Given the lack

of treatment effect, treatment and control groups were combined for the analyses of QLFTs in predicting clinical outcomes. Baseline patient characteristics and standard laboratory results of patients with and without subsequent clinical outcomes are listed in Table 2. Patients who developed outcomes Trichostatin A in vivo had higher bilirubin and international normalized ratio (INR) as well as lower albumin. Although these differences were statistically significant, means for these tests were within normal range, even in patients who developed outcomes. Only 6% of patients who developed outcomes had INR >1.2, 22% had bilirubin >1.2 mg/dL, and 52% had albumin INCB024360 molecular weight <3.5 g/dL. In contrast, mean platelet count of patients who developed outcomes was below the lower limit of normal range, and 70% had a platelet count <140,000/μL. Patients with subsequent

outcomes had higher fibrosis scores and were more likely to have cirrhosis on liver histology and varices at endoscopy. QLFTs were worse at baseline in patients who subsequently experienced clinical outcomes (Table 2). Although differences varied by test, patients who in follow-up had subsequent clinical outcomes had greater hepatic impairment, including microsomal (i.e., antipyrine [AP], caffeine, and lidocaine- monoethylglycine xylidide; MEGX), mitochondrial (methionine), and cytosolic (galactose) functions, and flow-dependent clearances (galactose, cholates [CAs], and perfused hepatic mass; PHM). QLFTs are more sensitive than standard liver blood tests in identifying patients with hepatic impairment. In contrast to standard laboratory tests, baseline medchemexpress QLFTs were beyond normal range in nearly all patients who developed outcomes. Sixty-four percent had a caffeine elimination rate (kelim) <0.05 h−1, 89% had AP kelim <0.04 h−1, 80% had AP clearance (Cl) <0.4 mL min−1 kg−1, 81% had monoethylglycylxylidide

concentration at 15 minutes postlidocaine (MEGX15min) <20 ng/mL, 73% had a methionine breath test (MBT) <50, 74% had galactose elimination capacity (GEC) <5 mg min−1 kg−1, 93% had CA Cl after oral administration (Cloral) <15 mL min−1 kg−1, 89% had CA shunt >30%, and 79% had PHM <100. Figure 1 shows the relationships of tertiles of baseline metabolic QLFTs to the subsequent development of clinical outomes. MBT and AP Cl performed best. The boundaries and hazard ratios (HRs) for high-risk tertiles, which also defined QLFT cutoffs, were MBT ≤48 (HR, 5.92), AP Cl ≤0.28 mL kg−1 min−1 (HR, 3.62), caffeine kelim ≤0.04 h−1 (HR, 2.67), MEGX15min ≤9.0 ng/mL (HR, 2.50), and GEC ≤4.32 mg kg−1 min−1 (HR, 2.21) (Table 3). By ROC analyses, the c-statistic for MBT was 0.79.

15 Some aspects of cirrhotic cardiomyopathy, such as diastolic dysfunction, reduced cardiac index, and Q-T interval prolongation, have been shown to be significantly associated with complications of cirrhosis, such as HRS, and death (Fig. 1).16, 17 Therefore, if NSBBs further impair cardiac function in a patient with cirrhotic cardiomyopathy, Selleck Roxadustat this could be another mechanism whereby propranolol administration would lead to an unfavorable outcome. From the opposite standpoint, propranolol reduces the risk of bleeding, and

therefore, bleeding-related death. By the same mechanism, NSBBs can also reduce bacterial translocation from the gut.18 Because bacterial translocation is the initial step in the pathogenesis of SBP, the use of propranolol has been shown to prevent the development of SBP18, 19 and postsurgical infections in cirrhosis (Fig.

1).20 It appears that the controversy regarding NSBB use in advanced cirrhosis might continue, the report from Lebrec et al. notwithstanding. NSBBs should continue to be used to prevent variceal bleeding. However, the risk/benefit ratio of such treatment may vary according to the stage of the cirrhosis, perhaps becoming unfavorable in patients with the most advanced stage. New studies BMS-907351 ic50 are necessary to establish if NSBBs exert different effects in different subsets of patients with cirrhosis, although it is unlikely that such studies are currently under way. Pending

the results of such studies, patients with ascites who are on NSBBs should be monitored closely, and consideration should be given to discontinuing NSBBs when either sepsis or HRS develop. “
“Peroxiredoxins (Prxs) are peroxidases that catalyze the reduction of reactive oxygen species (ROS). The active site cysteine residue of members of the 2-Cys Prx subgroup (Prx I to IV) of Prxs is hyperoxidized to cysteine sulfinic acid (Cys-SO2) during catalysis with concomitant loss of peroxidase activity. Reactivation of the MCE hyperoxidized Prx is catalyzed by sulfiredoxin (Srx). Ethanol consumption induces the accumulation of cytochrome P450 2E1 (CYP2E1), a major contributor to ethanol-induced ROS production in the liver. We now show that chronic ethanol feeding markedly increased the expression of Srx in the liver of mice in a largely Nrf2-dependent manner. Among Prx I to IV, only Prx I was found to be hyperoxidized in the liver of ethanol-fed wildtype mice, and the level of Prx I-SO2 increased to ≈30% to 50% of total Prx I in the liver of ethanol-fed Srx−/− mice. This result suggests that Prx I is the most active 2-Cys Prx in elimination of ROS from the liver of ethanol-fed mice and that, despite the up-regulation of Srx expression by ethanol, the capacity of Srx is not sufficient to counteract the hyperoxidation of Prx I that occurs during ROS reduction.

[21, 22] In this mini review, we briefly summarize the hepatoprotective functions of IL-22, highlight our recent findings about the effects of IL-22 on LPCs and HSCs, and discuss the therapeutic potential of IL-22 for the treatment of ALD. Numerous studies suggest that IL-22 plays key roles in the prevention of hepatocellular damage in a variety

of liver injury models.[10-15] IL-22 was first found to be hepatoprotective against murine liver injury induced by Concanavalin A (Con A), carbon tetrachloride, and Fas ligand,[10, 11] and was later confirmed in many other liver injury models.[12-15] IL-22 CT99021 chemical structure protects against hepatocyte damage and promotes hepatocyte proliferation by activating the STAT3 signaling pathway. BEZ235 order Activation of STAT3 subsequently leads to upregulation of a variety of anti-apoptotic (e.g. Bcl-2, Bcl-xL, Mcl-1) and mitogenic (e.g. c-myc, cyclin D1, Rb2, CDK4) genes, resulting in hepatoprotective effects

under conditions of liver injury.[10] The hepatoprotective functions of IL-22 were further supported in genetically modified mice where IL-22 transgenic mice with overexpression of IL-22 were resistant to Con A-induced liver injury,[19] while IL-22 deficient mice were highly susceptible to such injury.[12] In addition, IL-22 treatment ameliorated high fat diet (HFD)- or ethanol-induced liver lipogenesis and hepatic steatosis.[16, 18] IL-22 administration reduced HFD-induced elevation of serum alanine aminotransferase and aspartate aminotransferase (AST) levels, and partially inhibited HFD-induced upregulation of lipogenesis-related genes that are involved in lipid synthesis in the liver. Additionally, IL-22 treatment prevented

liver injury in mouse models induced by chronic-binge ethanol feeding[16] or acute ethanol challenge.[17] Finally, IL-22 was also shown to promote liver cell proliferation in vitro through the activation of AKT and STAT3 signaling; this mitogenic effect was abrogated by overexpression of suppressor of cytokine signaling-1/3, which inhibited STAT3 activation.[23] In a liver MCE regeneration model, the levels of serum IL-22 protein and hepatic IL-22R1 mRNA expression were significantly increased after 70% partial hepatectomy. Blockage of IL-22 with administration of an anti-IL-22 antibody before partial hepatectomy significantly decreased hepatocytes proliferation.[20] In agreement with the results from partial hepatectomy model, liver ischemia-reperfusion injury is also associated with elevation of hepatic IL-22 and IL-22R1 expression.[14] Although injection of an IL-22 neutralizing antibody did not exacerbate liver ischemia-reperfusion injury, treatment of mice with recombinant IL-22 protein markedly ameliorated serum AST levels, improved cardinal histological features of ischemia-reperfusion damage (Suzuki’s score), and abrogated leukocyte sequestration.

As described earlier, hepcidin

is the central mediator of systemic iron homeostasis through its interaction with ferroportin and control of its cell surface expression. Mutations in hepcidin are very rare possibly because of the small size of the molecule and account for only a small proportion of patients with JH. Roetto et al. originally identified HAMP as the gene responsible for JH in two families www.selleckchem.com/products/apo866-fk866.html who did not have linkage to the chromosome 1q region.[38] To date, only 12 mutations have been reported in the hepcidin coding sequence or promoter region that have either been associated with JH or have been implicated as modifiers of the HFE-HH phenotype. Within the Asia-Pacific region, three mutations have been reported (Fig. 2). The C78T mutation was detected in a consanguineous family of Middle Eastern origin residing in Australia.[39] The R42Sfs mutation was reported in a consanguineous family from Pakistan; this frameshift mutation results in an abnormally elongated protein with complete disruption of the mature peptide

sequence.[34] Finally, the R75X mutation was recently reported in a Japanese patient with early onset hemochromatosis.[40] Interestingly, this mutation would be predicted to result in a truncated, 15 amino acid version of the mature peptide. However, no detectable hepcidin, either full length or truncated, was detected in the patient’s serum or urine, suggesting that there may have been defective processing or secretion of the mutant MCE公司 peptide.[40]

Mutations in TFR2 as the cause of type 3 HH were first reported in 2000.[41] TFR2 is highly expressed in the hepatocytes MI-503 clinical trial of the liver where it has been implicated in the regulation of hepcidin. Cell surface TFR2 has the capacity to bind and internalize transferrin, although the affinity is significantly lower than that of TFR1.[42] Exactly how TFR2 in the hepatocyte regulates hepcidin is unclear. Some studies have suggested that TFR2 forms a complex with HFE and possibly HJV that is responsible for regulating hepcidin.[43-45] However, other reports suggest that a complex between HFE and TFR2 is not required for hepcidin regulation.[46, 47] While the mechanism of TFR2 action and the signal transduction to hepcidin remain unclear, reduced hepcidin relative to iron stores has been shown to be responsible for iron overload in patients with TFR2-HH.[48] While TFR2-HH was originally described as an adult-onset disease with similar age of presentation to HFE-HH, more recent evidence suggests that it has an earlier age of onset and a more severe clinical course.[49] Despite the earlier onset of TFR2-HH, the iron indices, tissue iron distribution, and clinical features are similar to HFE-HH. It now appears that TFR2-HH has a phenotypic severity that is intermediate between JH caused by HJV or HAMP mutations at one end of the spectrum and HFE-HH at the other. In contrast with JH, hypogonadism and cardiomyopathy are less common.

Capsaicin stimulated >3-fold expression of more proteins in the spinal trigeminal nucleus at 24 hours when compared to 2 hours. Similarly, sumatriptan/naproxen abolished capsaicin

stimulation of proteins in the spinal trigeminal nucleus at 2 hours and greatly suppressed protein expression 24 hours post-capsaicin injection. Interestingly, treatment with sumatriptan alone suppressed expression of different cytokines in trigeminal ganglia and the spinal trigeminal nucleus than repressed by naproxen sodium. Conclusion.— We found that the combination selleckchem of sumatriptan/naproxen was effective in blocking capsaicin stimulation of pro-inflammatory proteins implicated in the development of peripheral and central sensitization in response to capsaicin activation of trigeminal neurons. Based on our findings that sumatriptan and naproxen regulate expression of different proteins in trigeminal ganglia and the spinal trigeminal nucleus, we propose that these drugs function on therapeutically distinct cellular targets to

suppress inflammation and pain associated with migraine. “
“(Headache 2011;51:1305-1308) Transitory global amnesia and migraine without aura are diseases with unclear pathophysiologic mechanisms, but with evidence of comorbidity. We describe twin monozygotic brothers, both presenting episodes of transitory global amnesia occurring selleck only during attacks of migraine without aura. This report supports the hypothesis of a common underlying pathogenetic mechanism, possibly related to the cortical spreading depression. Furthermore, a common genetic trait in both the diseases or more probably in a particular subgroup of patients could be hypothesized. “
“Objective.— To determine whether the inhibitory effect of acute limb pain on pain to mechanical stimulation of the forehead is compromised in individuals with frequent episodes of tension-type headache. Background.— medchemexpress Central pain modulation processes are disrupted in patients with chronic tension-type headache. This deficit in pain modulation might be a predisposing characteristic that increases

vulnerability to tension-type headache and to symptoms such as scalp tenderness, or could be a feature that develops secondarily during attacks and that persists for a few days afterward. To distinguish between these 2 possibilities in the present study, inhibitory pain control was investigated in participants with episodic rather than chronic tension-type headache. Methods.— Pressure-pain thresholds and sensitivity to sharpness in the forehead were measured in 34 individuals with 1-10 episodes of tension-type headache per month and in 32 controls before and after immersion of their hand in painfully cold water. Results.— Before the cold pressor test, pressure-pain thresholds and sensitivity to the sharp stimulus were similar in both groups.

After track formation, we inserted 4.9-mm ultrathin endoscope into the abdominal cavity. The peritoneal cavity was examined, and peritoneal and liver biopsy was performed. The puncture site was closed with a single stitch. After procedure, we

observed the pigs’ general condition and abdominal wound for 2 weeks. Results: Percutaneous ultrathin flexible peritoneoscopy was successfully performed regardless of the location of the puncture site. Peritoneal and liver biopsy was also performed successfully. The mean procedure time was 20 minutes. However, formation of abdominal track is not easy using standard endoscopic equipment. There was no injury of abdominal organs. The post-procedure course was uneventful and the pigs showed normal activity and diet one day

after the procedure. Minor scar was observed on the incision site in 2 weeks after procedure. Conclusions: Percutanous ultrathin flexible peritoneoscopy is a relatively simple R788 in vivo and technically feasible method. However, to ensure safety of use on human, dedicated accessories for fascial dilation should be developed. BA HOLT,1 V JAYASEKERAN,1 F FAHRTASH-BAHIN,1 R SONSON,1 EY LEE,1 SJ WILLIAMS,1 RV LORD,2 MJ BOURKE1 1Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, Australia, 2Department of Upper Gastrointestinal Surgery, St Vincent’s Hospital, Ruxolitinib order Sydney, Australia Introduction: Complete excision is the gold standard for mucosal neoplasia of the gastrointestinal tract. It has the advantages of complete histology and the

clinical certainty of total excision. Complete Barretts Excision (CBE) is limited by stricture formation and technical difficulties with ≥2 stage resection. Temporary stenting MCE to avoid stricture may allow single session CBE without stricture in short segment disease. Patients and Methods: A single centre open label feasibility study of single-stage CBE and temporary stent insertion for circumferential Barretts (< C3 < M5) with high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) was performed (NCT01554280), with recruitment over 6 months to achieve full enrolment of 12 stented patients. If invasive cancer was suspected endoscopically, staging by prior focal endoscopic mucosal resection (EMR) was performed. CBE by multiband mucosectomy with same day discharge was done 2 weeks later. An anti-migration covered self-expanding metal stent (NITI-S, Taewoong Medical, Korea) was inserted 10 days post-CBE, and removed at 8 weeks (Figure 1). Surveillance endoscopy was performed 3, 6 and 12-months post-CBE, and oesophageal dilations as required. Primary outcome measure was complete endoscopic and histological elimination of Barrett's mucosa. Results: 28 patients consented (14 excluded: 2 cancer, 7 C0 or >C3). 14 patients had CBE (12M; mean age 67 yrs), with initial staging EMR in 9. Median Barrett’s length was C1M3. Pre-EMR histology showed IMC 3 and HGD 11.

“
“We tested, in the laboratory, the influence

of light intensity, temperature, and phosphorus (P) supply on fatty acid (FA) concentrations of four freshwater algae: the green algae Scenedesmus quadricauda (Turpin) Bréb. and Chlamydomonas globosa J. Snow, the cryptophyte Cryptomonas ovata Ehrenb., and the diatom Cyclotella meneghiniana Kütz. We investigated the main and interactive effects of http://www.selleckchem.com/products/hydroxychloroquine-sulfate.html two variables on algal FA concentrations (i.e., light intensity and P supply or temperature and P supply). Interactive effects of light intensity and P supply were most pronounced in C. meneghiniana, but were also found in S. quadricauda and C. ovata. Changes in several saturated and unsaturated FA concentrations with light were more distinct in the low-P treatments than in the high-P treatments. Interactive effects of temperature and P supply on various FA concentrations were observed in all four species, but there was no consistent pattern. In lake ecosystems, P limitation Histone Methyltransferase inhibitor often coincides with high light intensities and temperatures in summer. Therefore,

it is important to examine how combinations of these environmental conditions affect FA concentrations of primary producers that are important sources of FAs for higher trophic levels. “
“Morphological and phylogenetic analyses and sequencing of the partial LSU gene and internal transcribed spacer (ITS) regions of the rDNA gene were combined to study toxic strains of Alexandrium tamiyavanichi Balech collected from northeastern Brazilian coastal waters. All specimens were identified with A. tamiyavanichi mainly based on the shape of the anterior sulcal plate (S.a.), which was the most conservative

character. Among the specimens studied, 8% did not conform to the morphological description of A. tamiyavanichi. The occurrence of transitory states between A. tamiyavanichi and Alexandrium cohorticula (Balech) Balech tended to confirm that both species are conspecific. The posterior sulcal plate (S.p.) was not a good taxonomic character as variability in its shape did not allow a clear assignment of specimens from MCE the same clonal isolate to either morphologically defined species. Phylogenetic analyses confirmed the overall validity of morphological characters to delineate the evolutionary relationships among the clades of Alexandrium species analyzed here, indicating that A. tamiyavanchi is a valid species according to the morphological species concept. This analysis showed that the Brazilian strains form a monophyletic clade with Asiatic strains of A. tamiyavanichi, but with enough genetic distance to argue for long-term separation and isolation of locally established populations, extending the known biogeographic range of this species.

13 CD81 is also up-regulated in HCV-infected and MC patients and increases with viral load.14 Therefore, B cells with anti-HCV surface immunoglobulins receive a strong proliferation signal through binding of the HCV-specific BCR and viral binding to CD81.15 Furthermore, experimental sequencing of clonal immunoglobulin variable regions from both MC and HCV-associated NHL patients shows restricted expression of VH and VL genes (VH1-69 and VκA27) and

evidence of somatic hypermutation, suggesting exposure and response to a common antigen.16 Such sequence analysis has allowed identification of premalignant oligoclonal cell populations in MC patients years before lymphoma development.17 Whether HCV is CP-690550 cost this common antigen has been demonstrated by research from Stanford School Medical Center. The group showed that both normal B cells and HCV-associated B-NHL preferentially expressed the VH1-69 gene in response to E218 and that the BCRs from an HCV-associated B-NHL bound E2.19 This provides compelling evidence for the role of HCV and mechanism of antigen drive in learn more B-NHL. This concept is already accepted in gastric MALT and Helicobacter pylori.20 However, despite differences in antigenic origin, the outcomes are similar: chronic B cell proliferation and malignant

lymphomagenesis. The jump from lymphoproliferation to malignancy may require a second “hit and run” transforming event such as the antiapoptotic Bcl-2 rearrangement. The translocation t(14;18) is significantly associated with chronic HCV infection,20 particularly in MC.21 Moreover,

research has identified B cell clonal expansion with this translocation in MC22 and HCV-positive patients with MALT lymphoma.23 However, whether HCV is directly mutagenic or responsible for a clonal B cell population that becomes vulnerable to transforming mutations remains unclear. Epidemiologic studies have demonstrated a causal relationship between HCV and B-NHL (Table 1). However, the odds ratios are moderate (2-3 on average) MCE in comparison to HCV and hepatocellular carcinoma. One meta-analysis reviewed data from 23 studies (4,049 NHL patients and 1,813,480 controls) and found a strong association (odds ratio [OR] 5.70).24 It should be noted that studies reporting a significant association have originated from countries with a high HCV prevalence, such as Italy,25 Egypt,26 and Japan,27 as opposed to low in Northern Europe, North America, and the United Kingdom.28 These findings echo the north-south divide in European HCV prevalence, with recent figures of 0.1%-1%, 0.2%-1.2%, and 2%-5%-3%-5% quoted for Northern, Central, and Southern Europe, respectively.

Whether it has any additional effect in combination with naltrexone is controversial. A recent large randomized controlled clinical trial

did not suggest substantial benefit of acamprosate compared to naltrexone or to intensive counseling in maintaining abstinence.186 There is a paucity of data about ABT-263 nmr the use of these interventions in patients with advanced liver disease. One randomized clinical trial in patients with cirrhosis suggested benefit in achieving and maintaining abstinence with the use of baclofen, a γ-aminobutyric acid B receptor agonist.187 Recommendations: 6. In patients with evidence of alcohol-induced liver disease, strict abstinence must be recommended, because continued alcohol use is associated with disease progression (Class I, level B). 7. Naltrexone or acamprosate may be considered in combination with counseling to decrease the likelihood of relapse in patients with alcohol abuse/dependence

in those who achieve abstinence (Class I, level A). The cornerstone of therapy of alcoholic hepatitis is abstinence, although even patients who become abstinent remain at increased risk of developing Selleckchem KU-60019 cirrhosis. However, the risk of cirrhosis is clearly higher in those who continue to drink,188, 189 particularly among women.175, 190 Although there are no clear dose–effect data, a threshold exists for the development of alcoholic hepatitis, with risk increasing with consumption beyond 40 g of alcohol per day.46, 191 Furthermore, after an episode of AH, there is no safe amount of alcohol consumption which can be recommended, as alcoholic hepatitis can persist or redevelop. There is a significant risk of recidivism in patients who attempt to cut back but not stop drinking altogether.192 Complete abstinence is therefore

a reasonable lifetime recommendation. The need to consider therapy is less urgent in patients with alcoholic hepatitis who have a low risk of complications as defined by an MDF score of < 32, without hepatic encephalopathy, or a low MELD score (e.g., MELD <18), or GAHS score of <8. This is particularly true in those whose liver score improves during hospitalization, with a decrease in total bilirubin, as they will likely improve spontaneously medchemexpress with abstinence and supportive care alone. For those with more severe disease and therefore a more dismal prognosis, however, medical treatment should be considered. The presence of significant protein calorie malnutrition is a common finding in alcoholics, as are deficiencies in a number of vitamins and trace minerals, including vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.193 In a Veterans Administration Cooperative study of 363 patients with alcoholic hepatitis, 100% of patients were found to have protein and/or combined protein calorie malnutrition, based on anthropometric and laboratory testing.194 Moreover, the severity of malnutrition correlated with disease severity and outcomes.

As a result, a “rule-of-two” was defined that predicted see more hepatotoxicity more reliably when compared with dose alone. Applying the rule-of-two to the drug development process and to clinics will likely reduce

risk for DILI particularly in complex comedication. ADMET, absorption, distribution, metabolism, excretion, toxicity; ATC, Anatomical Therapeutic Chemical; CCR, correct classification rate; DILI, drug-induced liver injury; FDA, Food and Drug Administration; LTKB-BD, liver toxicity knowledge base benchmark data set; OR, odds ratio; OTC, over-the-counter; WHO, World Health Organization. Two publicly available drug databases were used to test for the relationship between lipophilicity, daily dose, and risk for DILI. The first data set is the liver toxicity knowledge base benchmark data set (LTKB-BD) recently published by MLN0128 mw our group17 that is available from the US Food and Drug Administration’s web site.18 It contains

287 drugs with the potential to cause liver injury as defined by the FDA-approved drug labels. Drugs were divided into three categories: most-DILI-concern, less-DILI-concern, and no-DILI-concern. The most-DILI-concern group contains drugs that were either withdrawn from the market due to hepatotoxicity or were assigned a black box warning for their potential to cause liver injury, or had a warnings and precautions section that specified concern about DILI that has a greater than moderate severity. The less-DILI-concern group contains drugs that specify a DILI concern in the warnings and precautions section with low severity or in an adverse reactions medchemexpress section, while the no-DILI-concern group comprised drugs with no DILI description mentioned in the labels. In the present study, we considered the most-DILI-concern (n = 116) and no-DILI-concern drugs (n = 48) (Supporting Table 1 and Supporting Fig. 1A). A second data set published

by Greene et al.19 was analyzed. The authors classified drugs into four groups, of which two groups were selected: those with evidence of hepatotoxicity in humans (hepatotoxic-positive) and those with no evidence of hepatotoxicity in any species (hepatotoxic-negative). Despite a difference in the approach to annotate a drug’s hepatotoxic potential, the concordance between the two data sets is high (∼90%).17 After removing drugs which overlapped with the LTKB-BD and mapping to the Anatomical Therapeutic Chemical (ATC) database of the World Health Organization (WHO), a total of 179 oral drugs remained of which 115 drugs were hepatotoxic positives and 64 negatives. The flowchart for drug inclusion is shown in Supporting Fig. 1B, and a full list of drugs is given in Supporting Table 2. Daily doses were retrieved from the WHO’s ATC database (http://www.whocc.no/atc_ddd_index), supplemented with FDA-approved drug labels (http://dailymed.nlm.nih.gov/dailymed/about.cfm) and literature searches.