One hundred and seventy HCCs were randomly retrieved from HCC patients who underwent curative resection at Eastern Hepatobiliary Surgery this website Hospital, Shanghai, China, from September 2001 to July 2007 (see detailed clinicopathological features in Supporting Table 1). All patients were followed up until March 2010, with a median observation time of 40 months. Overall survival (OS) was defined as the interval between the dates of

surgery and death. Disease-free survival (DFS) was defined as the interval between the dates of surgery and recurrence; if recurrence was not diagnosed, patients were censored on the date of death or the last follow-up. Matched pairs of primary HCC samples and adjacent liver tissues were used for the construction of a tissue microarray (in collaboration with Shanghai Biochip Company, Shanghai, China). Immunostaining

was performed on tissue microarray Talazoparib slides. Assessment of the staining was based on the percentage of positively stained cells and the staining intensity using software Image-Pro Plus 6.0 (Media Cybernetics, Inc., Bethesda, MD). Fifty-eight pairs of human HCC with pericancerous tissues and 38 pairs of HCC with portal vein tumor thrombus samples diagnosed by pathologist were obtained from Eastern Hepatobiliary Surgery Hospital. Patient samples were obtained following informed consent according to an established protocol approved by the Ethic Committee of Eastern Hepatobiliary Surgery Hospital. SMMC-7721/cyclin G1, HepG2/cyclin G1, and their control cells (1 × 103) were cultured in 96-well

plates for various time periods. Adenosine triphosphate activity was measured using Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) with a Synergy 2 microplate reader to assess the cell proliferation. Hepatoma cells (2.5 × 104) were seeded in 96-well plates coated with 10 μg/mL fibronectin (Calbiochem, La Jolla, CA) and cell adhesion was evaluated. For wound healing assay, monolayers of cells were wounded by scraping with a plastic pipette tip and rinsed several times with selleckchem medium to remove dislodged cells. Cells that had migrated into the wound area were photographed. For invasion assay, 2 × 105 cells were plated into the upper chamber of a polycarbonate transwell filter chamber coated with Matrigel (BD) and incubated for 60 hours. Cell counts are expressed as the mean number of cells per field of view. Six-week-old male BALB/c nude mice were randomized into two groups (n = 11) and inoculated with SMMC-7721/cyclin G1 or control cells (2 × 106) in spleen. Four mice were sacrificed 8 weeks after inoculation, and metastatic tumor colonies in the liver were measured. The remaining mice were observed for survival analysis. For the tail vein metastasis model, 22 nude mice were randomized into two groups. SMMC-7721/cyclin G1 or control cells (2 × 106) were injected into the tail vein of nude mice.

At baseline, a structured interview schedule was used to obtain information about potential risk factors including country of birth, education, smoking history, alcohol consumption, and for women, reproductive history and use of hormone replacement therapy. Current usual diet was assessed by a 121-item food frequency questionnaire.19 A blood sample www.selleckchem.com/products/acalabrutinib.html was collected and weight, height, waist, and hip circumferences were measured.20 Addresses and vital status of the subjects were determined by record linkage to electoral rolls, the National

Death Index, Victorian death records, and from electronic phone books and responses to mailed questionnaires and newsletters. Cancer cases were identified by linkage to population-based cancer registries in all Australian states. Blood samples were stored either in liquid nitrogen or dried on Guthrie cards. DNA was extracted from Guthrie cards by the Chelex method and from buffy coats using a guanidinium isothiocyanate–based method (Corbett Buffy Coat CorProtocol 14102). All samples were genotyped for the single-nucleotide Aloxistatin research buy polymorphism in the HFE gene that is responsible for the C282Y substitution in the HFE protein (rs1800562) using real-time polymerase chain reaction. Those samples with one copy of

the variant leading to C282Y were also genotyped for the variant leading to the H63D substitution (rs1799945).21 Therefore, there were four HFE genotype groups: (1) C282Y homozygotes, (2) simple heterozygotes with one copy of the C282Y variant and no copies of the H63D variant, (3) compound heterozygotes with one copy each of the C282Y and H63D variants, and (4) other HFE genotype with no copies selleck inhibitor of the C282Y variant and unknown number of copies of the H63D variant. The H63D and C282Y variants have only very rarely been reported to occur together on a single chromosome.22 For participants classified as C282Y homozygotes by this genotyping, additional genotyping was performed for confirmation. All participants homozygous for the C282Y variant (as part of an HFE-genotype stratified

random sample) were invited to participate in a study of iron and health (the “HealthIron” study) from 2004–2007, where we collected a cheek swab, with subsequent genotyping for C282Y and H63D in an independent laboratory. For those who did not participate in HealthIron, additional genotyping was done on a baseline plasma sample. Only those participants classified as C282Y homozygotes by the initial and confirmatory genotyping were considered to be homozygotes for this analysis, otherwise they were classified according to the results of the confirmatory genotyping. Hazard ratios were estimated using Cox regression with age as the time axis. Follow-up began at baseline and ended at death, date of diagnosis, date left Australia, or end of follow-up, whichever came first.

The cause of death from selleck chemical the toxic liver injury was not characterized, correction of any specific liver function by the engrafted

cells was not demonstrated, and whether the iPSC-derived hepatocytes responded appropriately to proliferation signals after loss of hepatocyte mass was not tested. In summary, the recent findings by Takebe et al. offer encouragement for the use of PSC-derived hepatocytes for tissue engineering. Nevertheless, it is important to recognize that a combination of vasculature, stromal cells, and hepatocytes does not an organ make. Liver architecture, including biliary structures, is critical for the liver’s exocrine function. Liver-like tissues have been generated from primary rodent and human hepatocytes,[11, 12] and primary hepatocytes that have colonized

lymph nodes can produce enough ectopic liver mass to rescue a mouse from a lethal metabolic disease, indicating that the lymph node contains enough structure for primary selleck screening library cells to support liver tissue and life-sustaining organ function. It may also be important to consider that nonparenchymal cells could have organ-specific characteristics that potentially have unique roles in controlling organ development and function.[14] Transplant of iPSC-derived liver buds into the native hepatic environment may therefore prove to be efficacious and could potentially promote cholangiocyte differentiation. The potential to generate organs from iPSCs is exciting and could have substantial ramification for the treatment of liver disease; however, more complete differentiation

of iPSCs to a mature hepatic phenotype with the capacity to expand as robustly as primary human hepatocytes will be required. Long-term engraftment in host animals has long been thought to be the most likely way to produce near-complete maturation of iPSC-derived hepatocytes. A significant finding from this study is that, unlike iPSC-derived pancreatic beta cells, the iPSC-derived hepatocytes in the cell clusters failed to completely differentiate after transplantation in immune-deficient adult hosts.[13] Thus, many important positive and negative lessons can be taken from this work, and, with them, many more questions will need answers. The authors thank Dr. Jayanta Roy-Chowdhury for his see more careful review of the manuscript and helpful suggestions. Ira J. Fox, M.D.1 “
“Background and Aim:  A number of hepatitis C virus (HCV) patients without a rapid virological response (RVR) achieved a sustained virological response (SVR) with peginterferon-α-2a/ribavirin. The aim of this study was to identify factors associated with SVR in non-RVR patients. Methods:  Baseline and on-treatment factors were used to explore the prognostic factors for SVR in 113 HCV genotype-1 (HCV-1) and 20 HCV-2 non-RVR patients in two randomized trials.

Pain because of cracked tooth syndrome is classically intermittent, provoked on biting or releasing biting on a hard object, and is notoriously difficult to diagnose. It may be described as sharp or sensitive, and is usually related to mastication. The tooth may also become sensitive to hot and cold stimuli. It is thought that the pain is due to fluid shifts within the dentine tubules, which are generated due to pressure differences as the crack opens and closes during mastication. It can be extremely difficult to diagnose.[15] Pain because of dentine sensitivity is classically stimulated by exposure to cold, heat, sweet foods/drinks, and mechanical trauma such as toothbrushing. The sensation is INCB024360 research buy due to the movement of fluid

in dentinal tubules in response to osmotic this website or temperature-related effects. Dentinal tubules contain the processes of cells residing in the dental pulp (odontoblasts), and fluid movement appears to trigger nociceptive output by mechanisms that are as yet unclear. Gingival recession can lead to exposure of the endings of dentine tubules, as can loss of enamel on the crown of the tooth. Dentinal sensitivity is described as very rapid, fleeting, shooting pain, or sensitivity, and is always in response to an identifiable stimulus. Intraoral pain may also arise from non-dental structures.[16] Oral mucosal malignancies such

as squamous cell carcinoma or salivary gland carcinoma may be painful because of ulceration or perineural invasion. Inflammatory oral mucosal diseases such as oral lichen planus, recurrent aphthous stomatitis, vesiculobullous diseases, and oral mucosal infections such as candidiasis or herpes viruses (herpes simplex, varicella zoster) may all cause significant oral selleck products pain.

Patients with hematinic deficiencies, diabetes, hematological malignancies, HIV/AIDS, and Behçet’s disease may have significant oral mucosal pain and/or ulceration. Examination will usually reveal the associated oral mucosal abnormalities.[17] Pain may be experienced in the oral cavity, face, and neck because of salivary gland pathology. Blockage of a major salivary gland duct may be due to infection, mechanical obstruction by tumors, docholithiasis, or ductal strictures. Obstruction of the duct will lead to pain as the gland fills with saliva, which cannot be released. Pain due to chronic ductal obstruction typically worsens preprandially or during meal times. Infection of the salivary glands will result in gland swelling, pain, and erythema/warmth of the overlying skin. This definition encompasses intraoral pain that is localized to a non-diseased dentoalveolar structure, such as a tooth or an area of alveolar ridge from which a tooth has previously been extracted.[18] The pain is often described as “burning,” “shooting,” or “shock-like,” and there may be significant hyperalgesia and allodynia of the affected region, often with an associated area of hypoesthesia or dysesthesia.

Pain because of cracked tooth syndrome is classically intermittent, provoked on biting or releasing biting on a hard object, and is notoriously difficult to diagnose. It may be described as sharp or sensitive, and is usually related to mastication. The tooth may also become sensitive to hot and cold stimuli. It is thought that the pain is due to fluid shifts within the dentine tubules, which are generated due to pressure differences as the crack opens and closes during mastication. It can be extremely difficult to diagnose.[15] Pain because of dentine sensitivity is classically stimulated by exposure to cold, heat, sweet foods/drinks, and mechanical trauma such as toothbrushing. The sensation is selleck inhibitor due to the movement of fluid

in dentinal tubules in response to osmotic DAPT molecular weight or temperature-related effects. Dentinal tubules contain the processes of cells residing in the dental pulp (odontoblasts), and fluid movement appears to trigger nociceptive output by mechanisms that are as yet unclear. Gingival recession can lead to exposure of the endings of dentine tubules, as can loss of enamel on the crown of the tooth. Dentinal sensitivity is described as very rapid, fleeting, shooting pain, or sensitivity, and is always in response to an identifiable stimulus. Intraoral pain may also arise from non-dental structures.[16] Oral mucosal malignancies such

as squamous cell carcinoma or salivary gland carcinoma may be painful because of ulceration or perineural invasion. Inflammatory oral mucosal diseases such as oral lichen planus, recurrent aphthous stomatitis, vesiculobullous diseases, and oral mucosal infections such as candidiasis or herpes viruses (herpes simplex, varicella zoster) may all cause significant oral find more pain.

Patients with hematinic deficiencies, diabetes, hematological malignancies, HIV/AIDS, and Behçet’s disease may have significant oral mucosal pain and/or ulceration. Examination will usually reveal the associated oral mucosal abnormalities.[17] Pain may be experienced in the oral cavity, face, and neck because of salivary gland pathology. Blockage of a major salivary gland duct may be due to infection, mechanical obstruction by tumors, docholithiasis, or ductal strictures. Obstruction of the duct will lead to pain as the gland fills with saliva, which cannot be released. Pain due to chronic ductal obstruction typically worsens preprandially or during meal times. Infection of the salivary glands will result in gland swelling, pain, and erythema/warmth of the overlying skin. This definition encompasses intraoral pain that is localized to a non-diseased dentoalveolar structure, such as a tooth or an area of alveolar ridge from which a tooth has previously been extracted.[18] The pain is often described as “burning,” “shooting,” or “shock-like,” and there may be significant hyperalgesia and allodynia of the affected region, often with an associated area of hypoesthesia or dysesthesia.

e., they had portal hypertension) and, upon follow-up, HVPG was more predictive of clinical decompensation than histological fibrosis staging. Simple histologic features may also

have important prognostic implications in cirrhotic liver biopsies. For example, the thickness of fibrous septa correlates with HVPG and is an independent predictor of both clinically significant portal hypertension (i.e., HVPG > 10 mmHg)20 and clinical decompensation.21 Moreover, digital image analysis of septal thickness, but not total fibrosis area, predicts cirrhosis decompensation.22 Studies performed in the past two decades have identified several attractive targets for antifibrotic treatment. These include the major cellular sources of scar, most notably activated hepatic stellate cells and Galunisertib portal myofibroblasts, as well as key cytokines such as platelet-derived growth factor and transforming growth factor beta.23 The roles of bone marrow–derived cells and those arising from epithelial-mesenchymal Y 27632 transition are still under evaluation, but it is unlikely that these sources of fibrogenic cells provide a major contribution to

hepatic extracellular matrix in chronic human liver disease. Cellular sources of proteases that degrade scar and the pathways that regulate them are better understood. Moreover, a more nuanced understanding of distinctive pathogenic features of fibrosis at different stages and from different etiologies means that fibrosis may be customized according to its duration and underlying cause. Cirrhosis in experimental models and human disease may be reversible.24 Following withdrawal of an injurious stimulus, learn more a dense micronodular cirrhosis can undergo remodeling to a more attenuated, macronodular pattern. However, some septa will persist, likely representing those laid down early in the injury and are

therefore the most “mature” (i.e., cross-linked). Moreover, in experimental models, such mature scars may be the site of neoangiogenesis. Such angiogenesis is already present in chronic inflammatory liver diseases25 concurrent with the fibrogenic process and may also play a role in the pathogenesis of portal hypertension.26 The effectiveness of therapeutic angiogenic inhibitors in not only improving fibrosis, but also in reducing portal pressure, is suggested by data from animal models but has not been established in humans.27 Although there are no data linking septal remodeling to portal pressure changes, recent work correlating increased portal hypertension with smaller nodule size and septal thickening suggests that reversal of these events might lower portal pressure.20 These rodent models and human studies throw into relief the inadequacy of a simple one stage classification, because although the micronodular and remodeled attenuated macronodular cirrhosis are very different, they are both defined by the same original pathologic description: “cirrhosis”.

e., they had portal hypertension) and, upon follow-up, HVPG was more predictive of clinical decompensation than histological fibrosis staging. Simple histologic features may also

have important prognostic implications in cirrhotic liver biopsies. For example, the thickness of fibrous septa correlates with HVPG and is an independent predictor of both clinically significant portal hypertension (i.e., HVPG > 10 mmHg)20 and clinical decompensation.21 Moreover, digital image analysis of septal thickness, but not total fibrosis area, predicts cirrhosis decompensation.22 Studies performed in the past two decades have identified several attractive targets for antifibrotic treatment. These include the major cellular sources of scar, most notably activated hepatic stellate cells and Wnt antagonist portal myofibroblasts, as well as key cytokines such as platelet-derived growth factor and transforming growth factor beta.23 The roles of bone marrow–derived cells and those arising from epithelial-mesenchymal mTOR inhibitor transition are still under evaluation, but it is unlikely that these sources of fibrogenic cells provide a major contribution to

hepatic extracellular matrix in chronic human liver disease. Cellular sources of proteases that degrade scar and the pathways that regulate them are better understood. Moreover, a more nuanced understanding of distinctive pathogenic features of fibrosis at different stages and from different etiologies means that fibrosis may be customized according to its duration and underlying cause. Cirrhosis in experimental models and human disease may be reversible.24 Following withdrawal of an injurious stimulus, see more a dense micronodular cirrhosis can undergo remodeling to a more attenuated, macronodular pattern. However, some septa will persist, likely representing those laid down early in the injury and are

therefore the most “mature” (i.e., cross-linked). Moreover, in experimental models, such mature scars may be the site of neoangiogenesis. Such angiogenesis is already present in chronic inflammatory liver diseases25 concurrent with the fibrogenic process and may also play a role in the pathogenesis of portal hypertension.26 The effectiveness of therapeutic angiogenic inhibitors in not only improving fibrosis, but also in reducing portal pressure, is suggested by data from animal models but has not been established in humans.27 Although there are no data linking septal remodeling to portal pressure changes, recent work correlating increased portal hypertension with smaller nodule size and septal thickening suggests that reversal of these events might lower portal pressure.20 These rodent models and human studies throw into relief the inadequacy of a simple one stage classification, because although the micronodular and remodeled attenuated macronodular cirrhosis are very different, they are both defined by the same original pathologic description: “cirrhosis”.

gAcrp increased IL-10 mRNA and protein expression, as well as expression of the IL-10 inducible gene, HO-1; expression was higher in Kupffer cells from ethanol-fed rats compared with pair-fed Ibrutinib price controls. Although IL-10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL-10–mediated phosphorylation of STAT3 and expression of HO-1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO-1 activity, either by treatment with the HO-1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO-1, prevented the inhibitory effect of gAcrp on LPS-stimulated

TNF-α expression in Kupffer cells. LPS-stimulated TNF-α expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO-1 expression, ethanol-induced sensitivity to LPS was ameliorated. Conclusion: gAcrp prevents LPS-stimulated TNF-α expression in Kupffer cells through the activation of the IL-10/STAT3/HO-1 pathway. Kupffer cells from ethanol-fed rats are highly sensitive to the anti-inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL-10. (HEPATOLOGY 2010.) Silmitasertib cost The innate and adaptive immune systems have been implicated in the progression of alcoholic liver disease. Disruption in the regulation of the innate immune response is thought to be particularly important

in the early stages of ethanol-induced liver injury.1 Accumulating evidence suggests that an imbalance between the activities of

pro-inflammatory and anti-inflammatory mediators contributes to ethanol-induced liver injury. For example, ethanol consumption leads to elevated lipopolysaccharide (LPS)/endotoxin in the portal blood, as well as a sensitization of Kupffer cells to activation, resulting in production of a number of inflammatory mediators, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and reactive oxygen species. Among the pro-inflammatory mediators, TNF-α plays a critical role in the pathogenesis of alcoholic liver disease1; treatment with TNF-α neutralizing antibody reduces selleck products ethanol-induced liver injury in animals, and TNF-α receptor 1 knockout mice are resistant to the toxic effects of ethanol exposure.1 Loss of anti-inflammatory mediators also may contribute to a pro-inflammatory state in the liver and facilitate injury. For example, IL-10 is an immunomodulatory cytokine with potent anti-inflammatory and immunosuppressive properties. IL-10 decreases production of pro-inflammatory cytokines, including TNF-α and IL-1β.2 Although little is known about the regulation of IL-10 expression and activity in the liver in response to chronic ethanol, impaired expression of IL-10 contributes to inflammation in alcoholic patients with cirrhosis,3 and IL-10–deficient mice are more sensitive to ethanol-induced liver injury.

gAcrp increased IL-10 mRNA and protein expression, as well as expression of the IL-10 inducible gene, HO-1; expression was higher in Kupffer cells from ethanol-fed rats compared with pair-fed selleck kinase inhibitor controls. Although IL-10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL-10–mediated phosphorylation of STAT3 and expression of HO-1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO-1 activity, either by treatment with the HO-1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO-1, prevented the inhibitory effect of gAcrp on LPS-stimulated

TNF-α expression in Kupffer cells. LPS-stimulated TNF-α expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO-1 expression, ethanol-induced sensitivity to LPS was ameliorated. Conclusion: gAcrp prevents LPS-stimulated TNF-α expression in Kupffer cells through the activation of the IL-10/STAT3/HO-1 pathway. Kupffer cells from ethanol-fed rats are highly sensitive to the anti-inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL-10. (HEPATOLOGY 2010.) selleckchem The innate and adaptive immune systems have been implicated in the progression of alcoholic liver disease. Disruption in the regulation of the innate immune response is thought to be particularly important

in the early stages of ethanol-induced liver injury.1 Accumulating evidence suggests that an imbalance between the activities of

pro-inflammatory and anti-inflammatory mediators contributes to ethanol-induced liver injury. For example, ethanol consumption leads to elevated lipopolysaccharide (LPS)/endotoxin in the portal blood, as well as a sensitization of Kupffer cells to activation, resulting in production of a number of inflammatory mediators, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and reactive oxygen species. Among the pro-inflammatory mediators, TNF-α plays a critical role in the pathogenesis of alcoholic liver disease1; treatment with TNF-α neutralizing antibody reduces find more ethanol-induced liver injury in animals, and TNF-α receptor 1 knockout mice are resistant to the toxic effects of ethanol exposure.1 Loss of anti-inflammatory mediators also may contribute to a pro-inflammatory state in the liver and facilitate injury. For example, IL-10 is an immunomodulatory cytokine with potent anti-inflammatory and immunosuppressive properties. IL-10 decreases production of pro-inflammatory cytokines, including TNF-α and IL-1β.2 Although little is known about the regulation of IL-10 expression and activity in the liver in response to chronic ethanol, impaired expression of IL-10 contributes to inflammation in alcoholic patients with cirrhosis,3 and IL-10–deficient mice are more sensitive to ethanol-induced liver injury.

2 By a fluorescence-based AdipoRed assay we observed a discrete lipid accumulation in the FA-treated cells compared to controls. Strikingly, in contrast to the therapeutic approach suggested by Guy et al., addition of cyclopamine R788 within

the 14 hours to the FA-containing medium did not counteract the intracellular lipid accumulation as expected, but rather, increased the lipid content (Fig. 1A). Moreover, in our experimental conditions, real-time polymerase chain reaction (RT-PCR) analysis showed that cyclopamine did not decrease the expression levels of the HH-target genes (Shh and Gli1) in FA-treated cells. Conversely, in line with the evidence reported in the literature, by administering only cyclopamine to the control cultures, with the timing described above, we observed its known inhibitory effect on the expression of the HH-target genes (Fig. 1B).3 Therefore, even though HH-antagonists could be useful to correct liver damage occurring in nonalcoholic steatohepatitis (NASH) (i.e., inflammation, ballooning, and fibrosis), cyclopamine does not work as HH-inhibitor when used under conditions of FA excess and even

exacerbates simple steatosis with still unknown consequences. Based on these findings, we want to point out the fact that pharmacologic administration of HH-pathway antagonists in NAFLD should be carefully evaluated. Manuele Gori Ph.D.*, Barbara Barbaro Ph.D.* †, Mario Arciello Ph.D.*, Clara Balsano M.D.* †, * Laboratory of Molecular Virology learn more and Oncology, Fondazione A. Cesalpino, Rome, Italy, † Department RG7204 manufacturer of Internal Medicine (M.I.S.P), University of L’Aquila, L’Aquila, Italy. “
“Dyspepsia is a symptom of post-prandial distress, early satiation, or epigastric discomfort that is described by patients by various terms, including “indigestion.” The etiology is suspected by the clinician to arise from the upper gastrointestinal tract, though additional etiologies must be considered. Most patients with these symptoms have functional dyspepsia. The most

common organic etiologies include peptic ulcer, gastroesophageal reflux disease, and medication side effect. In patients less than 55 years of age who have no alarm features, the most cost-effective approach is an initial test-and-treat strategy for H pylori, followed by empiric proton pump inhibitor therapy and ultimately upper endoscopy if symptoms persist. “
“A 20-year-old man presented to the emergency department 14 days after ingestion of a 2 cm diameter folded beer bottle top. He stated that he had ingested the object unintentionally as part of an alcohol drinking game where the cap was in the bottom of his glass. For the next several days, he experienced intermittent epigastric discomfort exacerbated by food and lying supine. There was no fever, vomiting, cough or shortness of breath. He denied hematemesis or presence of melena.