Gastroenterology - Articles in Press

This Month in Gastroenterology - Uncorrected Proof

Jan Tack, John M. Carethers — 2010-09-02

Acute diarrhea and its complications remain a major cause of morbidity and mortality in children in developing countries. Most episodes of acute diarrhea are short lived, but a subset with acute onset and a duration of >14 days is referred to as persistent diarrhea. Especially persistent diarrhea is associated with a disproportionately high morbidity and mortality, and may lead to undernutrition, impaired development, and increased morbidity and mortality from other childhood diseases. The impact of “prolonged episodes of acute diarrhea,” with a duration of 7–13 days, is less well known, and was identified as a priority for further research by and international Working Group on Prolonged Diarrhea.

An Unusual Cause of Upper Gastrointestinal Bleeding - Uncorrected Proof

Chih-Jung Chen, Hui-Ting Hsu, Hsu-Heng Yen — 2010-09-01

Question: A 71-year-old woman suffered from tarry stool episodes for 1 month. Upper endoscopy showed an ulcerative tumor over the low body posterior wall of the stomach (). An endoscopic biopsy showed a poorly differentiated adenocarcinoma. Abdominal computed tomography (CT) revealed a heterogeneous enhanced tumor from the stomach with compression to the pancreas and duodenum (). The serum CEA and CA199 were within the normal limits.

A Young Woman With Refractory GI Symptoms - Uncorrected Proof

George Sgourakis, Sophocles Lanitis, Constantine Karaliotas — 2010-09-01

Question: A 20-year-old woman presented with a 1- year history of persistent epigastric pain and periodic vomiting. Her past medical and family histories were unremarkable. The abdominal computerized tomography (CT) scan revealed a large, low-attenuation, retroperitoneal tumor, measuring 9 × 7 cm with crescent-shaped calcifications. The mass (white circle in [c]) was infiltrating the upper pole of the right kidney ([d, arrow]), and was in proximity with the right adrenal gland, the abdominal aorta and IVC ([c]), abating the right renal vein and duodenum (Figure 3 [a, d]) and encasing the right renal artery ([a, b; arrows). Screening to rule out a hormonally active adenoma or pheochromocytoma included serum electrolytes, plasma aldosterone/rennin activity ratio, plasma metanephrine levels and overnight low dexamethasone suppression test (1 mg). The tumor was proved to be hormonally inactive and serum tumor markers were within reference range. A CT-guided biopsy of the mass showed numerous ganglion cells with single nuclei surrounded by bundles of spindle-shaped Schwann cells, which were positive for S-100 protein. Because of the small sample size, the rest of the immunohistochemical markers were not evaluated. The patient underwent laparotomy and the tumor was excised en block along with the right adrenal gland and the upper pole of the ipsilateral kidney. The encased right renal artery was dissected free (). Frozen section was negative for malignancy. Microscopic examination revealed that the neoplasm developed from the adrenal gland and was extending diffusely to involve the extra-adrenal fat and kidney capsule. Mature ganglion cells of various sizes isolated or in clustering and abundant neuroid bundles surrounded by Schwann cells were recognized. In many locations, the peri-neuroid stroma was myxoid and in some instances perivascular lymphocellular clustering was observed. Neuroblasts were not found (). Immunohistochemistry showed the presence of abundant neuroid bundles along the neuroid bonds. Ganglion and Schwann cells were strongly immunoreactive for NSE and S100, respectively. Ki67 index was <1%.

A Rare Complication of Chemotherapy in a 56-Year-Old Patient - Uncorrected Proof

Jen-Wei Chou, Yu-Chi Tseng, Chun-Kai Tseng — 2010-09-01

Question: A 56-year-old man was admitted to our hospital because of a 1-day history of hematuria. He also had a medical history of gastric ulcer and renal stone. He denied history of trauma or fever before this admission. Serial surveys, including ureteroscopic biopsy, abdominal computed tomography (CT) scan and positron emission tomography scan, revealed that the patient had ureteral transitional cell carcinoma with liver and lung metastasis. Thereafter, the patient was treated with palliative chemotherapy with a combination of cyclophosphamide, doxorubicin, and methotrexate for his cancer. During the period of chemotherapy, the patient suffered severe nausea and vomiting despite of the use of antiemetic agents. Chest x-ray demonstrated a round linear gas bubble in the left upper quadrant of abdomen (, arrows). One week postchemotherapy, the patient suddenly experienced epigastric pain and bloody emesis. Subsequently, an emergency esophagogastroduodenoscopy (EGD) demonstrated diffuse edema and erythema of gastric mucosa in the body and fundus (). In addition, some fresh blood and blood clots were detected in the dependent part of the stomach, but no definite bleeding point was identified ().

Persistent Right-Sided Chest Pain - Uncorrected Proof

Wei-Chang Huang, Gwan-Han Shen, Chih-Wei Tseng — 2010-09-01

Question: A 64-year-old male presented with a 3-day history of persistent, right-sided chest pain, which was exacerbated by breathing, coughing, sneezing, or even talking. Upon arrival at our emergency room, he denied histories of external trauma, instrumentation of the esophagus, and severe cough in the past month. The patient had no fever. Physical examination and laboratory studies were unremarkable except for leukocytosis (16.53 × 103/μL). Chest radiography revealed multiple opacified lesions in the right lung field (). Computed tomography (CT) of the chest revealed an encapsulated right-sided pleural effusion with bubble formation (, black arrow head) and a high-density material (, black arrow) in the lower third of the esophagus.

October CME Exam 1 Questions - Uncorrected Proof

2010-09-01

October CME Exam 2 Questions - Uncorrected Proof

2010-09-01

Colonic Polyposis: More Than Meets the Eye - Uncorrected Proof

M.F. Dawas, A.E. Ibrahim, Y.M. Lee — 2010-08-30

Question: A 76-year-old woman presented with worsening fatigue and left leg pain accompanied by recent change in bowel habit. Her past medical history included a diagnosis of psoriasis 32 years previously, hiatal hernia, L4/L5 spondylisthesis requiring discectomy and laminectomy 14 years previously, orthostatic tremor, excision of conjunctival melanoma 3 years previously, hypertension, hypercholesterolemia, and triple vessel coronary artery disease requiring stent placement 18 months previously.

Proton Pump Inhibitor Therapy Improves Symptoms in Post Nasal Drainage - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: Gastroesophageal reflux is common among patients with post nasal drainage. We investigated whether proton pump inhibitor therapy improved symptoms in patients with post nasal drainage without sinusitis or allergies.Methods:: In a parallel group, double-blind, multi-specialty trial, we randomly assigned 75 participants with continued symptoms of chronic post-nasal drainage to groups that were given 30 mg of lansoprazole twice daily or placebo. Participants were followed for 16 weeks. Symptoms were assessed at baseline and after 8 and 16 weeks. Ambulatory pH and impedance monitoring assessed presence of baseline reflux. The primary objective of the study was to determine if acid suppressive therapy improved post-nasal drainage symptoms. The secondary objective was to assess if pH and impedance monitoring at baseline predicted response to treatment.Results:: Post-nasal drainage symptoms improved significantly among patients give lansoprazole, compared with placebo. After 8 and 16 weeks, participants given lansoprazole were 3.12-fold (1.28–7.59) and 3.50-fold (1.41-8.67) more likely to respond, respectively, than participants given placebo. After 16 weeks, median (interquartile) % symptom improvements were 50.0% (10.0%–72.0%) for participants given lansoprazole and 5.0% (0.0–40.0%) for participants given placebo (P=0.006). Neither baseline presence of typical reflux symptoms nor esophageal physiologic parameters predicted response to therapy.Conclusion:: Among participants with chronic post-nasal drainage without evidence of sinusitis and allergies, twice-daily therapy with proton pump inhibitors significantly improved symptoms after 8 and 16 weeks. The presence of heartburn, regurgitation, abnormal levels of esophageal acid, or non-acid reflux did not predict response to therapy.

NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: The Notch receptor family regulates cell fate through cell-cell communication. CSL (CBF-1/RBP-jκ, Su(H), Lag-1) drives canonical Notch-mediated gene transcription during cell lineage specification, differentiation and proliferation in the hematopoietic system, the intestine, the pancreas and the skin. However, the functional roles of Notch in esophageal squamous epithelial biology remain unknown.Methods:: Normal esophageal keratinocytes were stimulated with calcium chloride to induce terminal differentiation. The squamous epithelia were reconstituted in organotypic three-dimensional culture, a form of human tissue engineering. Notch was inhibited in culture with a γ-secretase inhibitor or dominant negative mastermind-like1 (DNMAML1). The roles of Notch receptors were evaluated by in vitro gain-of-function and loss-of-function experiments. Additionally, DNMAML1was targeted to the mouse esophagus by cytokeratin K14promoter-driven Cre ( K14Cre) recombination of Lox - STOP - Lox-DNMAML1. Notch-regulated gene expression was determined by reporter transfection, chromatin immunoprecipitation (ChIP) assays, quantitative reverse-transcription polymerase chain reactions (RT-PCR), Western blotting, immunofluorescence and immunohistochemistry.Results:: NOTCH1 (N1) was activated at the onset of squamous differentiation in the esophagus. Intracellular domain of N1 (ICN1) directly activated NOTCH3 (N3) transcription, inducing HES5 and early differentiation markers such as involucrin (IVL) and cytokeratin CK13 in a CSL-dependent fashion. N3 enhanced ICN1 activity and was required for squamous differentiation. Loss of Notch signaling in K14Cre;DNMAML1mice perturbed esophageal squamous differentiation and resulted in N3 loss and basal cell hyperplasia.Conclusions:: Notch signaling is important for esophageal epithelial homeostasis. In particular, the crosstalk of N3 with N1 during differentiation provides novel, mechanistic insights into Notch signaling and squamous epithelial biology.

Linaclotide Improves Abdominal Pain and Bowel Habits in a Phase IIb Study of Patients with Irritable Bowel Syndrome - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: Linaclotide, a minimally absorbed, 14 amino-acid, peptide agonist of guanylate cyclase-C, has shown benefit in a proof-of-concept study for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). We assessed the efficacy and safety of linaclotide at a daily dose range of 75–600 μg in IBS-C.Methods:: We performed a randomized, double-blind, multi-center, placebo-controlled study of 420 patients with IBS-C given oral linaclotide at doses of 75, 150, 300, or 600 μg or placebo once daily for 12 weeks. Endpoints included change from baseline in daily bowel habits, daily abdominal symptoms, and weekly global assessments, in addition to responder criteria.Results:: All doses of linaclotide significantly improved bowel habits, including frequency of spontaneous bowel movements (SBMs) and complete SBMs (primary endpoint), severity of straining, and stool consistency. Abdominal pain was significantly reduced from baseline, compared with placebo; mean changes in abdominal pain (assessed on a 5-point scale) from baseline were -0.71, -0.71, -0.90, and -0.86 for linaclotide doses of 75, 150, 300, and 600 μg, respectively, compared to -0.49 for placebo. Likewise, most doses of linaclotide significantly improved other abdominal symptoms, including discomfort and bloating, and global measures of IBS-C compared to placebo. Effects were observed within the first week and were sustained throughout 12 weeks of treatment. Except for diarrhea, the incidence of adverse events was similar between placebo and linaclotide groups.Conclusions:: Linaclotide, across a wide range of doses, significantly improved symptoms of IBS-C, including abdominal pain and bowel habits. Diarrhea was the only dose-dependent adverse event and was usually of mild or moderate severity.

Hepatoblast-like progenitor cells derived from embryonic stem cells can repopulate livers of mice - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: Hepatocyte-like cells can be derived from pluripotent stem cells such as embryonic stem (ES) cells, but ES cell-derived hepatic cells with extensive capacity to repopulate liver have not been identified. We aimed to identify and purify ES cell-derived hepatoblast-like progenitor cells and to explore their capacity for liver repopulation in mice after in vitro expansion.Methods:: Unmanipulated mouse ES cells were cultured under defined conditions and allowed to undergo stepwise hepatic differentiation. The derived hepatic cells were examined by morphologic, fluorescence-activated cell sorting, gene expression, and clonal expansion analyses. The capacities of ES cell-derived hepatic progenitor cells to repopulate liver were investigated in mice that were deficient in fumarylacetoacetate hydrolase (Fah) (a model of liver injury).Results:: Mouse ES cells were induced to differentiate into a population that contained hepatic progenitor cells; this population included cells that expressed EpCAM but did not express c-Kit. Clonal hepatic progenitors that arose from single c-Kit-EpCAM+ cells could undergo long-term expansion and maintained hepatoblast-like characteristics. Enriched c-Kit-EpCAM+ cells and clonally expanded hepatic progenitor cells repopulated the livers of Fah-deficient mice without inducing tumorigenesis.Conclusions:: ES cell-derived c-Kit-EpCAM+ cells contain a population of hepatoblast-like progenitor cells that can repopulate livers of mice.

H.pylori infection methylates and silences TFF2 leading to gastric tumor development in mice and humans - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: Trefoil factors (TFFs) regulate mucosal repair and suppress tumor formation in the stomach. Tff1 deficiency results in gastric cancer whereas Tff2 deficiency increases gastric inflammation. TFF2 expression is frequently lost in gastric neoplasms but the nature of the silencing mechanism and associated impact on tumorigenesis have not been determined.Methods:: We investigated the epigenetic silencing of TFF2 in gastric biopsies from individuals with Helicobacter pylori-positive gastritis, intestinal metaplasia, gastric cancer and disease-free controls. TFF2 function and methylation were manipulated in gastric cancer cell lines. The effects of Tff2 deficiency on tumor growth were investigated in the gp130 F/F mouse model of gastric cancer.Results:: In human tissue samples, DNA methylation at the TFF2 promoter began at the time of H. pylori infection and increased throughout gastric tumor progression. TFF2 methylation levels were inversely correlated with TFF2mRNA levels and could be used to discriminate between disease-free controls, H. pylori-infected, and tumor tissues. Genome demethylation restored TFF2 expression in gastric cancer cell lines, so TFF2 silencing requires methylation. In Tff2-deficient gp130F/F /Tff2-/- mice, proliferation of mucosal cell s and release of T-helper (Th)-1 cytokines increased, whereas expression of other gastric tumor suppressor genes and Th-2 cytokines were reduced, compared to gp130 F/F controls. The fundus of gp130F/F /Tff2-/- mice displayed glandular atrophy and metaplasia, indicating accelerated pre-neoplasia. Experimental H. pylori infection in wild-type mice reduced antral expression of Tff2 by increased promoter methylation.Conclusions:: TFF2negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H. pylori infection.

Dysfunctional gastric emptying with downregulation of muscle-specific microRNAs in Helicobacter pylori-infected mice - Accepted Manuscript

2010-08-30

Abstract: Background & Aims:: Little is known about the pathogenic mechanisms of functional dyspepsia. We investigated the role of microRNAs (miRNAs) in gastric motility disorders associated with Helicobacter pylori infection.Methods:: Male C57BL/6 mice were infected with H. pylori. After long-term infection, gastric emptying was examined and compared with that of uninfected mice (controls). The miRNA expression profile was analyzed by miRNA microarray and quantitative reverse-transcriptase PCR. The results obtained from the animal study were confirmed by in vitro experiments.Results:: Gastric emptying was significantly accelerated in mice after chronic infection with H. pylori. Histological examination showed that the muscular layers of the stomachs of H. pylori -infected mice were significantly thickened. The miRNA expression profile revealed that the muscle-specific miRNAs miR-1 and miR-133were significantly downregulated in the stomachs after long-term infection with H. pylori. However, expression of histone deacetylase 4 (HDAC4) and serum response factor (SRF), which are reported target genes of miR-1 and miR-133, increased. Downregulation of miR-1 and miR-133 and increased cell proliferation were observed in C2C12 mouse myoblast cells after co-culture with H. pylori.Conclusions:: Chronic infection with H. pylori downregulates expression of muscle-specific miRNAs and upregulates expression of HDAC4 and SRF. These might cause hyperplasia in the muscular layer of the stomach and dysfunction in gastric emptying. These findings provide insight into the molecular pathogenesis of gastric motility disorders, including functional dyspepsia.

Long-Term Therapy with Tenofovir is Effective for Patients Co-Infected with HIV and HBV - Accepted Manuscript

2010-08-30

Abstract: Background and aims: We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with HIV and hepatitis B virus (HBV) as a part of anti-retroviral therapy.Methods: We performed a multicenter, prospective cohort study of 102 patients co-infected with HIV and HBV who were treated with TDF.Results: At baseline, 80% of patients had a detectable viral load (HBV DNA>20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg, n=67), 92% had a virologic response (HBV DNA < 20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine-resistance at baseline (P=0.39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n=15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up of 52 months (41–63 months), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum levels of creatinin. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73m2, which was most pronounced shortly after TDF therapy was initiated.Conclusions: TDF, administered as part of anti-retroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small, non-progressive decreases in renal function were observed.

Trouble with a Shunt: Alcohol and Spastic Paraparesis - Uncorrected Proof

Julia O'Brien, Christopher Staples, Timothy Florin — 2010-08-27

Question: A 37-year-old man with an 18-month history of progressive difficulty walking, presented completely unable to ambulate for the last 4 months. He was using a bucket next to his bed for toileting, which was emptied daily by his parents. He did not complain of pain or other symptoms. On admission he was intoxicated, encephalopathic, and gave a history of very heavy alcohol intake for a number of years.

Acute Obstructive Cholangitis Due to Foreign Body in the Common Bile Duct - Uncorrected Proof

Su Lim Lee, Hyung-Keun Kim, Young-Seok Cho — 2010-08-27

Question: A 32 year-old woman was hospitalized with a 2-day history of right upper quadrant pain. The patient had a history of a laparoscopic cholecystectomy (LC) for symptomatic gallstones on an elective basis two years prior to the current visit. The past medical history was significant only for the cholelithiasis. The physical examination revealed a fever, the sclera was icteric and there was tenderness at the right upper quadrant of the abdomen as well as the epigastric area; there was no rigidity or rebound tenderness. The laboratory tests showed abnormal liver function, with a total bilirubin of 3.91 mg/dL, aspartate transaminase 788 U/L, alanine transaminase 603 U/L, gamma glutamyl transpeptidase 164 U/L, and alkaline phosphatase 778 U/L. Abdominal computed tomography (CT) showed a small round radio-opaque density in the distal common bile duct (). An ERCP was performed. Purulent discharge was observed in the papilla during cannulation (). The bile duct was catheterized. A metallic radiodensity was noted in the distal common bile duct (). A sphincterotomy was performed. The foreign body was removed with an extraction balloon catheter (). What is the diagnosis?

A Pancreatic Mass Presented With Multiple Hot Spots in the Subcutaneous Fat Layer on Positron Emission Tomography - Uncorrected Proof

Kyung Ah Kim, Myeong-Jin Kim, Seon-Jung Jang — 2010-08-27

Question: A 63-year-old man was admitted to our hospital to evaluate a pancreatic tail mass detected on a ultrasound examination performed for a health checkup. The patient had been diagnosed with diabetes mellitus 5 years earlier and had been treated for the disease since then. The patient presented with no symptoms or signs of discomfort. The results of laboratory tests for serum amylase (73 U/L), carcinoembryonic antigen (2.47 ng/mL), and carbohydrate antigen 19-9 (7.8 U/mL) were normal. Only C-reactive protein (170.0 mg/L) and the erythrocyte sedimentation rate (25 mm/hr) were elevated. A 4.5-cm, well-circumscribed, enhancing, solid mass with a central necrotic portion in the pancreas tail was detected upon pancreaticobiliary magnetic resonance imaging (). The patient underwent fluoro-18-deoxyglucose positron emission tomography computed tomography (FDG-PET/CT), and mild FDG uptake was demonstrated within the pancreatic mass. Multiple nodules with increased FDG uptake were additionally detected in the subcutaneous layer of the face, neck, and anterior abdominal wall (). We suspected these subcutaneous nodules as metastatic deposits from the pancreatic tail mass, but those nodules showed faintly increased fat attenuation or grossly normal fat density without an abnormal finding on CT in the corresponding sites. Multiple subcutaneous nodules were not observed or palpated on physical examination and the patient had no pain or any other discomfort about these nodules.

In the Absence of HCV Infection, Interferon Stimulated Gene Expression in Liver is Not Associated With IL28B Genotype - Uncorrected Proof

2010-08-27

Up-regulation of interferon-stimulated genes (ISGs) in the liver of patients with chronic hepatitis C has been associated with impaired response to treatment with interferon and ribavirin. Genetic variation in IL28B is another factor that has been associated with hepatitis C virus (HCV) treatment response. Honda et al have now shown that the IL28B rs8099917-G allele is associated with higher expression of hepatic ISGs, as well as poorer treatment response, and these findings may provide a functional explanation for the association between IL28B genotype and response to interferon alfa/ribavirin treatment of chronic hepatitis C. It is not known, however, whether genetic variation in IL28B also affects ISG expression in the liver of persons who are not infected with HCV. To address this question, we examined the association between ISG expression and IL28B rs8099917 genotype in liver samples from 960 European American subjects without HCV infection.

Pathogenesis of Achalasia: Lessons From Mutant Mice - Uncorrected Proof

Raj K. Goyal, Arun Chaudhury — 2010-08-27

See “Loss of lsc/p115-protein leads to neuronal hypoplasia in the esophagus and an achalasia-like phenotype in mice,” by Zizer E, Beilke S, Bäuerle T, et al, on page 000.

Why Do We Need Another Interferon? - Uncorrected Proof

Paul J. Pockros — 2010-08-27

See “Randomized trial of albinterferon alfa-2b for the treatment of patients with chronic hepatitis C virus genotype 1,” by Zeuzem S, Sulkowski MS, Lawitz EJ, et al, on page 000; and “Randomized trial of albinterferon alfa-2b for the treatment of patients with chronic hepatitis C virus genotype 2 or 3,” by Nelson DR, Benhamou Y, Chuang W-L, et al, on page 000.

DLC1 and Liver Cancer: The Akt Connection - Uncorrected Proof

Torsten Wuestefeld, Lars Zender — 2010-08-27

See “Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis,” by Ko FCF, Chan L-K, Tung EK-K, et al, on page 000.

Epithelial to Mesenchymal Transition in Injury of Solid Organs: Fact or Artifact? - Uncorrected Proof

Jeremy S. Duffield — 2010-08-27

More than 20 years ago a breakthrough occurred in the fledgling field of fibrosis with the purification of hepatic stellate cells (HSCs) from liver, separated by virtue of their distinct cell buoyancy. These unusual cells store retinoic acid in health and line the specialized fenestrated capillaries of the liver called hepatic sinusoids. Some investigators have described these cells as pericytes, mural cells of capillaries that have been shown in other tissue beds to be important in sprouting angiogenesis and vascular stability by virtue of cell–cell signaling with underlying endothelial cells. When cultured in vitro and activated with serum factors, HSCs generated a pathologic collagen matrix and activated intermediate genes involved in migration and contraction, including α-smooth muscle actin (SMA) and it became widely accepted that HSCs were progenitors of the liver myofibroblast. In other organs, including the pancreas and kidney, similar pericyte-like cells have been much harder to detect or define. Furthermore, other adherent cell types, including endothelial, epithelial, and myeloid cells, generate collagen matrix and activate expression of the intermediate filament αSMA when cultured in vitro. This combination of findings led to several questions: (1) Is the presence of the pericyte-like HSC myofibroblast precursor a peculiarity of the liver?; (2) Could other cells become myofibroblasts? (A).

Interventional and Therapeutic Gastrointestinal Endoscopy - Uncorrected Proof

Craig A. Munroe, Jacques Van Dam — 2010-08-27

As our understanding of gastrointestinal disease progresses and novel therapeutic interventions are introduced, modern endoscopy is rapidly evolving. The practicing clinician is charged with providing safe and effective endoscopic therapy while staying up to date on emerging therapies. Many books have been published in an attempt to provide a current overview of endoscopic techniques, yet as our knowledge improves and technology advances, the existing selection of reference books becomes less relevant.

An Acknowledgment of Deceased AGA Members - Uncorrected Proof

2010-08-27

Edmund J. Bini, MD, MPH

New Cell Culture Models of Hepatitis C Virus Entry, Replication, and Virus Production - Uncorrected Proof

Brett D. Lindenbach — 2010-08-26

See “Production of infectious hepatitis C virus in primary cultures of human adult hepatocytes,” by Podevin P, Carpentier A, Pène V, et al, on page 000.; and “Hepatitis C virus infection of neuroepithelioma cell lines, by Fletcher NF, Yang JP, Farquhar MJ, et al, on page 000.

Upregulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma - Accepted Manuscript

2010-08-23

Abstract: Background & Aims:: The transcription factor Krüppel-like factor 8 (KLF8) has roles in tumor development, growth, and metastasis, but its role in hepatocellular carcinoma (HCC) is not clear.Methods:: KLF8 expression in human HCC cell lines and tumor tissues was measured by quantitative real-time PCR, immunoblot, and immunochemical analyses. The effects of KLF8 depletion or overexpression in HCC cells were observed in cultured cells and in mice. Changes in gene expression patterns in HCC cells in which levels of KLF8 were reduced using small interefering RNA were investigated by microarray analysis. The clinical significance of KLF8 expression levels were validated using tissue microarray analysis of surgical samples from 314 HCC patients.Results:: KLF8 was overexpressed in highly metastatic HCC cell lines and in samples from patients with recurrent HCC. In cultured cells, KLF8 upregulation promoted cell proliferation and invasion; inhibited apoptosis; downregulated N-cadherin, vimentin, and fibronectin; and up-regulated E-cadherin. In mice, overexpression of KLF8 increased HCC progression and metastasis. Microarray analysis showed that reduction of KLF8 in HCC cells downregulated expression of multiple genes involved in tumor progression and metastasis. KLF8 expression was a significant predictor of overall survival ( P =0.040) and time to HCC recurrence ( P =0.006) and was associated with early tumor recurrence (P=0.001).Conclusions:: KLF8 promotes HCC cell proliferation and invasion, inhibits apoptosis, and induces the epithelial-to-mesenchymal transition. KLF8 upregulation might used to indicate poor prognosis or early recurrence of cancer in patients that have had surgery for HCC.

Corticotropin-Releasing Factor Regulates Tlr4 Expression in the Colon and Protects Mice from Colitis - Accepted Manuscript

2010-08-23

Abstract: Background & Aims:: Defects in the colonic innate immune response have been associated with inflammatory bowel disease. Corticotropin-releasing hormone (CRH, or factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and -4. We investigated the role of CRF in an innate immunity-dependent mouse model of IBD.Methods:: Crh-/- and wild-type (Crh+/+) mice, which are glucocorticoid insufficient, were given dextran sodium sulphate (DSS) in their drinking water to induce colitis; in some experiments mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators.Results:: Crh-/- mice had more colonic inflammation than Crh+/+ mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the pro-inflammatory factors interleukin-12 and prostaglandin E2 were increased in the Crh-/- mice. Colons of Crh-/- mice expressed lower levels of Tlr-4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh -/- mice from developing severe colitis. Crh-/- mice were unable to recover from acute colitis, indicated by their increased death rate.Conclusions:: Mice deficient in CRF downregulate TLR-4 and are more susceptible to DSS-colitis. CRF has anti-inflammatory effects in innate immunity-dependent colitis and its recovery phase; these are independent of glucocorticoid. CRF might therefore be developed as a therapeutic target for patients with IBD.

At the Movies: 3-Dimensional Technology and Gastrointestinal Histology - Uncorrected Proof

Ya-Yuan Fu, Shiue-Cheng Tang — 2010-08-23

Gastrointestinal (GI) tissues consist of 3-dimensional (3D) microstructure, vasculature, and innervation to coordinate physiologic activities. To examine these cellular architectures, investigators often use microtome-based 2-dimensional (2D) analysis, such as hematoxylin and eosin or antibody staining and subsequent optical or electron microscopy, to visualize the molecule/structure of interest at a specific or a series of cut planes. Because microtome slicing creates disconnections between tissue sections as well as distortions and artifacts, a microtome free, nondestructive imaging approach is preferable to provide an integral visualization of the tissue structure in situ.

Uncorrected Proof

Dirk J. Gouma — 2010-08-23

In this issue of Gastroenterology, Shah and Ahmad nicely summarized the ongoing debate about preoperative biliary drainage (PBD), the recent meta-analysis on PBD (Pancreas 2010;39:119–126), and our trial early surgery versus PBD (N Engl J Med 2010;362:129–137).

To Drain or Not to Drain: That Is the Question - Uncorrected Proof

Pari Shah, Nuzhat A. Ahmad — 2010-08-23

Van der Gaag NA, Rauws EAJ, van Eijck CHJ, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010;362:129–137. Pancreatic cancer remains the 4th leading cause of cancer related deaths in the US (N Engl J Med 2010;362:170–172). Cancer of the pancreatic head or periampullary region commonly presents as jaundice secondary to obstruction of the bile duct from tumor encasement. The only potentially curative option for pancreatic cancer is operative resection. In patients with biliary obstruction who are considered candidates for resection, biliary drainage is often performed before surgery. This practice is based on the argument that preoperative biliary drainage (PBD) may translate into improved surgical outcomes by restoring metabolic abnormalities associated with obstructive jaundice (J Gastrointest Surg 2009;13:814–820). However, to date, the evidence supporting PBD in this particular setting is equivocal (Pancreas 2010;39:119–126; Cochrane Database Syst Rev 2008;CD005444; Cochrane Database Syst Rev 2007;CD006001; Gastrointest Endosc 2002;56:529–534).

Telaprevir for Hepatitis C Retreatment: An Open Door on a Long and Winding Road - Uncorrected Proof

Alessio Aghemo, Massimo Colombo — 2010-08-23

McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303. Hepatitis C virus (HCV)-infected patients have greatly benefited from the recent drug developments starting from the introduction of the guanosine analog ribavirin (Rbv) in the late 1990s (Lancet 1998;352:1426–1432; N Engl J Med 1998;339:1485–1492) to finish with the development of pegylated interferon (PegIFN) at the beginning of the century (Lancet 2001;358:958–965; N Engl J Med 2002;347:975–982). Indeed, the therapeutic combination of the 2 drugs has elevated the achievable sustained virologic response (SVR) rates to nearly 50% in HCV-1 and -4 patients and 80% in HCV-2 and -3 patients (Gastroenterology 2010;138:108–115). However, even in the most favorable setting, roughly 50% of HCV-1 and -4 treated patients ultimately will not achieve a SVR, effectively being classified as treatment failures (Hepatology 2009;49:1335–1374). It is intuitive that these figures coupled with the decrease in newly acquired cases of HCV infection (J Hepatol 2008;49:625–633), will progressively shift the balance from the development of effective treatment options in naïve patients to the always growing treatment-experienced patient population. Unfortunately, current treatment options in the latter group of IFN-refractory patients are rather limited, because retreatment with PegIFN and Rbv leads to disappointing SVR rates, especially in those who failed to reach HCV RNA undetectability during the previous PegIFN plus Rbv course (Ann Intern Med 2009;150:528–540; Gastroenterology 2009;136:1618–1628), currently cautioning against the broad retreatment of these patients with PegIFN and Rbv (Hepatology 2009;49:1335–1374). In light of these findings, there is a strong need for the development of effective regimens to retreat patients with chronic infection who did not have an SVR to the previous therapy. The important technical advances in cell culture systems and replication assays introduced in the last decade (J Hepatol 2009;51:939–948; Hepatology 2006;43[Suppl 1]:S207–220), have dramatically changed the landscape of HCV infection finally providing researchers and pharmaceutical companies with the tools to develop and study directly acting antiviral (DAA) drugs for the treatment of chronic hepatitis C. Although many DAA agents remain in the early phases of development (Gastroenterology 2010;138:447–462), the orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV protease telaprevir, has finished Phase II evaluation (N Engl J Med 2009;360:1827–1838; N Engl J Med 2009;360:1839–1850) and is currently in the late stages of the Phase III registration trials that should lead to its broad commercialization in 2011. In the April 8, 2010, issue of the New England Journal of Medicine, McHutchison et al report on the final results of the Phase II, randomized, partially placebo-controlled, partially double-blind PROVE3 study, which was designed to assess the safety and efficacy of telaprevir in combination with PegIFN/Rbv in the re-treatment of HCV-1 patients with a previous treatment failure to PegIFN and Rbv therapy (New Engl J Med 2010;362:1292–303). In 53 international sites, 465 HCV-1 patients were randomly assigned to 4 different treatment groups to receive either telaprevir plus PegIFNalfa2a plus Rbv for 12 weeks followed by placebo plus PegIFNalfa2a plus Rbv for the next 12 weeks (T12PR24), telaprevir plus PegIFNalfa2a plus Rbv for 24 weeks followed by PegIFNalfa2a plus Rbv for the next 24 weeks (T24PR48), telaprevir plus PegIFNalfa2a for 24 weeks (T24P24), or placebo plus PegIFNalfa2a plus Rbv for 24 weeks followed by PegIFNalfa2a plus Rbv for the next 24 weeks as a control group (PR48). Telaprevir was given during the treatment period in a single initial dose of 1125 mg, followed by a dose of 750 mg every 8 hours thereafter; PegIFNalfa2a and Rbv were given at standard dose for HCV-1 patients. Randomization was stratified to balance race (black versus non-black) and previous virologic response (achievement or nonachievement of undetectable HCV RNA). The study was designed to have a 90% statistical power to detect a 25% difference in SVR rates, the primary end point of the study, between the telaprevir groups and the control group. The vast majority of the 465 enrolled patients were white (89%), 58% had HCV genotype 1a, and 16%, cirrhosis. Fifty-seven percent of the patients had a nonresponse to the previous treatment PegIFN plus Rbv treatment course, defined as the lack of HCV RNA undetectability; 36% were classified as relapsers, because HCV RNA was undetectable for ≥42 weeks of the previous treatment course with subsequent HCV RNA detectability during follow-up; and 7% had a breakthrough, that is undetectable HCV RNA during treatment but detectable at the end of the treatment period. In this particularly hard-to-cure treatment population, SVR rates were significantly higher in each of the 3 telaprevir groups than in the standard of care (SOC) control arm, being 51% for T12PR24, 53% for T24PR48, 24% for T24P24, and 14% in the SOC group. Not surprisingly, the SVR rates were higher in previous relapsers than in previous nonresponders, being 69% and 39% in the T12PR24 arm, 76% and 38% in the T24PR48 arm, 42% and 11% in the T24P24 arm, and 20% and 9% in the SOC arm, mimicking what already reported by retreatment studies with dual therapy (Gastroenterology 2009;136:1618–1628). Although the SVR rates did not differ significantly between the T12PR24 and the T24PR48 arms (51% vs 53%), the relapse rates were significantly lower in the latter group (4%) compared with the former (28%). This notwithstanding, viral breakthrough, the surrogate marker of the development of resistant variants, was observed in the same proportion (12%–13%) of the patients in the T12PR24 and T24PR48 arms, whereas it was much higher (32%) in the telaprevir arm without Rbv (T24P24). When looking only at the 2 telaprevir treatment regimens that received Rbv, breakthrough rates were significantly higher in previous nonresponders than in previous relapser patients both in the overall population (25% vs 2%) as in the single treatment arms (T12PR24: 20% vs 2% and T24PR48: 22% vs 2%). Logistic regression analysis identified assignment to the T12PR24 or T24PR48 group, baseline viral load <800,000 IU/mL and achievement of undetectable HCV RNA during the previous treatment course as independent predictors of an SVR.

Uncorrected Proof

John G. McHutchison, Shelley George, Robert S. Kauffman — 2010-08-23

We thank Professor Colombo for his thorough review of the PROVE 3 trial published in New England Journal of Medicine. We also appreciate the opportunity to comment and discuss the results and implications of the trial in more depth (N Engl J Med 2010;362:1292–1303).

Rifaximin in Hepatic Encephalopathy: Is an Ounce of Prevention Worth a Pretty Penny? - Uncorrected Proof

Michael D. Leise, W. Ray Kim — 2010-08-23

Bass NM, Mullen KD, Sanyal A, et al. (University of California, San Francisco, California). Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med 2010;362:1071–1081. Hepatic encephalopathy (HE) is an important event in the natural progression of end-stage liver disease, resulting in diminished quality of life (Gastroenterology 2001;120:170–178), increased risk of hospitalization, increased health care costs (Aliment Pharmacol Ther 2007;25[Suppl 1]:3–9), and heightened risk of death (J Hepatol 1999;30:890–895; Liver Transpl 2007;13:1366–1371). Treatment has focused on attenuating production of ammonia in the gut and traditionally includes lactulose, neomycin, or metronidazole, and most recently, rifaximin. Previous therapeutic studies have largely focused on treatment of HE episodes. Bass et al have recently reported a randomized, double-blind, placebo-controlled trial of rifaximin for secondary prevention of HE episodes.

Diagnostic Yield of Upper Endoscopy in Treated GERD Patients - Uncorrected Proof

Lauren B. Gerson — 2010-08-23

Poh CH, Gasiorowska A, Navarro-Rodriguez T, et al. (Division of Gastroenterology Southern VA Health Care System and University of Arizona Health Sciences Center, Tucson, Arizona). Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment. Gastrointest Endosc 2010;71:28–34.

Paediatric Gastroenterology - Uncorrected Proof

William Dickey — 2010-08-23

This textbook is described as an Atlas of Investigation and Management. There is a risk that such a book will fail through compromise: Insufficiently focused on endoscopic aspects of practice to be of value to the hardcore pediatric endoscopist, while too low in word count to be adequate as a reference volume—a lightweight publication (156 pages in a hardback format) with high-quality pictures.

Colonoscopy: Principals and Practices, 2nd Edition - Uncorrected Proof

Carol A. Burke — 2010-08-23

Doctors Waye, Rex, and Williams have hit it out of the park again in the second edition of their book Colonoscopy: Principles and Practice, published in 2009. The first edition, published in 2003, won the medical society award for gastroenterology first prize conferred by the British Medical Association in 2004. The second edition includes 6 additional chapters and 34 new authors; the original chapters have undergone extensive updates from the first edition. The team of editors suggests the aim of the second edition is to enhance the knowledge of all practitioners in the field of colonoscopy and colonic imaging. I can attest that the comprehensive yet eclectic content, which ranges from a historic review of endoscopic instruments, to actions to consider when a sedated patient yells “stop the procedure,” to the future of colonoscopy with the use of self-propelled microrobots, will appeal to anyone involved in the field of colonoscopy. Undoubtedly, this 816-page book and accompanying CD-ROM will provide great educational benefit to any clinician, academician, trainee, or allied health professional lucky enough to delve into any of the book chapters or superb video clips provided by the international sages and masters of colonoscopy and therapeutic polypectomy.

Novel Mechanism in Salmonella Virulence, Drug Susceptibility - Uncorrected Proof

Les Lang — 2010-08-20

Researchers have discovered a novel mechanism in Salmonella that affects its virulence and its susceptibility to antibiotics by changing its production of proteins in order to respond to inhospitable conditions.

Emerging Escherichia coli Strain Causes Antimicrobial-Resistant Infections in the United States - Uncorrected Proof

Stories by Les Lang — 2010-08-20

A new, drug-resistant strain of Escherichia coli is causing serious disease, according to a new study published recently in Clinical Infectious Diseases. The authors note that E. coli sequence type ST131 (O25:H4), associated with the CTX-M-15 extended-spectrum β-lactamase, has emerged internationally as a multidrug-resistant pathogen but has received little attention to date in the United States.

New Health Reform Law to Benefit 30 Million Women - Uncorrected Proof

Les Lang — 2010-08-20

Thirty million women will benefit from the new health reform law over the next decade, either through new or strengthened insurance coverage, according to a new report from The Commonwealth Fund.

Molecular Signatures for Biliary Atresia - Uncorrected Proof

Les Lang — 2010-08-20

Researchers have identified a set of molecular signatures for biliary atresia that can help to identify the progression of disease after diagnosis, and then predict clinical outcomes.

Hereditary Pancreatic Cancer - Uncorrected Proof

Shilpa Grover, Sapna Syngal — 2010-08-20

Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an estimated 43,000 new diagnoses and 36,800 deaths annually. The low 5-year overall survival rate of patients with pancreatic adenocarcinoma of 6% is attributable to the largely characteristically late stage of pancreatic cancer at the time of diagnosis. Although most cases of pancreatic adenocarcinomas are thought to be sporadic, up to 10% may be due to an underlying genetic predisposition. This article reviews the epidemiology and genetic basis of hereditary pancreatic cancer and the emerging strategies for detection of early pancreatic neoplasms in high-risk individuals.

A National Study of H. pylori Infection in Gastric Biopsy Specimens - Accepted Manuscript

Amnon Sonnenberg, Richard H. Lash, Robert M. Genta — 2010-08-20

Abstract: Background & Objective:: We investigated whether infection with Helicobacter pylori and signs of chronic active gastritis and intestinal metaplasia in gastric biopsy samples were inversely associated with Barrett’s metaplasia.Methods:: We studied gastric biopsy samples from 78,985 unique patients. Histologic findings were correlated with socio-demographic patient characteristics using multivariate logistic regression to calculate odds ratios and 95% confidence intervals.Results:: H. pylori infection, chronic active gastritis, and intestinal metaplasia had similar epidemiologic patterns. The presence of each, based on histology analyes, was significantly associated with that of the others. They were also characterized by similar geographic distributions within the United States. All 3 disorders were more common among men and among Medicaid patients (compared with those with other insurance) and were inversely associated with Barrett’s metaplasia (less frequent in patients with Barrett’s metaplasia).Conclusions:: H. pylori infection and associated disorders, such as chronic active gastritis and intestinal metaplasia, are inversely associated with Barrett’s metaplasia.

Abdominal Visceral Adipose Tissue Volume is Associated with Increased Risk of Erosive Esophagitis in Men and Women - Accepted Manuscript

Su Youn Nam, Il Ju Choi, Kum Hei Ryu, Bum Joon Park, Hyun Bum Kim, Byung-Ho Nam — 2010-08-20

Abstract: Background & Aims:: Data on the association between erosive esophagitis and obesity are inconsistent because of variations in study populations and methods used to determine obesity.Methods:: Participants in a prospective health screening cohort underwent esophagogastroduodenoscopy and computed tomography. The association between erosive esophagitis and obesity (measured by body mass index [BMI], waist circumference, and abdominal visceral adipose tissue volume) was estimated with odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounding factors. We also analyzed the association between obesity and erosive esophagitis by sex.Results:: The prevalence of erosive esophagitis was 9.3% (495/5329). The OR for erosive esophagitis correlated with obesity measured by BMI, waist circumference, and abdominal visceral adipose tissue volume ( P < .001 for each factor). The multivariate OR for erosive esophagitis was 1.97 (95% CI, 1.34–2.90) for a visceral adipose tissue volume of 500–999 cm3, 2.27 (95% CI, 1.51–3.39) for 1000–1499 cm3, and 2.94 (95% CI, 1.87–4.62) for 1500 cm3, compared with participants that had visceral adipose tissue volumes less than 500 cm3. When measures of obesity were analyzed simultaneously, abdominal visceral adipose tissue volume, but not BMI or waist circumference, was associated with erosive esophagitis. The 3 measures of obesity were significantly associated with erosive esophagitis in men, but only visceral adipose tissue volume was associated with erosive esophagitis in women ( P = 0.002).Conclusions:: In contrast to BMI or waist circumference, abdominal visceral adipose tissue volume is associated with an increased risk of erosive esophagitis in men and women.

Type I Interferons Protect from Toll-like Receptor 9-Associated Liver Injury and Regulate IL-1 Receptor Antagonist in Mice - Accepted Manuscript

Jan Petrasek, Angela Dolganiuc, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo — 2010-08-20

Abstract: Background & Aims:: Liver inflammation and injury are mediated by the innate immune response, which is regulated by Toll-like receptors (TLR). Activation of TLR9 induces Type I interferons (IFNs) via the interferon regulatory factor (IRF)-7. We investigated the roles of Type I IFNs in TLR9-associated liver injury in mice.Methods:: Liver injury was induced in wild-type (WT), IRF7-deficient, and IFN-α /β receptor-1 (IFNAR1)-deficient mice by administration of ligands for TLR9 or TLR2. Findings from mice were verified in cultured hepatocytes and liver mononuclear cells, and in vivo experiments using recombinant Type-I IFN and interleukin-1 receptor antagonist (IL-1ra).Results:: Type I IFNs were upregulated during TLR9-associated liver injury in WT mice. IRF7- and IFNAR1-deficient mice, which have disruptions in Type I IFN production or signaling, respectively, had greater amounts of liver damage and inflammation, decreased recruitment of dendritic cells, and increased production of TNF-α by liver mononuclear cells (LMNC). These findings indicate that Type I IFNs have anti-inflammatory activities in liver. The IL-1ra, which is produced by LMNC and hepatocytes, is an IFN-regulated antagonist of the pro-inflammatory cytokine IL-1β; IRF7- and IFNAR1-deficient mice had decreased levels of IL-1ra, compared with WT mice. IL-1ra protected cultured hepatocytes from IL-1β-mediated sensitization to cytotoxicity from TNF-α. In vivo exposure to Type I IFN, which induced IL-1ra, or administration of IL-1ra reduced TLR9-associated liver injury; the protective effect of Type-I IFNs therefore appears to be mediated by IFN-dependent induction of IL-1ra.Conclusions:: Type I IFNs have anti-inflammatory effects mediated by endogenous IL-1ra which regulates the extent of TLR9-induced liver damage. Type I interferon signaling is therefore required for protection from immune-mediated liver injury.

The PREMM 1,2,6 Model Predicts Risk of MLH1, MSH2, and MSH6 Germline Mutations Based on Cancer History - Accepted Manuscript

2010-08-20

Abstract: Background & Aims:: We developed and validated a model to estimate the risks for mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6based on personal and family history of cancer.Methods:: Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM1,2,6) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The model’s discriminative ability was validated in 1827 population-based CRC cases.Results:: Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CI]): male sex (1.9; 1.5–2.4), a CRC (4.3; 3.3–5.6), multiple CRCs (13.7; 8.5–22), endometrial cancer (6.1; 4.6–8.2), and extracolonic cancers (3.3; 2.4–4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI: 0.82–0.91) for MLH1mutation carriers, 0.87 (95% CI: 0.83–0.92) for MSH2, and 0.81 (95% CI: 0.69–0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI: 0.86–0.90) and the population-based cases (95% CI: 0.83–0.92).Conclusions:: We developed the PREMM1,2,6 model that incorporates information on cancer history from probands and their relatives to estimate an individual’s risk for mutations in the MMR genes MLH1, MSH2, and MSH6. This web-based decision making tool can be used to assess risk for hereditary CRC and guide clinical management.

KLF4α Upregulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients with Pancreatic Cancer - Accepted Manuscript

2010-08-20

Abstract: Background & Aims:: Krüppel-like factor (KLF)4 is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation.Methods:: We identified different isoforms of KLF4 in pancreatic cancer cells by reverse transcriptase-PCR, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4α and characterize its function. Using real-time PCR, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4α in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4α on pancreatic tumorigenesis.Results:: We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4α, KLF4β, KLF4γ, and KLF4δ. KLF4α localized primarily to the cytoplasm; its protein and mRNA were upregulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors, compared with normal pancreatic tissue. Transgenic expression of KLF4α reduced expression of p27Kip1 and p21CIP1, promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4α in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma.Conclusions:: We identified a splice variant of KLF4 (KLF4α) that is upregulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice is associated with reduced survival times of patients.

Safety of Proton Pump Inhibitor Exposure - Uncorrected Proof

Yu–Xiao Yang, David C. Metz — 2010-08-20

Proton pump (H+/K+–adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents.

Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine - Accepted Manuscript

2010-08-19

Abstract: Background & Aims:: In the small intestine, the paracellular transport of Na+ is thought to be critical for luminal Na+ homeostasis and the transcellular absorption of nutrients by Na+-driven transporters. Na+ is supplied to the intestinal lumen from the submucosa and serum through tight junctions, which form a paracellular barrier between the cells of epithelial sheets. However, the molecular basis for this paracellular transport of Na+ is not well understood. Here we examined this mechanism by performing loss-of-function studies of claudin-2 and claudin-15, two tight-junctional membrane proteins that are specifically and age-dependently expressed in the villi and/or crypts of small intestinal epithelia.Methods:: Knockout mice for claudin-2 or claudin-15 were subjected to histological, cell biological, electrophysiological, and physiological analyses.Results:: Examination of the knockout mice revealed that both claudin-2 and claudin-15 play crucial roles in the transepithelial paracellular channel-like permselectivity for extracellular monovalent cations, particularly Na+, in infants and adults. Especially in Cldn15-- adults, the luminal Na+ concentration in the small intestine measured directly in vivo was abnormally low, and glucose absorption was impaired, as assessed by the oral glucose tolerance test and estimation of unabsorbed glucose.Conclusions:: We propose that the “Na+-leaky” claudin-15 is indispensable in vivo for the paracellular Na+ permeability, luminal Na+-homeostasis, and efficient glucose absorption in the small intestine, but claudin-2 is indispensable for only the first of these functions. Claudin-15 knockout leads to Na+ deficiency and glucose malabsorption in the mouse adult small intestine.

HCV treatment-related anemia is associated with higher sustained virologic response rate - Accepted Manuscript

2010-08-18

Abstract: Background & Aims:: Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN)– related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and its management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs).Methods:: We analyzed data from a trial conducted at 118 United States academic and community centers in treatment-naïve patients with HCV genotype 1. Patients were treated for as many as 48 weeks with 1 of 3 PEG-IFN/RBV regimens. ESAs were given to anemic patients (Hb <10 g/dL) after RBV dose reduction. Sustained virologic responses (SVR) were assessed based on decreases in Hb, anemia, and ESA use.Results:: While patients received treatment, 3023 had their Hb levels measured at least once. A SVR was associated with the magnitude of Hb decrease: >3 g/dL, 43.7%; ≤3 g/dL, 29.9% ( P <0.001). Anemia occurred in 865 patients (28.6%); 449 of these (51.9%) used ESAs. In patients with early-onset anemia (≤8 weeks of treatment), ESAs were associated with higher SVR rate (45.0% > 25.9%; P <0.001) and reduced discontinuation of treatment because of adverse events (12.6% < 30.1%, P <0.001). ESAs did not affect SVR or discontinuation rates among patients with late-stage anemia.Conclusion:: Among HCV genotype 1–infected patients treated with PEG-IFN/RBV, anemia was associated with higher rates of SVR. The effect of ESAs varied by time to anemia; patients with early-onset anemia had higher rates of SVR with ESA use whereas no effect was observed in those with late-onset anemia. Prospective trials are needed to assess the role of ESAs in HCV treatment.