm.nih.gov/). These cases were chosen arbitrarily. The causality assessment was performed by a panel of independent physicians/health care professionals as described in detail at http://livertox.nlm.nih.gov/. The Cochran-Armitage test was applied to assess the relationship between logP and DILI in different daily dose groups. The odds ratio (OR) obtained from the logistic regression was used to measure

the relative risk for DILI in a specific group. A two-sided Fisher’s exact test was used to examine statistical significance of the association. The Cochran-Armitage test was performed using the “Coin” package (http://cran.r-project.org/web/packages/coin/index.html), ALK inhibitor and estimates for the OR and Fisher’s exact tests were obtained using R and the “Stats” package.20 First, we analyzed 164 medications of the LTKB-BD 上海皓元医药股份有限公司 database to explore the relationship between lipophilicity, daily

dose, and hepatotoxicity. As shown in Fig. 1A, at daily doses of <100 mg, no clear trend could be observed with most-DILI-concern and no-DILI-concern drugs being scattered across different logP values. In contrast, at daily doses of ≥100 mg and logP of ≥3, most-DILI-concern drugs (n = 44) were distributed into the upper right quadrant. Only two no-DILI-concern drugs appeared in this region, while no-DILI-concern drugs are associated with lower logP and daily doses, respectively. A Cochran-Armitage test9 was employed to assess the statistical significance of the relationship between logP, daily dose, and risk for DILI. Drugs were assigned into various subgroups defined by daily dose and logP. A summary of the prevalence of most-DILI-concern drugs for individual subgroups is given in Table 1. A statistically significant association between logP and risk for DILI was observed (P = 1.86E-7) for drugs given at daily doses of ≥100 mg. Here, 96%, 92%, and 65% were most-DILI-concern drugs with logP of either ≥3, 3-1, or <1, respectively. At daily doses of <100 mg, no statistically significant relationship between logP and hepatotoxicity was obtained.

The overall prevalence of inhibitors in hemophilia is estimated at 5–7% for hemophilia A and 1.5–4% for hemophilia B. Inhibitor incidence is higher in severe hemophilia A patients at initial treatment (previously untreated patients, PUPs, average incidence 25%),

with a peak incidence after 14–20 days of treatment (exposure days, ED). In severe hemophilia B patients the incidence varies R428 manufacturer between 9 and 23%, with a peak incidence at 7–10 ED. The incidence of inhibitors in hemophilia A patients after the initial treatment period (previously treated patients, PTPs) is estimated at around 0.2/100 patient years, with the upper limit of the confidence interval at 0.4. Very little is known about the natural history of inhibitors in the absence of treatments aiming at their eradication (immunotolerance induction, ITI). “
“The principles of pharmacokinetic (PK) dose tailoring in clinical practice, using

limited blood sampling and Bayesian PK analysis, have been described for factor VIII (FVIII). This study applied the same procedure to recombinant FIX (rFIX), i.e. population PK modelling and the use of a simplified (one-compartment) model to describe only the terminal part of the coagulation factor vs. time curve. Data from a previous study on rFIX in 56 patients (4–56 years, 18–133 kg) were used to define a three-compartment population PK model. The average FIX clearance was 8.4 mL h−1 kg−1. DMXAA order Elimination half-life ranged between 14 and 27 h. Data obtained from 24 h after the infusion were found to define the terminal phase of FIX disposition. MCE公司 Doses to produce a target trough FIX level (set at 0.01 IU mL−1) at 72 h predicted by the Bayesian analysis, with blood sampling at either 24, 48 and 72 h or at only 24 and 48 h, were within −40% to +67% of those predicted using the three-compartment model, and within −57% to +125% for targeting a level at 96 h. These errors were lower than the overall interindividual variance in dose requirements. As three-compartment models are needed to characterize the PK of both plasma-derived

FIX and rFIX, simplification to a one-compartment model is less straightforward than for FVIII, and the methodology should be investigated further before clinical application. Limited blood sampling and Bayesian analysis could still, however, be potentially useful for targeting rFIX trough levels during prophylaxis. “
“Summary.  Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS.

The overall prevalence of inhibitors in hemophilia is estimated at 5–7% for hemophilia A and 1.5–4% for hemophilia B. Inhibitor incidence is higher in severe hemophilia A patients at initial treatment (previously untreated patients, PUPs, average incidence 25%),

with a peak incidence after 14–20 days of treatment (exposure days, ED). In severe hemophilia B patients the incidence varies 3-MA cost between 9 and 23%, with a peak incidence at 7–10 ED. The incidence of inhibitors in hemophilia A patients after the initial treatment period (previously treated patients, PTPs) is estimated at around 0.2/100 patient years, with the upper limit of the confidence interval at 0.4. Very little is known about the natural history of inhibitors in the absence of treatments aiming at their eradication (immunotolerance induction, ITI). “
“The principles of pharmacokinetic (PK) dose tailoring in clinical practice, using

limited blood sampling and Bayesian PK analysis, have been described for factor VIII (FVIII). This study applied the same procedure to recombinant FIX (rFIX), i.e. population PK modelling and the use of a simplified (one-compartment) model to describe only the terminal part of the coagulation factor vs. time curve. Data from a previous study on rFIX in 56 patients (4–56 years, 18–133 kg) were used to define a three-compartment population PK model. The average FIX clearance was 8.4 mL h−1 kg−1. U0126 Elimination half-life ranged between 14 and 27 h. Data obtained from 24 h after the infusion were found to define the terminal phase of FIX disposition. 上海皓元 Doses to produce a target trough FIX level (set at 0.01 IU mL−1) at 72 h predicted by the Bayesian analysis, with blood sampling at either 24, 48 and 72 h or at only 24 and 48 h, were within −40% to +67% of those predicted using the three-compartment model, and within −57% to +125% for targeting a level at 96 h. These errors were lower than the overall interindividual variance in dose requirements. As three-compartment models are needed to characterize the PK of both plasma-derived

FIX and rFIX, simplification to a one-compartment model is less straightforward than for FVIII, and the methodology should be investigated further before clinical application. Limited blood sampling and Bayesian analysis could still, however, be potentially useful for targeting rFIX trough levels during prophylaxis. “
“Summary.  Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS.

A 20-year-old male patient with a parietal lobe brain lesion was studied by magnetic resonance imaging and magnetic resonance spectroscopy in a 1.5-T Philips scanner. The lesion presented atypical MR spectra with presence of alanine (1.46 ppm), lactate (1.31 ppm), and amino acids such as valine, isoleucine (0.97 ppm), and glicine (3.52 ppm). No evidence of normal parenchyma tissue metabolites (N-acetylaspartate, creatine, and choline) or succinate and acetate signals was observed. This spectral pattern Proteasome cleavage was unexpected being proposed the differential diagnosis

of brain abscess versus epidermoid cyst. Finally, surgical total excision biopsy confirmed the diagnosis of epidermal cyst. In this report, we describe a case of an epidermal cyst with an unusual metabolic pattern observed by magnetic resonance spectroscopy mimicking a brain abscess. “
“Presentation of an interrupted aortic arch (IAA) in adulthood is extremely rare. Nonhemorrhagic stroke has not been reported previously in any adult with IAA. We, herein, describe a formerly asymptomatic 52-year-old male presenting with recurrent vertebrobasilar circulation ischemic strokes resulting from accelerated atherosclerotic arteriopathy secondary to

IAA associated upper body hypertension. Surgical correction of IAA led to treatment of hypertension and cessation of ischemic attacks together with regression of collateral arterial networks as shown by computer tomography angiography. “
“Head rotation can cause occlusion of the vertebral artery most commonly at http://www.selleckchem.com/products/R788(Fostamatinib-disodium).html the atlas loop, and repetitive compression from head turning induces vertebral artery dissection (VAD). Although ultrasound examinations are useful in diagnosis, dissected lesions unaccompanied

by hemodynamic changes can be overlooked. Because the narrowed, dissected medchemexpress vessel in the atlas loop may cause rotational occlusion, we confirmed whether adding submaximal head rotation to a cervical ultrasound examination would facilitate the detection of VAD in the atlas loop. We investigated 7 patients who developed infarction in the posterior circulation and were clinically suspected of VAD. Using a 7.5-MHz linear probe, we recorded the waveform of the vertebral artery at the C4-C6 level and diagnosed rotational vertebral artery occlusion (RVAO) when head rotation induced the disappearance of end-diastolic flow. All 3 patients with VAD in the atlas loop demonstrated RVAO of the dissected vertebral arteries in the acute stroke phase. RVAO was not observed in the dissected vertebral arteries excepting the atlas loop, nor in the nondissected vertebral arteries of any patients. For posterior circulation stroke patients, adding submaximal head rotation to the cervical ultrasound examination facilitated the detection of VAD in the atlas loop.

HFE gene mutations were linked to Hereditary Hemochromatosis. They were associated with hepatic iron overload, liver fibrosis, and response to interferon in chronic HCV patients. The aim of this study is to evaluate the effect of HFE mutation on response to standard of care (SOC) treatment of Egyptian patients. Patients and Methods the study comprised 657 patients with HCV who took SOC treatment and were accordingly divided into responders(301) and non-responders(356), as well as 160 age and sex

matched healthy controls. The following parameters were measured: complete iron profile, hepatic iron content, as well as frequency of HFE 187C>G and HFE193A>T genotypes. Results There was a statistically significant difference

in the Hedgehog antagonist frequency of HFE187C>G and HFE193A>T genotypes between responders, nonresponders and controls. There was a statistically significant association between the C allele of HFE187C>G and Lapatinib price response to interferon. Carriers of G allele had a 9.3 odds ratio for non-response to SOC treatment than C allele. Carriers of T allele of HFE193A>T gene mutation had a 9.2 time risk for nonre-sponse to treatment. Conclusion Determination HFE gene polymorphism in chronic HCV patients may become an important tool in patient selection for theapy as it appears to play a role in the response to treatment. Frequency of the genotypes of HFE gene polymorphisms in the studied groups: Disclosures: The following people have nothing to disclose: Mazen I. Naga, Mona A. Amin, Dina A. Algendy, Ahmed I. El Badry, Mai M. Fawzi, Ayman R. Foda, Serag M. Esmat, Dina Sabry, Laila A. Rashed, Samia M. Gabal, Manal Kamal Background: Although many studies have tried to clarify the association between hepatitis C virus (HCV) infection and metabolic syndrome, few studies have comprehensively assessed their relationship stratified by different demographic characteristics.

Aims: To investigate the correlation between metabolic syndrome and HCV infection in Taiwan. Methods: We enrolled consecutive subjects who had received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Metabolic syndrome was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention. Results: 上海皓元医药股份有限公司 Among the 30616 subjects enrolled in this study, the prevalence of positive anti-HCV serology was 2.7%, and 28.8% were diagnosed with metabolic syndrome. In compared to those without HCV infections, patients with HCV infection were older in age and more females, with higher serum alanine aminotransferase (ALT), aspartate aminotransferase, gamma-glutamyltransferase, and fasting glucose levels, higher systolic and diastolic blood pressure, and lower cholesterol, high-density lipoprotein-cholesterol (HDL), low-density lipoprotein, and triglycerides levels, and lower platelet counts.

Cellular atypia and diminished reticulin fibers around the hepatic column were not observed. A survey

of the background livers of 13 patients with cavernous hemangioma disclosed similar hemangioma-like vessels in hepatic parenchyma in six patients (46%), but similar nodular lesions were not detected in any patients. Taken together, the hepatic lesions in these two patients may be hither-to unrecognized types of hyperplastic hepatocellular lesion associated with localized hemangiomatous lesion that may cause irregular blood flow. Hypervascular hepatocellular ACP-196 mouse lesions include hepatocellular carcinoma (HCC), hepatocellular adenoma, focal nodular hyperplasia (FNH) and FNH-like nodule.[1-6] Differential diagnosis between HCC and other

benign nodules is important and occasionally difficult.[6] The recent progress of imaging modalities including computed tomography (CT) and magnetic resonance imaging (MRI) with various enhancements, such as gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced (EOB), contribute to make the differential diagnosis among these hypervascular hepatic nodules.[6-8] Hepatocellular carcinoma usually arises in chronic advanced liver disease due to viral hepatitis B and C, chronic alcoholism and non-alcoholic fatty liver disease. Hepatocellular adenoma is a benign hypervascular hepatocellular neoplasm. Recent progress in the molecular analysis of hepatocellular adenoma revealed subtypes of hepatocellular RG7204 clinical trial adenoma[1-5] that can be diagnosed by immunostaining for liver fatty acid binding protein (LFABP), glutamine synthetase (GS) and serum amyloid A (SAA).[1-5] FNH is a benign hepatocellular hyperplastic lesion usually associated with abnormal vessels, such as abnormal thickened

arteries, and half of them have a central stellate scar.[1] Irregular blood flow due to abnormal vessels is thought to cause hyperplasia of hepatic parenchyma.[1] Furthermore, several studies have demonstrated a hypervascular liver nodule showing similar imaging findings to HCC; so-called FNH-like nodules.[7, 9, 10] We have recently reported that some MCE FNH-like nodules in patients with alcoholic cirrhosis share histological and immunohistochemical features with inflammatory hepatocellular adenoma and refer to them as “SAA-positive hepatocellular neoplasms”.[11] Hepatic hemangioma is the most common benign mesenchymal tumor with an estimated prevalence of 0.4–20%, which is also detected as a hypervascular lesion of the liver on imaging.[6, 12, 13] It is thought that a part of hepatic hemangiomas may be anomalous lesions, not true neoplastic lesions.[6, 12-14] It is usually a well-circumscribed lesion with a distinct fibrous interface of less than 2 cm in diameter and is located under the hepatic capsule. Cavernous accumulation of vessels is seen and sometimes organization and sclerosis are associated.

0 days in the onabotulinumtoxinA group vs 6.7 days in the placebo group, P = .038). A significant reduction at 6 months in the mean frequency of headaches per 30 days that favored onabotulinumtoxinA treatment was also observed (−7.8 in the onabotulinumtoxinA group vs −4.5 in the placebo group; P = .032).39 This subgroup analysis was conducted also based on recommendations from migraine controlled-trial guidelines that recommend monotherapy studies because

concomitant treatment may confound study results.40-42 Overall, these exploratory phase 2 studies provided guidance and shaped the study design and ICG-001 price the injection paradigm of the phase 3 PREEMPT clinical program. Another controlled study demonstrated the effectiveness of 100 U onabotulinumtoxinA in the treatment of patients with CM who specifically did not overuse pain medication. In this study, which used a fixed-site administration approach, patients in the onabotulinumtoxinA treatment group had a statistically significant and clinically click here meaningful (31.0%) decrease in migraine frequency (primary end-point) compared with the 8.9% decline for those in the placebo-treated group (P < .001).9 More recently, the PREEMPT clinical program has confirmed onabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM.27 These two phase 3, multicenter studies (PREEMPT 1 & 2), each of which

had a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week open-label phase, enrolled 1384 patients with CM. In these studies,

all patients received a minimum intramuscular (IM) dose of 155 U of onabotulinumtoxinA administered to 31 injection sites across 7 head and neck muscles using a fixed-site, fixed-dose MCE公司 (FSFD) injection paradigm (each injection was 5 U in 0.1 mL). In addition, up to 40 U onabotulinumtoxinA, administered IM to 8 additional injection sites across 3 head and neck muscles, was allowed, using a FTP approach. Thus, the minimum dose was 155 U and the maximum dose was 195 U.27 Important end-points (primary and secondary) were change from 28-day baseline compared with the 28 days ending at Week 24 for frequency of headache days (primary PREEMPT 2; secondary PREEMPT 1) and headache episodes (primary PREEMPT 1; secondary PREEMPT 2). Statistically significant reductions from baseline for frequency of headache days after onabotulinumtoxinA treatment compared with placebo treatment in both PREEMPT 1 (P = .006) and PREEMPT 2 (P < .001) were observed.28,29 Statistically significant improvement from baseline after onabotulinumtoxinA compared with placebo treatment was seen for headache episodes in PREEMPT 2 (P = .003),29 but not in PREEMPT 1.28 Pooled analysis demonstrated that onabotulinumtoxinA treatment significantly reduced mean frequency of headache days (−8.4 onabotulinumtoxinA, −6.6 placebo; P < .001) and headache episodes (−5.2 onabotulinumtoxinA, −4.9 placebo; P = .009).

23, 24 However, it should be noted that the role of IL-6 is not fully resolved because recent data suggest that total body IL-6 KO and

liver-specific gp130 (a transdomain receptor that binds IL-6 and signals through the signal transducer and activator of transcription 3/1 [STAT3/1] pathways) KO mice have enhanced steatosis and inflammation when fed a choline-deficient ethionine diet.10 Wueest et al.18 did not examine hepatic STAT3/1 signaling; thus, it remains open as to the contribution of Fas-induced IL-6 signaling to hepatocyte IR and steatosis. HFD-fed AFasKO mice have decreased hepatic CD36 mRNA, and this could explain the reduced ceramide and steatosis in these mice, but how adipocyte-expressed Fas regulates hepatic CD36 expression is unknown. Thus, at this stage it remains unresolved whether adipocytes hatch the egg that initiates

hepatocyte IR and steatosis. Like many areas of biology, findings INCB024360 datasheet in highly artificial systems, although ABT-199 cell line highly informative are unlikely to be the complete answer from a systems biology approach while both adipose and hepatic compartments, are likely to play critical, complementary, and interdependent roles. Looking into the future, obesity and the Fas ligand and receptor system are clearly drivers of IR and hepatic steatosis, and their identification opens the way for the development of new therapeutic approaches that target this relationship. “
“Single nucleotide polymorphisms (SNPs) near 7 loci have been associated with liver function tests or with liver steatosis by magnetic resonance spectroscopy. In this 上海皓元 study we aim to test whether

these SNPs influence the risk of histologically-confirmed nonalcoholic fatty liver disease (NAFLD). We tested the association of histologic NAFLD with SNPs at 7 loci in 592 cases of European ancestry from the Nonalcoholic Steatohepatitis Clinical Research Network and 1405 ancestry-matched controls. The G allele of rs738409 in PNPLA3 was associated with increased odds of histologic NAFLD (odds ratio [OR] = 3.26, 95% confidence intervals [CI] = 2.11-7.21; P = 3.6 × 10−43). In a case only analysis of G allele of rs738409 in PNPLA3 was associated with a decreased risk of zone 3 centered steatosis (OR = 0.46, 95% CI = 0.36-0.58; P = 5.15 × 10−11). We did not observe any association of this variant with body mass index, triglyceride levels, high- and low-density lipoprotein levels, or diabetes (P > 0.05). None of the variants at the other 6 loci were associated with NAFLD. Conclusion: Genetic variation at PNPLA3 confers a markedly increased risk of increasingly severe histological features of NAFLD, without a strong effect on metabolic syndrome component traits. (HEPATOLOGY 2010) Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. It is frequently associated with obesity, insulin resistance and features of the metabolic syndrome.1, 2 The histologic phenotype of NAFLD extends from fatty liver to steatohepatitis.

In tgUGT1A WT mice, a significant increase of all hepatic UGT1A genes was detected after BDL, contrasting upregulation of UGTs in the liver of tgUGT1A SNP mice, which was only observed for selleck compound UGT1A6 along with a reduced expression of UGT1A3, UGT1A4

and UGT1A7. TCDD administration after BDL lead to a further induction of hepatic UGT1A1- and UGT1A6-expression in tgUGT1A WT and SNP mice, while UGT1A3 and UGT1A4 were only upregulated in the liver of SNP mice. Analysis of hepatic transcription factors after BDL revealed a significant inhibition of AhR expression in tgUGT1A WT and SNP mice as well as a decreased FXR mRNA level in SNP mice. Moreover, an induction of the oxidative stress sensor Nrf2 was observed in tgUGT1A WT mice. In BDL+TCDD mice, expression levels of Nrf2 and FXR were significantly increased in tgUGT1A WT and SNP mice, whereas AhR induction was only observed in WĪ mice. Conclusion: Our data show a differential regulation of glucuronidation in tgUGT1A WT and SNP mice during cholestasis. TCDD-treatment after BDL resulted in a further induction of hepatic UGT1A genes in tgUGT1 A WT and SNP mice. Although tgUGT1A SNP mice show relative transcriptional inducibility of hepatic glucuronidation, absolute UGT expression levels remain below those observed in tgUGT1A WĪ mice

due to functional polymorphism in the human transgene UGT1A locus. Therefore, the increase of UGT1A genes is not sufficient to antagonize TCDD-mediated toxicity during obstructive cholestasis in tgUGT1A SNP mice. MCE Disclosures: Michael Ibrutinib mw P. Manns – Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer

Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis The following people have nothing to disclose: Anja Winkler, Sandra Kalthoff, Nicole Freiberg, Christian P. Strassburg Background: The mechanism by which bile salts (BS) induce liver injury in cholestasis is controversial. Although high levels of BS are toxic when applied to liver cells, the level of toxic BS in the liver of most cholestatic animals and patients is < 10 μM. Instead, serum BS levels but not liver, correlate with the severity of liver injury in BS-fed mice. This suggests that serum BS may initiate the cholestatic response. Aim: To assess this possibility we determined the temporal profile of inflammatory cytokines and chemokines in cholestatic Abcb4-/- mouse livers, as well as the ability of various BS to induce these cytokines in isolated mouse hepatocytes and macrophages. Methods: Abcb4-/mice and wild-type (WĪ) littermates were sacrificed at 10 days, 3, 6 and 12 wks after birth and assessed for [BS] in serum and liver, histological evidence of liver injury, and hepatic levels of cytokines and chemokines. Isolated hepatocytes and liver nonparenchymal cells from WT mice were treated with various BS.