However, the observed effects of CagA were rather small. While the literature on NF-κB activation and IL-8 release is contradictory [11], it is nonetheless clear that the pro-inflammatory Protease Inhibitor Library response of gastric epithelial cells is dominated by the presence of the cagPAI. This has been further validated in rhesus monkey and mouse isolates in which CagY protein mutations directly affected the ability to induce IL-8 in gastric epithelial cells ex vivo [12]. While the cagPAI clearly produces a pro-inflammatory response, its primary benefit

to the bacteria appears to be its ability to suppress the host defense. Upon CagA translocation, gastric epithelial cells were found to downregulate β-defensin-3 secretion via a CagA-SHP-2-complex-dependent signaling pathway [13]. Intriguingly, two opposing H. pylori-triggered regulatory circuits seem to control expression of this defensin so that its particular relevance in host defense is not directly revealed by an upregulation in the infected host tissue [14]. In addition, a mouse cathelicidin antimicrobial peptide, CRAMP, was found to be effective against H. pylori in vitro and in vivo [15]. The second line of defense against H. pylori is controlled by the phagocytic

cells of the stomach. Fehlings et al. [16] observed similar patterns of IL-6, IL-1β, IL-10, and IL-12 upregulation in monocytes, macrophages, and DCs ex vivo upon H. pylori Pritelivir order infection. Macrophage migration inhibitory factor (MIF) was downregulated in DCs but not in the other cell types [16]. Different members of the TLR family mediate recognition of H. pylori by DCs and macrophages in vitro [17]. In a recent report, TLR9−/− mice were found to show increased signs of gastritis upon H. pylori infection [18], indicating that the pro-inflammatory 上海皓元 response to H. pylori is negatively modulated via TLR9 expressed in DCs and macrophages. However, the question remains whether gastric tissue DCs and macrophages in vivo are anergic to TLR ligands, as suggested for intestinal macrophages [19]. Cole et al. showed that H. pylori sonicate can induce

tolerance in bone marrow-derived DCs, leading to significantly reduced TNF-α release in response to a second stimulation. By contrast, the release of IL-10 was increased [20], suggesting that although DCs and macrophages show no TLR response, they can nevertheless respond to other H. pylori-dependent stimuli. The dendritic cell-specific ICAM-grabbing nonintegrin (DC-SIGN) that binds to fucose sugar residues in the Lewis antigen of H. pylori could be such a factor [21]. Bone marrow-derived macrophages lacking TLR and NOD1/2 responses can detect the functional CagT4SS, as evidenced by induction of miR-155 expression, suggesting that there is a direct interaction between the cagT4SS and macrophages [22]. The question remains, “How H. pylori survives despite such a strong innate immune response?” It has been hypothesized that H.

2). A 6.3 Mb region of homozygosity on chromosome 16 (25,073063-31,378235) that was shared by the proband and her affected cousin but not with the unaffected cousin harbored an excellent candidate gene,

HSD3B7. We PCR-amplified and sequenced Selleck XL765 the coding region of HSD3B7 in the proband using flanking oligonucleotides to amplify each of the nine exons of the gene.3 The proband and her affected first cousin (III.5) were both homozygous for a 2-basepair deletion in exon 1 of HSD3B7 (c.45_46del AG, p.T15Tfsx27) that was not present in the unaffected cousin. Exon 1 of HSD3B7 was then sequenced in the other family members. Both parents of the affected first cousin (III.5) were heterozygous selleckchem for the mutation. The proband’s parents were not available for sampling but four of their siblings were heterozygous for the mutation (II.2, II.4, II.7, and II.14) (Fig. 1). We confirmed the diagnosis of 3β-HSD deficiency by using negative ion FAB-MS21 to analyze the bile acids in the serum of family member III.5. The results definitively established a defect in bile acid synthesis consistent with a deficiency in the activity

of 3β-HSD (formally called 3β-hydroxy-Δ5-C27 steroid dehydrogenase/isomerase). The negative ion mass spectrum of the serum (Fig. 3) was remarkable in revealing the presence of ions consistent with an array of atypical bile acids not normally detected in serum by FAB-MS. The triplets of ions at m/z 453, 469, and 485 (sulfate conjugates) and m/z 510, 526, and 542 (glyco-sulfate conjugates) are characteristic of monohydroxy, dihydroxy, and trihydroxy bile acids, respectively, with a structural feature of a 3β-hydroxy-Δ5 structure (i.e., unsaturated C24 bile acids), respectively, and these are signature metabolites for this genetic defect 上海皓元医药股份有限公司 in bile acid synthesis.2, 21 There was a complete absence of the glycine and taurine conjugates of the primary bile acids of cholic (m/z 498 and 514) and chenodeoxycholic acids (m/z 448 and 464), typically observed

in patients with cholestasis when bile acid synthesis is intact. Family member III.5 was referred to a hepatologist to commence treatment with bile acids. Here we report the identification of a family with 3β-HSD deficiency in which affected individuals show striking phenotypic variability. The proband had chronic liver disease from childhood, but survived without medical care into her early 20s and then died at age 24. Her paternal first cousin (III.1) died at age 6 years of liver disease. The sister of III.1 (III.5) had an apparently self-limited liver disorder in childhood that was severe enough to require multiple hospitalizations and yet she has been asymptomatic for the last 22 years. We confirmed that she was homozygous for a null allele of HSD3B7, yet her liver function tests were normal at age 32 years. The lack of 3β-HSD activity was biochemically confirmed by FAB-MS analysis of the serum.

Disclosures: The following people have nothing to disclose: Fen Liu, Fang Wei, Xiwei Wang, Huaidong Hu, Peng Hu, Dazhi Zhang, Hong Ren Background: It has been one of unsolved issues and unmet needs in chronic

hepatitis B (CHB) treatment to manage multi-drug resistant (MDR) hepatitis B virus. The aim of this study was to elucidate the antiviral efficacy and safety of entecavir plus tenofovir combination therapy in patients with MDR CHB. Methods: In this prospective ongoing multicenter study, patients with MDR CHB defined as detectable HBV DNA (> 60 IU/mL) while on any rescue treatment regimen for at least 24 weeks and prior experience of genotypic resistance to both nucleoside Palbociclib analogue(s) and nucleotide analogue are treated with entecavir and tenofovir combination therapy. The primary endpoint is the proportion of patients Wnt pathway with HBV DNA < 60 IU/ml at Week 48. We present here the first 12 week interim analysis. Results: 61 patients were enrolled at the time interim analysis and 42 of these reached week 12. At baseline, mean age was 47.4 years, 83% were male, 86% were HBeAg(+), mean HBV DNA was 4.55 (±1.23) log 10IU/ml, and

mean ALT was 41.3 IU/ml; 4 patients (9.5%) had documented resistance mutations to lamivudine (LAM) only, 3 (7.1%) to LAM and adefovir (ADF), 14 (33.3%) to ADF, 4 (9.5%) to LAM and entecavir, and 8 (19.0%) to all. By week 4, 9 (21.4%) patients achieved HBV DNA < 60 IU/ml and the mean reductions in HBV DNA was 1.39 ± 0.77 log 10IU/ml. By week 12, 24 (57.1%) patients achieved HBV DNA < 60 IU/ml and the mean reductions in HBV DNA was 2.11 ± 0.77 log 10IU/ml. On-treatment ALT flare was reported in 1 patient during the first 12 week. There was no serious adverse event. Conclusions: In the first 12 week interim analysis in patients with MDR CHB, entecavir plus tenofovir combination therapy early suppressed HBV replication to undetectable HBV DNA levels in the majority (57.1%) of patients.

Disclosures: Chang Wook Kim – Consulting: Gilead; Grant/Research Support: BMS, Boehringer Ingelheim, Pharmicell; Speaking and Teaching: BMS, GSK, Dae-woong The following 上海皓元医药股份有限公司 people have nothing to disclose: Jun Yong Park, Si Hyun Bae, Sang Hoon Ahn Background: ETV is one of the most effective antiviral drugs for the treatment of chronic hepatitis B (CHB). Some patients, however, will have suboptimal response to ETV; and there are limited data in how to proceed with alternative treatment. Methods: This is a retrospective cohort study of 51 consecutive adult patients with CHB who, as ETV partial responders (detectable HBV DNA levels >60 IU/mL after ≧12 months of ETV), were switched to either TDF monotherapy or TDF+ETV combination therapy at four U.S. liver/gastroenterology clinics.

Results: In the 4 months preceding the CDC recommendation a mean of 6, 1/3 unique patient visits occurred each month.13.8% of the patients were known/negative.1.1% of the patients were unknown/assessed (see figure).4 patients were found to be HCV Ab positive but only 1 was PCR positive. In the months following the recommendation a mean of 7,444 unique patient visits occurred per month. The percentage of patients see more known/negative increased to 16.3% in the last month of

data. Within 2 months of the recommendation the percentage of patients unknown/assessed peaked at 2.6% and subsequently decreased to 1.7% in the last month of data.9 patients were found to be HCV Ab positive and none were PCR positive. Conclusions: The release of the CDC recommendation has had little impact on HCV screening in primary care clinics. HCV status is unknown in more than 80% of patients in this cohort seen each day yet only between 1 and 2% of these patients are then screened for HCV. Disclosures: Fredric D. Gordon – Advisory Committees or Review Panels: Vertex, Gilead; Grant/Research Support: Vertex,

Gilead; Speaking and Teaching: Merck The following people have nothing to disclose: Chris Albers, Amir A. Qamar, Maureen A. Tellier Background: Chronic infection with hepatitis C virus (HCV) is closely related to hepatic fibrosis and hepatocellular carcinoma (HCC), but the clinical course of HCC development differs among patients. Epacadostat solubility dmso Recently, DEPDC5 rs1012068 and MICA rs2596542 上海皓元 genetic variations were identified to associate with HCV-related HCC by two independent genome-wide association studies in two different Japanese populations. However, in a Caucasian population, only the MICA single nucleotide polymorphism (SNP) was associated with HCC development. The aim of the present study was to determine whether these SNPs are predictive of HCC development in a unique Japanese population of chronic hepatitis C (CHC) patients.

Methods: A total of 800 CHC patients (141 HCC cases and 659 non-HCC controls) from the Osaka area were enrolled in the study from May 2003-March 2013. Genotyping of DEPDC5 rs1012068 and MICA rs2596542 SNPs was performed using a ĪaqMan SNP genotyping and direct sequencing methods. Results: The major, heterozygous, and minor genotypes of the DEPDC5 SNP were found in 42, 93, 6 HCC patients and 173, 474, 12 non-HCC patients, respectively. We did not find a significant difference between DEPDC5 genotype and HCC development (P = 0.1235). This result is consistent with a previous study in a Caucasian population but differs from results in a Japanese population. However, the minor genotype of the MICA SNP was found in 18.44% (26/141) of HCC patients and 11.38% (75/659) of non-HCC patients, and was significantly associated with HCC development (P = 0.022; odds ratio =1.76).

Results: In the 4 months preceding the CDC recommendation a mean of 6, 1/3 unique patient visits occurred each month.13.8% of the patients were known/negative.1.1% of the patients were unknown/assessed (see figure).4 patients were found to be HCV Ab positive but only 1 was PCR positive. In the months following the recommendation a mean of 7,444 unique patient visits occurred per month. The percentage of patients Sirolimus manufacturer known/negative increased to 16.3% in the last month of

data. Within 2 months of the recommendation the percentage of patients unknown/assessed peaked at 2.6% and subsequently decreased to 1.7% in the last month of data.9 patients were found to be HCV Ab positive and none were PCR positive. Conclusions: The release of the CDC recommendation has had little impact on HCV screening in primary care clinics. HCV status is unknown in more than 80% of patients in this cohort seen each day yet only between 1 and 2% of these patients are then screened for HCV. Disclosures: Fredric D. Gordon – Advisory Committees or Review Panels: Vertex, Gilead; Grant/Research Support: Vertex,

Gilead; Speaking and Teaching: Merck The following people have nothing to disclose: Chris Albers, Amir A. Qamar, Maureen A. Tellier Background: Chronic infection with hepatitis C virus (HCV) is closely related to hepatic fibrosis and hepatocellular carcinoma (HCC), but the clinical course of HCC development differs among patients. Trichostatin A order Recently, DEPDC5 rs1012068 and MICA rs2596542 medchemexpress genetic variations were identified to associate with HCV-related HCC by two independent genome-wide association studies in two different Japanese populations. However, in a Caucasian population, only the MICA single nucleotide polymorphism (SNP) was associated with HCC development. The aim of the present study was to determine whether these SNPs are predictive of HCC development in a unique Japanese population of chronic hepatitis C (CHC) patients.

Methods: A total of 800 CHC patients (141 HCC cases and 659 non-HCC controls) from the Osaka area were enrolled in the study from May 2003-March 2013. Genotyping of DEPDC5 rs1012068 and MICA rs2596542 SNPs was performed using a ĪaqMan SNP genotyping and direct sequencing methods. Results: The major, heterozygous, and minor genotypes of the DEPDC5 SNP were found in 42, 93, 6 HCC patients and 173, 474, 12 non-HCC patients, respectively. We did not find a significant difference between DEPDC5 genotype and HCC development (P = 0.1235). This result is consistent with a previous study in a Caucasian population but differs from results in a Japanese population. However, the minor genotype of the MICA SNP was found in 18.44% (26/141) of HCC patients and 11.38% (75/659) of non-HCC patients, and was significantly associated with HCC development (P = 0.022; odds ratio =1.76).

In elderly patients and in patients with underlying cardiovascular disease and other risk factors for thrombosis, these agents should be used, when strictly indicated. Anamnestic response with the increase in FVIII inhibitor after APCC treatment has been reported only in the haemophilic patients [14]. Data on the use of FVIII replacement therapy in acquired haemophilia are scanty. Its use should be attempted only in case of low inhibitor

titre (<5 BU mL), minor bleeding and no bypassing agents availability. According to the experience in congenital haemophilia with alloantibodies, a loading dose should be given as bolus to neutralize the inhibitor and to achieve the haemostatic level, followed by subsequent doses given by bolus or by continuous infusion for maintenance [15]. The Fluorouracil research buy recovery and half-life of the infused RG7204 mouse FVIII:C cannot be predicted because of the variable kinetics of FVIII:C. In case of no satisfactory response within 24–48 h, one should resort to a by-passing agent. Desmopressin, a synthetic vasopressin analogue, releases FVIII/von Willebrand factor from the vascular endothelium. Its use in acquired haemophilia is

anecdotal; the indications are the same as for FVIII concentrates [16]. When infused intravenously or administered subcutaneously or intranasally, FVIII:C increases three- to five-fold above the baseline and reach a value sufficient to treat minor bleeding. The tachyphylaxis phenomenon limits it use to 3 or 4 上海皓元 consecutive days. The antidiuretic and vasomotor side-effects require caution in older patients. The response to high-dose immunoglobulins has been attributed to the presence of anti-idiotype antibodies in the pooled immunoglobulins, but at present, there is no evidence for its use as a single agent in acquired haemophilia [17]. A possible application is as an integral component of immune tolerance induction protocol [18–20]. The aim of the immunosuppressive therapy is the eradication of the inhibitor. Spontaneous complete remission (e.g. children, post-partum, drug-associated cases) were reported up to 36% of the patients [21], but are unpredictable and the

patients remain at great risk of severe bleeding if the inhibitor persists [1,22,23]. Therefore, immunosuppressive therapy should be initiated as soon as the diagnosis is established. No prospective, controlled studies evaluating the efficacy of the different therapeutic agents have been published. Prednisone as monotherapy or in combination with cyclophosphamide and azothioprin is the standard intervention [1,24] (Table 3). The therapy should be carried out with adequate doses and duration: previous experience in haemophiliacs points to the importance of carrying out the treatment according to haematological tolerance [25]. Complete remission rate is higher and overall mortality is lower in the treated patients. Response rate with prednisone alone is high, but a sustained remission after prednisone discontinuation is rare.

10, 11 CHO oxidation = (4.585 × VCO2) − (3.226 × VO2). The CO2 and O2 volume data from the metabolic chamber test were used in the calculation. Energy expenditure was calculated as before.12 Stable

CAV1 knockdown AML12 cell lines were developed using SHVRS MISSION short hairpin RNA (shRNA) Lentiviral Particles (Sigma Mission shRNA set) against mouse caveolin-1 following manufacturer protocols. Two of the five different lentiviral particles with shRNA targeting different sequences of mRNA codifying for CAV1 were able to knockdown CAV1 LGK-974 solubility dmso to around 90% of the CAV1 expression shown by the WT AML12 hepatocytes. These stable CAV1-deficient AML12 hepatocytes were termed CAV1-kd#2 and CAV1-kd#4, respectively. Cells were selected using puromycin (1 μg/mL) and pooled populations were used PI3K inhibitor for

experiments. WT AML12 hepatocytes were infected with lentiviral particles coding for a scrambled shRNA. Glycolytic rate was measured using the Seahorse XF24 analyzer. Cells were seeded into Seahorse V7 plates at 40,000 cells/well and 24 hours later cells were incubated in either high glucose media (25 mM glucose) or low glucose/oleate media (10 mM glucose, 100 μM oleate) for a further 24 hours. Cells were then washed twice in assay running media (unbuffered Dulbecco’s modified Eagle’s medium [DMEM] with 5 mM glucose) before being incubated in assay running media in a non-CO2 incubator at 37°C for 60 minutes. Basal extracellular acidification rate (ECAR), a proxy measure of glycolysis was then measured using the Seahorse XF analyzer over three measurement periods, each comprised of a 3-minute mix, 2-minute wait, and 3-minute measure cycles. To determine the effect of impaired oxidative

adenosine triphosphate (ATP) production on ECAR, oligomycin was injected into the system at a final MCE concentration of 1 μM. ECAR was then determined, again over three measurement periods, each comprised of a 3-minute mix, 2-minute wait, and 3-minute measure cycles. At the conclusion of the assay the assay media was removed and the Seahorse plate and cells were immediately frozen at −80°C for 24 hours. Plates were then thawed and the cell number in each well was determined using the CyQuant kit (Invitrogen) according to the manufacturer’s instructions. ECAR values were then normalized to cell number, expressed as a ratio of 50,000 cells. Statistical significance was assessed using Student’s t test or analysis of variance (ANOVA) II in combination with Bonferroni’s multiple comparison test unless otherwise indicated. Significance is indicated as (asterisks or another symbol) *P < 0.05; **P < 0.01; ***P < 0.001. To examine the apparent inconsistency in liver regeneration between genetic backgrounds we generated and analyzed a third CAV1−/− mouse strain on a pure BalbC genetic background (Balb/CCAV1) (see Materials and Methods).

Nonuniform sampling with respect to size within age is another potential

source of bias. This is especially an issue if, for example, large territorial males or perhaps pregnant females are more likely to be available for capture. Monk seals do not maintain territories and obviously pregnant females were not captured. Emaciated animals Dasatinib ic50 were also typically not captured, which might have resulted in some positive bias in our sample. Variability in the measurement date could influence results if there are pronounced seasonal patterns in body condition as is the case with many pinnipeds (Schusterman and Gentry 1971, Ryg et al. 1990, Boyd and Duck 1991, Renouf et al. 1993, Trites and Bigg 1996, Winship et al. 2001). The measurement data in this study were collected throughout the year, with 26%, 40%, 24%, and 10% of sampling in the first through fourth quarters, respectively. Although there was greater sampling in the second quarter and less in the fourth, Hawaiian monk seals are not known to undergo marked variation in body condition seasonally, with the exception of pregnant, currently or recently lactating females, and possibly around the time of molting. Pregnant females were avoided, whereas lactating and

check details molting seals were not captured. We thus conclude that date of sampling likely had little influence on the results. Size-biased mortality likely affected the shape of fitted growth curves. Weaning size (girth) strongly influences Hawaiian monk seal first year survival (Craig and Ragen 1999, Baker 2008). It seems likely that this holds true for immature animals as well. Baker and Thompson (2007) found that Hawaiian monk seals achieve adult survival rates at least by age 5 yr and, thereafter, survival remained high (typically >0.90) and relatively invariant until senescence was apparent after approximately

age 18 yr. Size-selective survival, then, would have the greatest potential effect on our fitted growth curves up to age 5 yr. 上海皓元医药股份有限公司 If smaller immature animals died at a higher rate, then the subsequent ages would be represented by relatively larger seals, resulting in positively biased growth rates. The fitted curves (Fig. 3, 4) may consequently be steeper for the first few age classes than if sufficient longitudinal data had been available. Winship et al.’s (2001) final factor influencing growth curves derived from cross-section data is that environmental conditions vary over time. In the present study, measured seals had different histories of exposure to environments that were relatively more or less conducive to growth. A likely effect of this is apparent in the length and girth data from French Frigate Shoals (Fig. 3, 4). Note that most of the measurements of 5 to 8 yr old seals are below the fitted line.

0%) groups. Treatment discontinuation due to adverse effects and the development www.selleckchem.com/products/H-89-dihydrochloride.html of bacterial infection did not differ between the Spx and non-Spx/TCP groups. The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse

or IL28B TT allele. “
“Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 also displays strong attenuation of macrophage reactivity in vitro, but the physiological roles of TGR5 in inflammatory response, and its mechanism, is unknown. Here, we demonstrate that TGR5 is a negative modulator of nuclear factor kappa

light-chain enhancer of activated B cells (NF-κB)-mediated inflammation. TGR5 activation suppresses the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), the translocation of p65, NF-κB DNA-binding activity, and its transcription activity. Furthermore, TGR5 activation enhances the interaction of IκBα and β-arrestin2. Suppression of NF-κB transcription activity and its target gene expression by TGR5 agonist are specifically abolished by the expression of anti-β-arrestin2 small interfering RNA. These results show that TGR5 suppresses the NF-κB pathway by mediation of the interaction between IκBα and β-arrestin2. In a lipopolysaccharide (LPS)-induced inflammation model, TGR5−/− mice show more severe Androgen Receptor antagonist liver necroses and inflammation, compared with wild-type (WT) mice. Activation of TGR5 by its agonist ligand inhibits the expression of inflammatory mediators in response to NF-κB activation induced by LPS in WT, but not TGR5−/−, mouse liver. Conclusion:

These findings identify TGR5 as a negative mediator of inflammation that may serve as an attractive therapeutic tool for immune and inflammatory liver diseases. (HEPATOLOGY 2011;) Chronic inflammation is increasingly recognized as an important component of tumorigenesis and metabolic MCE公司 diseases.1, 2 For example, hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer that often occurs secondary to chronic hepatitis. Moreover, chronic inflammation is an important mediator of insulin resistance and type 2 diabetes in obese individuals.2 Thus, the precise control of inflammation is essential for the prevention of chronic inflammatory disorders, including many types of cancers and metabolic disorders.3, 4 Nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) has received considerable attention as a key regulator of immunity, inflammation, and carcinogenesis.1, 5 The classic NF-κB consists of a p65 (RelA) and p50 heterodimer sequestered in the cytoplasm of unstimulated cells by its assembly with the inhibitor, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα).

As illustrated in Fig. 1, a range of CCrs12979860 genotype frequencies may evolve in patients with chronic HCV infection; this depends on the frequencies in uninfected subjects and

the rates of spontaneous resolution of infection. However, from this figure, it is obvious that a 67% CC genotype rate at rs12979860 should not develop in an uninfected population learn more with a 45% CC genotype rate, as reported for HCV genotype 2/3 by Montes-Cano et al.,4 unless the clearance rate in patients carrying a non-CC genotype is higher than that in the CC genotype group. An alternative explanation might be that, for epidemiological reasons, HCV genotype 2/3 preferentially spreads in populations with higher frequencies of the CC genotype. We propose that these putative mechanisms should be explored, although, as suggested by Montes-Cano et al., a positive selection on the basis of unknown

virological or biological phenomena might also explain the high frequency of the CC genotype in patients with genotype 2/3. Magnus Lindh M.D.*, Martin Lagging M.D.*, Gunnar Norkrans M.D.*, Kristoffer Hellstrand M.D.*, * Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden. “
“A young woman, aged 19, presented to the Emergency Department with abdominal pain and gastrointestinal bleeding. Pain had been present for 4 days and, on the day of admission, she had episodes of nausea and vomiting. Subsequently, MCE she NVP-BEZ235 cost began to vomit blood and also developed melena. She had been previously diagnosed with a hypercoagulable state resulting from a JAK-2 mutation and was known to have portal vein thrombosis with extension of the thrombosis into the splenic and superior mesenteric veins. She had also been previously diagnosed with esophageal varices but had not had episodes of gastrointestinal bleeding. She ceased treatment with warfarin 1 month prior to admission but restarted the drug after the onset of abdominal pain. Blood tests revealed a hemoglobin

of 7.6 g/dL (76 g/l) with an international normalized ratio (INR) of 2.1. After fluid resuscitation and the correction of coagulopathy, upper gastrointestinal endoscopy was performed. Esophageal varices of moderate size were present but did not appear to be responsible for bleeding. However, there was a bleeding lesion in the duodenal cap that seemed likely to be related to a duodenal varix (Figure 1). A contrast-enhanced computed tomography scan showed extensive thromboses in the portal venous system with the formation of a portal cavernoma. An endoscopic ultrasound study confirmed the presence of periduodenal varices (Figure 2) and a subsequent angiogram confirmed the presence of extensive portal thromboses with large intra-abdominal collaterals that precluded treatment with a transjugular intrahepatic portosystemic shunt.