TUNEL-positive cells per high-power field (200×) were counted. All measurements were performed blindly. Results are expressed as the mean ± standard error of the

mean. Significance was established using Student t test, two-way analysis of variance Selleck GDC0068 with Bonferroni’s post hoc test and Mann-Whitney assay. Differences were considered significant if P < 0.05. Other methods are shown in Supporting Materials and Methods. Losartan was conjugated to manose-6-phosphate coupled to human serum albumin (M6PHSA) (Fig. 1A). After its reaction to the linker at a stoichiometric ratio (Fig. 1B), the losartan-ULS adduct was conjugated to M6PHSA. An average of seven losartan-ULS molecules were coupled to M6PHSA, as assessed by HPLC and confirmed

by inductive coupled plasma-atomic emission spectroscopy (ICP-AES) (data not shown). Conjugation of losartan to M6PHSA did not change the charge or size features of M6PHSA, as assessed by anion-exchange chromatography and size exclusion chromatography, respectively (Fig. 1C,D). Because ULS is a derivative of cisplatin, an antitumor agent that may cause cell toxicity, we studied the effects of losartan-M6PHSA on cultured HSCs. Losartan-M6PHSA did not cause cell toxicity, PF-01367338 while cisplatin induced cell death, suggesting that occupation of the coordinative sites of platinum with drug and carrier prevents its disruptive reactivity with cellular components (Fig. 1E). To test whether losartan-M6PHSA is biologically active in cultured HSCs, cells were stimulated with angiotensin II in the presence or absence of either free losartan or losartan-M6PHSA. We found that both treatments equally blunted angiotensin II–induced intracellular calcium increase (Fig. 1F). Also, we detected intracellular staining for HSA after incubating HSCs with losartan-M6PHSA for 10 minutes. Ixazomib research buy This staining was strongly blunted by excess of M6P sugars and an antibody against the M6P/IGF II receptor. We found 25.2 ± 2.4, 0.2 ± 0.1, and 5.3

± 0.6 positive cells in cultures incubated with isotype-matched antibody, excess of M6P, and anti-IGFRII antibody, respectively (P < 0.001 of isotype-matched antibody respect to the other two conditions) (Fig. 2A). These results indicate that losartan-M6PHSA directly interacts with IGF II receptors present in HSCs, and is internalized to inhibit angiotensin II–induced biological actions. M6PHSA binds to M6P/IGFII-R, which is expressed in activated HSCs in the fibrotic liver.16 In the bile duct ligation model, we administered losartan-M6PHSA (3.3 mg/kg, corresponding to 125 μg losartan/kg) daily from day 12-14 and animals were sacrificed at day 15. For pharmacokinetic purposes, a subgroup of the animals received an additional dose of the conjugate at 10 minutes before sacrifice. Control groups were treated with equivalent doses of M6PHSA (3.

9-fold lower than the average ratio calculated for normal liver tissues (Table 4). Furthermore, our data demonstrating the susceptibility of HCCs to HDV infection in vivo suggest that if the above proposed superinfection exclusion for hepadnavirus occurs see more in HCCs, it is mediated by a block at the post-entry step. Currently, superinfection of hepadnavirus-induced HCCs with either HBV or WHV has yet to be demonstrated. The observed absence of a correlation between HDV and WHV replication levels in both normal liver tissues and HCCs suggests that, because HDV requires only the envelope proteins from the helper hepadnavirus,2 then as long as a sufficient supply of the envelope

proteins is available, the extent of HDV infection is not directly dependent on the rate of hepadnavirus replication. This may explain at least in part why some anti-HBV drugs do not inhibit HDV infection. Woodchucks used in the study were bred, infected with WHV, and maintained as chronic WHV carriers under the NIH contract NIAID N01-AI-05399 until the development of HCC. We thank Eva Permaul and Deborah Berry from

the histology laboratory of the Lombardi Cancer Center at Georgetown University for excellent assistance with the immunohistochemistry of infected tissues. We also thank William Mason for encouragement, Bud Tennant for support, and Igor Prudovsky and Steven Weinman for constructive comments. Additional Supporting Information may be found in the online version of this article. “
“Portal CCI-779 clinical trial fibroblasts are an important yet often overlooked nonparenchymal cell population in the liver. They are distinct from hepatic stellate cells, yet like stellate cells differentiate in the setting of chronic injury to fibrogenic myofibroblasts, playing an important role in collagen production in the fibrotic liver. Portal fibroblasts (PFs) are located adjacent to bile duct epithelia NADPH-cytochrome-c2 reductase and thus play a particularly significant role in biliary fibrosis. New data suggest that they may also have key functions independent of fibrogenesis. This review addresses the definition and characteristics

of PFs as well as their signaling pathways, interactions with the biliary epithelium, and contributions to liver pathobiology. Conclusion: PFs are an important and multifunctional nonparenchymal cell population in need of further study. (HEPATOLOGY 2010.) Fibrosis and cirrhosis have been referred to as the final common pathway of chronic liver injury. Although anatomists and pathologists have always stressed the differences between biliary and nonbiliary etiologies of fibrosis, the landmark isolation of hepatic stellate cells (HSCs) and demonstration of their in vitro activation resulted in 20 years of fibrosis research focused on understanding HSC behavior in culture and applying these findings to animal models of disease. Recent work, however, has led to a renewed appreciation for the cellular complexity of fibrosis.

Fibrosis and inflammatory activity (including the amount of periportal piecemeal necrosis, lobular necrosis, and portal inflammation) were evaluated separately. In addition, the most characteristic

histological features of chronic hepatitis and Enzalutamide solubility dmso AIH were recorded, including plasma cell infiltrates (semiquantitatively evaluated as +++ severe, ++ moderate, or + mild), lymphoid follicles, rosette formation, acidophilic degeneration, parenchymal collapse, hepatocellular ballooning, multinucleated hepatocytes, intrasinusoidal infiltrates of lymphocytes, Kupffer’s cell hyperplasia, and hepatocellular dysplasia. Specific findings suggestive of GVHD, including bile duct damage (i.e., ductopenia and dystrophia), cholangitis, nuclear pleomorphism, and epithelial cell dropout were also recorded. Routine biochemical liver function tests were performed systematically throughout the clinical course of all patients. Investigations of hepatitis A and E virus (HAV and HEV) antibodies (Abs) (i.e., immunoglobulin IgM), hepatitis B surface antigen, and Abs to hepatitis B virus (HBV) surface and core antigens were carried out on serum samples. A diagnosis of hepatitis C was based on serum positivity for Abs

to hepatitis C virus (HCV) and HCV RNA. Markers for other types of viral hepatitis, such as CMV, Epstein Barr virus (EBV), and herpes simplex virus HSV1-2, were also tested. Human herpes virus HHV6 was detected by polymerase chain MK-8669 reaction (PCR) in the plasma and liver. The presence in sera of autoimmune liver Abs, such as antinuclear Abs (ANA), PAK6 anti–smooth muscle antigen (SMA), anti–liver-kidney microsome type 1 (LKM-1), antiliver cytosol type 1 (LC1), and antimitochondrial Abs (AMA), was investigated using indirect immunofluorescence (IIF) on frozen tissue sections of rat stomach, liver, and

kidney. Immunoreactivity of sera from 3 patients (P1, P2, and P3) was determined by two-dimensional (2D) immunoblotting before, and at the onset of, liver dysfunction. The immunoreactive spots of interest were identified by mass spectrometry (MS). All chemical reagents used were obtained from Sigma-Aldrich (St-Quentin, France), unless otherwise stated. Rat livers from male Wistar rats (Charles River, Saint Germain sur l’Arbresle, France) were homogenized in 10 mM of Tris, 250 mM of sucrose, and 1 mM of 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) buffer using a Potter-Elvehjem apparatus. Liver homogenates were then fractionated by differential centrifugation (as described elsewhere) to obtain mitochondrial, microsomal, and cytosolic fractions.14 Nuclear fractions were obtained after sucrose gradient density ultracentrifugation.15 All subcellular fractions were stored as aliquots at −80°C until use. Fraction aliquots were solubilized in a buffer (7 M of urea, 2 M of thiourea, and 4% CHAPS; w/v) in the presence of Orange G and 0.

1, 2 However, a shortage of available donor organs for transplantation results in the death of many patients awaiting liver transplantation. Hepatocyte transplantation

provides a promising alternative, and numerous experiments have demonstrated that hepatocyte transplantation improves liver function in animals with hepatic failure and innate liver-based metabolic disorders.3, 4 However, hepatocyte transplantation has rarely produced therapeutic effects, because mature hepatocytes cannot be effectively expanded in vitro and the availability of hepatocytes is often limited by shortages of donor organs.5, 6 Thus, previous studies have focused on the development of selleck screening library various stem cells that could be readily isolated using noninvasive procedures to yield hepatocytes in vitro and in vivo. Bone marrow mesenchymal stem cells http://www.selleckchem.com/products/Adrucil(Fluorouracil).html (BMSCs) can differentiate into osteoblasts, adipocytes,

and other mesenchymal cell lineages.7-10 The hepatocyte differentiation capacity of human BMSCs (hBMSCs) has been characterized in vitro and in vivo.11-13 These cells can also be expanded in culture for long periods without any apparent loss of differentiation capacity. Some groups have already started transplanting autologous bone marrow cells into patients with chronic liver fibrosis or cirrhosis.12, 14, 15 However, little is known about the use of hBMSCs to treat fulminant hepatic failure (FHF) in animal models or in human patients with FHF, even though such studies would be clinically important.5 Furthermore, because of difficulties in tracking transplanted hBMSC-derived hepatocytes in patients, and because previous experiments were performed in small animal (mouse or rat) models of chronic liver injury, the roles of BMSCs in liver regeneration have not been fully elucidated.5 FHF-derived BMSCs demonstrate a hepatic transcriptional

profile and express many of the same genes expressed by hepatic progenitor cells,16-18 suggesting that extrahepatic stem cells, especially BMSCs, may be a resource for hepatocyte repopulation and can play an important role in liver regeneration. Thus, we investigated Pyruvate dehydrogenase whether the intraportal transplantation of hBMSCs is a safe and effective method to prevent FHF in a large animal (pig) model. ALB, albumin; ALT, alanine aminotransferase; BMSC, bone marrow mesenchymal stem cell; D-gal, D-galactosamine; ELISA, enzyme-linked immunosorbent assay; FHF, fulminant hepatic failure; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; hBMSC, human BMSC; H&E, hematoxylin and eosin; HNF-1α, hepatocyte nuclear factor-1α; HSA, hepatocyte-specific antigen; IPT, intraportal transplantation; PVT, peripheral transplantation; qPCR, quantitative real-time polymerase chain reaction. Human BMSCs were isolated by bone marrow aspiration from the iliac crest of 30 healthy male volunteers.

[51] Activation of PPAR leads to the formation of heterodimers with retinoid-X receptors (RXR). These PPAR-RXR dimers bind to DNA-specific sequences called peroxisome proliferator-response EX 527 solubility dmso elements, thus stimulating or dampening the transcription of target genes.[52] Target genes of PPARα include CPT1, long chain fatty acyl-CoA synthetase (ACS) and the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2).[53] ACS catalyzes the esterification of free fatty acids, forming fatty acyl-CoA esters which are subsequently trans-esterified by CPT1 into acyl carnitines, thus facilitating transport into mitochondria,[53] and HMGCS2

is a key enzyme of ketogenesis,[54] which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form HMG-CoA.[54] AMPK, which is inhibited by CB1R stimulation, activates

PPARα.[55] Treatment of diet-induced obese mice with a CB1R inverse agonist increased hepatic expression of PPARα.[23] These data imply that inhibition of PPARα by reduced AMPK activity may Gefitinib contribute to hepatic steatosis caused by CB1R activation. CB1R has been demonstrated to activate PI3K.[56] PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). AKT and 3-phosphoinositide-dependent protein kinase-1 (PDK1) bind to PIP3 at the plasma membrane, and PDK1 phosphorylates the activation loop of AKT at T308. AKT can phosphorylate proline-rich Akt substrate of 40 kDa (PRAS40), relieving its inhibition of mammalian target of rapamycin complex 1 (mTORC1).[57] mTORC1 can then activate SREBP-1c.[58] The relevance of this signaling pathway is further supported by studies showing that neuronal mTORC1 is activated by CB1R stimulation.[59]

Mitogen-activated protein kinases (MAPK) are a family of serine/threonine Uroporphyrinogen III synthase kinases that includes extracellular-regulated kinase (ERK)1 and ERK2, which influence a wide range of cellular activities.[60] Hepatic myofibroblasts from CB1R–/– mice and rimonabant-treated wild-type hepatic myofibroblasts showed decreased phosphorylation of ERK and AKT compared to wild-type, untreated cells.[61] Intracellular CB1Rs were found to interact with Gαi protein subunits in endosomal/lysosomal compartments and mediate signal transduction by stimulating ERK phosphorylation.[62] One of the actions of ERK1 and ERK2 is to phosphorylate ser-117 of SREBP-1a, thereby activating this transcription factor.[63] Although the side-chain containing ser-117 is conserved between different isoforms of SREBP, inhibition of the ERK pathway has not been shown to decrease SREBP-1c activity,[64, 65] which contradicts the notion that CB1R activates SREBP-1c via ERK. Although this article deals mostly with the role of CB1R in fatty liver, because liver fat, steatohepatitis and liver fibrosis are associated with insulin resistance,[66, 67] CB1R’s effects on insulin sensitivity are worth mentioning.

7%2 to 42%3 and poor 5-year transplantation-free survival of 28%3 for primary BCS. We aimed to investigate the epidemiology, natural history and outcomes of BCS patients at Austin Health. Method: This study was retrospective and was performed at the Austin Hospital. We searched the hospitals computerised diagnosis database and the hospital’s liver transplant database for cases of Budd Chiari syndrome from January 2000

until August 2012. Patients with hepatic venous outflow obstruction at any point from the small hepatic veins to the inferior vena cava were included. Patients with secondary Budd Chiari syndrome were excluded. Results: Median age at diagnosis was 42 years (range 21–76). 59% were female. Eight patients (30%) had concomitant portal vein thrombosis (PVT). Twenty four patients (89%) had learn more at least one identifiable risk factor. The most common risk factor was myeloproliferative neoplasm check details (MPN, n = 16) with polycythaemia rubra vera (PRV) being the most common subtype. JAK-2 was positive in 12 of 18 patients tested. The primary intervention was transjugular intrahepatic portosystemic shunting (TIPS) in thirteen patients (48%) and angioplasty/stenting in eleven

(41%). One patient had a splenorenal shunt. No patients required transplantation during the 10 year follow up period. At median follow-up of 5 years; 16 patients had compensated liver disease, 3 had decompensated liver disease, 2 patients died a liver related death (one from hepatorenal syndrome and bilateral pulmonary Astemizole emboli, one death secondary to hepatic encephalopathy) , 4 died from a non liver related death and 2 patients were lost to follow-up. The overall transplant free one year survival was 96% and 81% at five years. Discussion: In this retrospective study, we aimed to characterise the aetiology and treatment outcomes of patients with Budd Chiari syndrome treated in our institution. This is the only published cohort

of Budd Chiari patients where no liver transplantations were required. We postulate that this is due to intensive TIPS surveillance at our hospital to prevent TIPS failure. MPN is the most common aetiological factor in BCS. This can be missed at diagnosis, and all patients should have JAK2 testing or bone marrow biopsy. TIPS or angioplasty/stenting, together with anticoagulation and treatment of any MPN, results in favourable long term transplantation-free outcomes and represents optimal standard of care. (1) Plessier A et al, Management of hepatic vascular disorders, Journal of Hepatology. 2012, S25–38 (2) Seijo, Plessier et al. Good-long term outcome of Budd-Chiari Syndrome with a Step-wise approach. Hepatology. 2013.

7%2 to 42%3 and poor 5-year transplantation-free survival of 28%3 for primary BCS. We aimed to investigate the epidemiology, natural history and outcomes of BCS patients at Austin Health. Method: This study was retrospective and was performed at the Austin Hospital. We searched the hospitals computerised diagnosis database and the hospital’s liver transplant database for cases of Budd Chiari syndrome from January 2000

until August 2012. Patients with hepatic venous outflow obstruction at any point from the small hepatic veins to the inferior vena cava were included. Patients with secondary Budd Chiari syndrome were excluded. Results: Median age at diagnosis was 42 years (range 21–76). 59% were female. Eight patients (30%) had concomitant portal vein thrombosis (PVT). Twenty four patients (89%) had selleck chemicals at least one identifiable risk factor. The most common risk factor was myeloproliferative neoplasm see more (MPN, n = 16) with polycythaemia rubra vera (PRV) being the most common subtype. JAK-2 was positive in 12 of 18 patients tested. The primary intervention was transjugular intrahepatic portosystemic shunting (TIPS) in thirteen patients (48%) and angioplasty/stenting in eleven

(41%). One patient had a splenorenal shunt. No patients required transplantation during the 10 year follow up period. At median follow-up of 5 years; 16 patients had compensated liver disease, 3 had decompensated liver disease, 2 patients died a liver related death (one from hepatorenal syndrome and bilateral pulmonary Etomidate emboli, one death secondary to hepatic encephalopathy) , 4 died from a non liver related death and 2 patients were lost to follow-up. The overall transplant free one year survival was 96% and 81% at five years. Discussion: In this retrospective study, we aimed to characterise the aetiology and treatment outcomes of patients with Budd Chiari syndrome treated in our institution. This is the only published cohort

of Budd Chiari patients where no liver transplantations were required. We postulate that this is due to intensive TIPS surveillance at our hospital to prevent TIPS failure. MPN is the most common aetiological factor in BCS. This can be missed at diagnosis, and all patients should have JAK2 testing or bone marrow biopsy. TIPS or angioplasty/stenting, together with anticoagulation and treatment of any MPN, results in favourable long term transplantation-free outcomes and represents optimal standard of care. (1) Plessier A et al, Management of hepatic vascular disorders, Journal of Hepatology. 2012, S25–38 (2) Seijo, Plessier et al. Good-long term outcome of Budd-Chiari Syndrome with a Step-wise approach. Hepatology. 2013.

radiata. Variable pigment content indicated photoacclimation at the inner site. Morphological differences were observed between sites, with E. radiata from the inner site having longer, wider, thinner blades and longer stipes. While E. radiata displayed spatial differences in growth, erosion, productivity, and morphology, populations displayed no temporal differences. These results highlight the need for greater understanding of the mechanisms influencing kelp growth and productivity in a unique marine environment. “
“Several unknown mycosporine-like amino

acids (MAAs) have been previously isolated from some cultured species of toxic dinoflagellates of the Alexandrium genus (Dinophyceae). One of them, originally called M-333, was tentatively identified as a shinorine methyl ester, but

the precise nature selleck of this compound is still unknown. Using a high-resolution reversed-phase liquid chromatography mass spectrometry analyses (HPLC/MS), we found that natural populations of the red tide dinoflagellate Prorocentrum micans Ehrenberg showed a net dominance of M-333 together with lesser amounts of other MAAs. We also documented the isolation and characterization of this MAA from natural dinoflagellate populations and from Alexandrium tamarense (Lebour) Balech cultures. Using a comparative fragmentation study in electrospray mass spectrometry between deuterated and non-deuterated M-333 compounds and synthesized mono and dimethyl esters of shinorine, this novel compound was characterized as mycosporine-serine-glycine buy PF-01367338 methyl ester, a structure confirmed by nuclear magnetic

resonance. These isobaric compounds can be differentiated by their fragmentation patterns in MS3 experiments because the extension and the specific Vasopressin Receptor site of the methylation changed the fragmentation pathway. “
“Key Laboratory of Coastal Wetlands, China Geological Survey Qingdao Institute of Marine Geology, Qingdao, China The marine diatom Thalassiosira weissflogii (Grunow) G. A. Fryxell & Hasle was grown in a chemostat over a series of phosphate-limited growth rates. Ambient substrate concentrations were determined from bioassays involving picomolar spikes of 33P-labeled phosphate, and maximum uptake rates were determined from analogous bioassays that included the addition of micromolar concentrations of unlabeled phosphate and tracer concentrations of 33P. The relationship between cell phosphorus quotas and growth rates was well described by the Droop equation. Maximum uptake rates of phosphate spikes were several orders of magnitude higher than steady state uptake rates. Despite the large size of the T. weissflogii cells, diffusion of phosphate through the boundary layer around the cells had little effect on growth kinetics, in part because the cellular N:P ratios exceeded the Redfield ratio at all growth rates.

Pancreatic adenocarcinoma is a highly-aggressive disease with a propensity for early metastasis and drug resistance. Tumorigenic pancreatic cancer cells have been identified using the cell surface antigens CD44, CD24, and CD133, as well as the high expression of aldehyde dehydrogenase (ALDH). In vitro and in vivo studies have shown that ALDH- and CD133-expressing pancreatic CSC have a greater propensity for metastasis, and ALDH-expressing CSC have been shown to be resistant to conventional chemotherapy. In clinical samples from patients with resected

pancreatic adenocarcinoma, the presence of ALDH-expressing CSC was associated with worse overall survival. The development of CSC-targeting PXD101 clinical trial therapies might be important

in changing the clinical outcomes of patients with this disease, and others and we have begun to identify novel compounds that block CSC function. This review will discuss the biological and clinical relevance of CSC in pancreatic cancer, and will discuss novel therapeutic strategies to target them. “
“Eosinophilic gastroenteritis (EG) is a rare and heterogeneous disorder characterized by gastrointestinal (GI) symptoms and eosinophilic infiltration of the GI tract. Symptoms are dependent upon site of the GI tract involved and selleck inhibitor depth of involvement. The diagnostic criteria includes: 1) the presence of GI symptoms, 2) histopathology demonstrating predominant eosinophilic infiltration, 3) the absence of other conditions that cause eosinophilia, and 4) no eosinophilic involvement of organs outside the GI tract. Diagnosis requires a clinical history, physical exam, and documentation of any history of atopic disorders, allergies, and drug allergies. Laboratory evaluation includes a complete blood count with differential to evaluate for peripheral eosinophilia. Endoscopic evaluation with random biopsies remains the cornerstone for diagnosis. Histopathologic Erlotinib diagnosis typically requires an infiltration level of >20 eosinophils per high power field. Management strategies are based upon severity

of symptoms and include anti-diarrheals, dietary adjustments, and steroid therapy. “
“Hepatocyte growth factor (HGF)/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem-cell–mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by polymerase chain reaction analysis of fluorescence-activated cell-sorted epithelial cell adhesion molecule (EpCam)-positive cells.

16,17 The two variant alleles, designated as CYP2C9*2 and CYP2C9*3, consist of single-nucleotide substitutions that cause the amino acid changes R144C and I359L, respectively. Both variant alleles lead to decreased enzyme activity on CYP2C9 substrates compared with the wild-type allele. Martinez LY294002 purchase et al.17 demonstrated that

the frequency of CYP2C9 variant alleles was increased in patients with acute bleeding (OR = 1.64, 95% CI = 1.05–2.58; P = 0.02). In another case–control study of 26 patients with NSAID-related upper GI bleeding and 52 controls, setting the CYP2C9*1/*1 wild type as reference, there were significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < 0.001; Wnt inhibitor OR = 12.9, 95% CI = 2.9–58) and CYP2C9*1/*2 (26.9% vs 15.4%; P = 0.036; OR = 3.8, 95% CI = 1.1–13) identified in the patients with

bleeding compared to control patients. The presence of the CYP2C9*3 allele was associated with a significantly high risk of bleeding (adjusted OR = 7.3, 95% CI = 2.1–26).16 In contrast, another study from the Netherlands found no association between the CYP2C9 genotype and development of serious NSAID-related ulcers. There are no previous clinical data indicating a significant relationship between polymorphisms of UGT1A6 or CYP2C9 and aspirin-induced peptic ulcer.18 The frequencies of these gene variants in Japanese are less than those in Western populations.12,19–22 In our recent study of low-dose aspirin users, which included 40 patients with peptic ulcer, there was no significant association between these gene variants and peptic ulcer;12,19 however, we could not evaluate bleeding risk because of the small number of subjects, and the number of patients with peptic ulcer was also small. A further large-scale clinical study is required to investigate PLEKHB2 the association between aspirin-induced ulcer and the genotype of enzymes metabolizing aspirin, especially CYP2C9. Helicobacter pylori and NSAIDs are now recognized as

the two most important etiological factors in peptic ulcer and its complications;23–25 however, the studies report conflicting findings that H. pylori infection increases, has no effect on, or even decreases the risk of NSAID-related ulcers. A meta-analysis of randomized trials (five studies and 939 patients) evaluating whether eradication of H. pylori prevented peptic ulcer in NSAID users suggested that H. pylori eradication reduced the incidence of peptic ulcer in the NSAID-naive patients (OR = 0.26, 95% CI = 0.14–0.49), but not in previously treated patients (OR = 0.95, 95% CI = 0.53–1.72).25 The fact that eradication appears to be effective when performed in NSAID-naive patients is consistent with H. pylori infection having an enhancing effect on NSAID gastrotoxicity or NSAIDs exacerbating H. pylori ulcer or H. pylori ulcerogenesis. We have previously found no association between H.