Gastroenterology

This Month in Gastroenterology

Jan Tack, John M. Carethers — 2009-12-21

Whipple's disease is a rare inflammatory disorder caused by infection of different organ systems with Tropheryma whipplei. In the gastrointestinal tract, jejunal infection with T whipplei causes diarrhea or steatorrhea with weight loss. Treatment with a combination of doxycycline, hydroxychloroquine, and sulfamethoxazole or sulfadiazine is usually recommended, but prospective data assessing the efficacy of these antibiotics are lacking. Moreover, retrospective case series report failure rates of up to 30% using these antibiotic regimens.

More Than $500 Million Spent for Lobbying by Health Care Interest Groups in 2009

Les Lang — 2009-12-17

The health care sector and the insurance industry will have likely set a record for annual lobbying expenditures—more than a half of a billion dollars—in 2009. The health sector includes health care professionals (including physicians and nurses), pharmaceutical and health care products companies, hospitals and nursing homes, health services, and health maintenance organizations.

GINA, Imperfect But Official

Les Lang — 2009-12-17

On November 21, 2009, 18 months after President Bush signed it into law, the Genetic Information Nondiscrimination Act of 2008 became officially effective. Also known as GINA, the law prohibits employer discrimination based on genetic information and also prohibits health insurers from denying coverage or setting rates based on a person's genetic makeup, such as a predisposition to a disease.

Sustained Virologic Response to Hepatitis C Virus Therapy and Spontaneous Viral Clearance Found Linked to Genotype

Les Lang — 2009-12-17

A pair of papers in the journal Nature offer strong evidence that genotype dictates sustained virologic response (SVR) to hepatitis C therapy and is also associated with spontaneous viral clearance. A paper published is September 2009 involved a genome-wide association study of >1600 individuals chronically infected with hepatitis C participating in the IDEAL clinical treatment trial. The study compared the effectiveness of three treatment regimens involving pegylated interferon (PegIFN)-a-2b or PegIFN-a-2a combined with ribavirin (RBV). Patients received 48 weeks of treatment and 24 weeks of follow-up.

New Appointments to the Board of Editors

Les Lang — 2009-12-17

Pankaj Jay Pasricha, MD, and Ralf Kiesslich, MD, PhD, have joined the Gastroenterology Board of Editors, effective November 2009. Dr Pasricha will serve as an Associate Editor for manuscripts related to imaging and technology, and will assist in the areas of pancreatology and enteric neurobiology. He will also share co-editorship of the “Imaging and Advanced Technology” section with Dr Kiesslich.

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

2009-12-17

This is the second update for the state of research in pediatric gastroenterology, hepatology, and nutrition for Gastroenterology. It is commonly accepted among clinical gastroenterologists that this subspecialty requires a comprehensive knowledge of diseases crossing all age groups to provide appropriate care for their patients. Many gastrointestinal conditions that are present during childhood also require long-term care as chronic diseases extending into adulthood. The classic example is inflammatory bowel disease (IBD), particularly Crohn's disease (CD), which is occurring with increasing frequency in developed countries during childhood but, despite improved treatment, requires ongoing care well into adulthood. Identification of polymorphisms in receptors and signaling molecules for the enterocyte's innate immune response genes have been associated with an increased incidence of IBD. By screening possible children at risk for disease, an approach to prevention can be initiated. However, this requires care in the pediatric as well as the adult age group. With this concept in mind, academic centers (eg, the University of Pennsylvania/Children's Hospital of Philadelphia) have begun joint pediatric/adult medicine clinics in gastrointestinal diseases beginning in childhood. Accordingly, in this update we have expanded comments to include not only disease of the gastrointestinal tract, but also hepatology, as well as an update on current exciting clinical trials.

The Development of Clinical Guidelines by the American Gastroenterological Association

Themistocles Dassopoulos, John M. Inadomi, James D. Lewis, John I. Allen — 2009-12-23

Included in this issue of Gastroenterology is a medical position statement and technical review (TR) on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease by Farraye et al. The American Gastroenterological Association (AGA) Institute Clinical Practice and Quality Management Committee (CPQMC) is charged with developing evidence-based, clinical practice guidelines. We take this opportunity to report on the mechanisms and challenges of the current AGA process for development of position statements, and to offer insight into procedures for their future development.

Optical Molecular Imaging Approaches in Colorectal Cancer

Umar Mahmood — 2009-12-21

See “In vivo molecular imaging of colorectal cancer with confocal endomicroscopy by targeting epidermal growth factor receptor,” by Goetz M, Ziebart A, Foersch S, et al, on page 435.

IV or Not IV? Just One of the Antibiotic Questions in Whipple's Disease

Cynthia L. Sears, Sara E. Cosgrove — 2009-12-23

See “Efficacy of ceftriaxone or meropenem as initial therapies in Whipple's disease,” by Feurle GE, Junga NS, Marth T, on page 478.

Sonic Hedgehog: A Link Between Inflammation, Gastric Atrophy, and Acid Suppression?

Willemijn A. Van Dop, Gijs R. Van Den Brink — 2009-12-23

See “Loss of parietal cell expression of Sonic Hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells,” by Xiao C, Ogle SA, Schumacher MA, et al, on page 550; and “Interleukin-1β promotes gastric atrophy through suppression of Sonic Hedgehog,” by Waghray M, Zavros Y, Saqui–Salces M, et al, on page 562.

The Role of Bile Acids in Gallstone-Induced Pancreatitis

Markus M. Lerch, Ali A. Aghdassi — 2009-12-23

See “Biliary acute pancreatitis in mice is mediated by the G-protein–coupled cell surface bile acid receptor Gpbar1,” by Perides G, Laukkarinen JM, Vassileva G, et al, on page 715.

Colonoscopy: An Unusual Complication

Adam C. Alder, Daniel L. Scott, Jeffrey D. Browning — 2009-12-23

See related article, Ko CW et al, on page 166 in CGH.

Recurrent Nausea, Vomiting, and Abdominal Pain

Christine Y. Hachem, N. Cem Balci, Devang Desai — 2009-12-21

Question: A 34-year-old woman presented with recurrent nausea, vomiting, and abdominal pain over a 6-month period. She denied respiratory or cutaneous symptoms. Her past medical history was significant for a history of hypertension, gastroesophageal reflux, and melanoma, which was resected from her left thigh 3 years ago. Lymph node dissection at the time was negative. During these episodes, she was afebrile and had a normal serum white blood cell count, electrolytes, and liver function tests. Complement and C1 esterase inhibitor levels were normal. However, her C-reactive protein was elevated. Her medications included lisinopril, hydrochlorothiazide, Protonix, an oral contraceptive, iron, and occasional nonsteroidal anti-inflammatory drugs. For each episode, she was admitted to the hospital and nonspecific bowel wall thickening was noted on cross-sectional imaging. Magnetic resonance imaging (MRI) performed during an episode of pain revealed segmental ileal wall thickening with associated ascites ().

Esophageal Blebs and Blisters

Klaus Mönkemüller, Helmut Neumann, Lucía C. Fry — 2009-12-21

Question: A 65-year-old man was admitted because of dysphagia and coffee-ground emesis of 2 days duration. His past medical history was remarkable for end-stage renal disease, peripheral vascular disease, coronary artery disease, pemphigoid, and pulmonary embolism. On physical examination, he appeared chronically ill but nontoxic. The skin had multiple erythematous patches and small, fluid-filled blebs on both hands and feet. Abnormal laboratory data included: hemoglobin of 6.1 mmol/L (normal range, 7.4–10.0), hematocrit of 0.31 (normal range, 0.35–0.47), mean corpuscular volume of 84 (normal range, 80–95), International Normalized Ratio 2.67, and C-reactive protein of 67.2 (normal, <5). Esophagogastroduodenoscopy (EGD) disclosed a vulnerable esophageal mucosa with 2 bloody, fluid-filled blebs ranging from 2 to 4 cm in diameter (). More blebs developed on endoscopic contact with the esophageal mucosa. Biopsies of 1 of these lesions resulted in “pilling-off” of the mucosa (). The remaining EGD was normal. Histology revealed normal layers of squamous epithelium and elongation of the papillae with epithelial detachment from the submucosa ().

A Georgian Woman With Dysphagia and Stridor

Philipp Kiewe, Stefanie Hammersen, Thomas Schneider — 2009-12-25

See related article, Prince M et al, on page xxv in CGH.

An Unusual Liver Mass

Paolo Cabassa, Mario Morone, Luigi Matricardi — 2009-12-28

Question: A 54-year-old man was admitted to our institution because of epigastric discomfort and no other symptoms. His medical history was unremarkable. Esophagogastroduodenoscopy revealed a chronic gastritis associated with Helicobacter pylori infection. Clinical examination was normal. Routine clinical laboratory parameters were within normal ranges. Hepatitis tests revealed positive HBs-antigen. Abdominal ultrasound revealed a hypoechoic lesion in the hepatic right lobe (VI–VII segment), bulging the hepatic capsule (, left). Contrast-enhanced ultrasonography was performed using second generation contrast media (sulfur hexafluoride; Bracco, Milan, Italy). The lesion showed no enhancement during arterial and was hypoechoic during portal and late phases (, right) corresponding with a high probability of malignancy. The patient underwent MDCT. The lesion was hypodense on unenhanced scans. The mass was hysodense on arterial phase and hypodense on portal phase compared to the surrounding normal liver parenchyma. Compression of adjacent vessels was also noted (). Furthermore, CT showed no sign of other organ involvement or major lymphadenopathy.

In Vivo Molecular Imaging of Colorectal Cancer With Confocal Endomicroscopy by Targeting Epidermal Growth Factor Receptor

2009-10-22

Background & Aims: Epidermal growth factor receptor (EGFR) is a therapeutic target for colorectal cancer (CRC). However, technical challenges have limited in vivo imaging of EGFR in CRCs. Confocal laser endomicroscopy (CLE) enables accurate microscopic visualization of CRC in patients during endoscopy. We evaluated the ability to use CLE in vivo for instantaneous molecular imaging of EGFR in CRC models.Methods: Tumors were grown in mice (n = 68) from human CRC cell lines that expressed high (SW480 cells) or low (SW620 cells) levels of EGFR. Tumors were visualized in vivo with a handheld CLE probe after injection of fluorescently labeled EGFR antibodies. EGFR-specific fluorescence was graded from 0 to 3+. Neoplastic and non-neoplastic specimens from human colorectal mucosa were examined. In vivo findings were correlated with histopathology, immunohistochemistry, and fluorescence microscopy analyses.Results: CLE analysis of cell cultures confirmed the different expression levels of EGFR between cell lines. In living animals, CLE differentiated EGFR expression levels between tumor cell limes (mean fluorescence, 1.92 ± 0.22 [SW480] and 0.59 ± 0.21 [SW620], P = .0004). CLE analysis of EGFR expression in human specimens allowed distinction of neoplastic from non-neoplastic tissues (mean fluorescence, 2.0 ± 0.37 vs 0.25 ± 0.16, respectively, P = .0035).Conclusions: CLE can be used for in vivo, molecular analysis of CRC and to differentiate EGFR expression patterns in xenograft tumors and human tissue samples. Because CLE can be performed during endoscopy, in vivo molecular imaging might be used in diagnosis of CRC and to predict response to targeted therapies.

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

Christoph Sarrazin, Stefan Zeuzem — 2009-12-14

Chronic hepatitis C virus (HCV) infection is one of the major causes of cirrhosis, hepatocellular carcinoma, and liver failure that leads to transplantation. The current standard treatment, a combination of pegylated interferon alfa and ribavirin, eradicates the virus in only about 50% of patients. Directly acting antiviral (DAA) agents, which inhibit HCV replication, are in phase 1, 2, and 3 trials; these include reagents that target the nonstructural (NS)3 protease, the NS5A protein, the RNA-dependent RNA-polymerase NS5B, as well as compounds that directly inhibit HCV replication through interaction with host cell proteins. Because of the high genetic heterogeneity of HCV and its rapid replication, monotherapy with DAA agents poses a high risk for selection of resistant variants. We review the parameters that determine resistance, genotypic and phenotypic resistance profiles of DAA agents, and strategies to avoid the selection of resistant variants.

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

2009-10-09

Background & Aims: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohn's disease.Methods: One-hundred thirty-three newly diagnosed and treatment-naïve Crohn's disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began.Results: Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score >0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10−17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144−20.844).Conclusions: Complete mucosal healing in patients with early-stage Crohn's disease is associated with significantly higher steroid-free remission rates 4 years after therapy began.

Postprandial Changes in Small Bowel Water Content in Healthy Subjects and Patients With Irritable Bowel Syndrome

2009-11-11

Background & Aims: Postprandial symptoms are common in patients with irritable bowel syndrome with diarrhea (IBS-D) and could be diet related. We studied postprandial changes in distribution of water in the upper gastrointestinal tract of healthy volunteers (HVs) and patients with IBS-D after contrasting meals.Methods: In study 1, 11 HVs consumed 350-mL test meals with 5% mannitol (unabsorbable) or 5% glucose (readily absorbed). In study 2, 17 HVs consumed a 331-kcal meal, with or without 15 g bran. In study 3, 26 patients with IBS-D consumed the study 2 diet with bran meal. All subjects underwent serial magnetic resonance imaging analysis.Results: In study 1, subjects' small bowel water content (SBWC) increased after the mannitol but not glucose meals, reaching 381 mL (interquartile range, 343–491 mL) and 47 mL (18–78 mL), respectively, 40 minutes after eating (P < .001). In study 2, SBWC initially decreased after both meal types and then increased, plateauing at 180–405 minutes and was greater after the bran meal (P = .02). In study 3, fasting and postprandial SBWC was lower in IBS-D than in HVs (P < .05 and P < .0001, respectively). Patients with IBS-D had faster orocecal transit times (135 minutes; 90–180 minutes) compared with HVs (225 minutes; 203–293 minutes; P < .0001) and reduced terminal ileum diameter (P < .003).Conclusions: Postprandial SBWC initially decreases, because of rapid, nutrient-driven fluid absorption, and then increases after a mixed liquid/solid meal. Patients with IBS-D have reduced fasting and postprandial SBWC with faster transit, possibly indicating increased small intestinal tone.

Efficacy of Ceftriaxone or Meropenem as Initial Therapies in Whipple's Disease

Gerhard E. Feurle, Natascha S. Junga, Thomas Marth — 2009-10-30

Background & Aims: Whipple's disease is a chronic infection caused by the actinomycete Tropheryma whipplei. We conducted a randomized controlled trial of the efficacy of antimicrobials that are able to cross the blood-brain barrier and to which T whipplei is susceptible.Methods: Patients from central Europe with previously untreated Whipple's disease (n = 40) were assigned randomly to groups given daily infusions of either ceftriaxone (1 × 2 g, 20 patients) or meropenem (3 × 1 g, 20 patients) for 14 days, followed by oral trimethoprim–sulfamethoxazole for 12 months. The primary outcome measured was maintenance of remission for 3 years, determined by a composite index of clinical and laboratory data as well as histology.Results: All patients were observed for the entire follow-up period (median, 89 mo; range, 71–128 mo); all achieved clinical and laboratory remission. Remission was maintained in all patients during the time of observation, except for 2 who died from unrelated causes. A single patient with asymptomatic cerebrospinal infection who was resistant to both treatments responded to chloroquine and minocycline. The odds ratio for the end point (remission for at least 3 years) was 0.95 (95% confidence interval, 0.05–16.29; P = 1.0).Conclusions: This was a randomized controlled trial to show that treatment with ceftriaxone or meropenem, followed by trimethoprim–sulfamethoxazole, cures patients with Whipple's disease. One asymptomatic individual with infection of the cerebrospinal fluid required additional therapy.

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands

2009-11-09

Background & Aims: Although gastric cancer forms part of the Lynch syndrome tumor spectrum, the risk of developing gastric cancer in Lynch syndrome families is unknown, resulting in a lack of clear guidelines for surveillance. The aim of this study was to evaluate incidence trends and risk of developing gastric cancer among Lynch syndrome mutation carriers in a Western population.Methods: Lynch syndrome mutation carriers were selected from the Dutch Hereditary Cancer Registry. The gastric cancer incidence in Lynch syndrome mutation carriers was compared to the gastric cancer incidence in the Dutch population between 1970 and 2003. Standardized incidence ratios were calculated by a Poisson model. Cumulative risks were calculated by Kaplan-Meier analysis.Results: Overall, 2014 Lynch syndrome mutation carriers were identified. Gastric cancer was diagnosed in 32 (1.6%) subjects (male/female: 21/11), 22 (69%) of them had a negative family history of gastric cancer. The standardized incidence ratios of gastric cancer was 3.4 (95% confidence interval, 2.1–5.2) and showed a nonsignificant decline between 1970 and 2003 (P = .30). Absolute risk of developing gastric cancer also showed no significant change over time (P = .51). Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females (P = .02), and 4.8% and 9% for MLH1 and MSH2 carriers, respectively. None of the 378 MSH6 carriers developed gastric cancer (P = .002 vs MLH1 and MSH2 combined lifetime risk).Conclusions: Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

Des-γ-Carboxy Prothrombin and α-Fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma

2009-10-22

Background & Aims: The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) in the early diagnosis of HCC.Methods: Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month −12) to the time of HCC diagnosis (month 0).Results: The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/mL and 22% and 100% at a cutoff of 200 ng/mL. At month −12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients.Conclusions: Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal.

Peginterferon Alfa-2a/Ribavirin for 48 or 72 Weeks in Hepatitis C Genotypes 1 and 4 Patients With Slow Virologic Response

2009-11-11

Background & Aims: This randomized multicenter trial evaluated individualization of treatment duration with peginterferon alfa-2a 180 μg/wk plus ribavirin 1000/1200 mg/day in patients with chronic hepatitis C genotype 1/4 based on the rapidity of virologic response (VR).Methods: Patients with a rapid VR (RVR; undetectable hepatitis C virus [HCV]-RNA level (<50 IU/mL at week 4) were treated for 24 weeks, those with an early VR (EVR; no RVR but undetectable HCV-RNA level or ≥2-log10 decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B; peginterferon alfa-2a was reduced to 135 μg/wk after week 48). Patients without an EVR continued treatment until week 72 if they had undetectable HCV-RNA levels at week 24. The primary end point was relapse; sustained VR (SVR; undetectable HCV-RNA level after 24 weeks of follow-up evaluation) was a secondary end point.Results: Of 551 genotype 1/4 patients starting treatment, 289 were randomized to group A (N = 139) or group B (N = 150). The relapse rate was 33.6% in group A (95% confidence interval [CI], 24.8%–43.4%) and 18.5% in group B (95% CI, 11.9%–27.6%; P = .0115 vs group A) and the SVR rate was 51.1% (95% CI, 42.5%–59.6%) and 58.6% (95% CI, 50.3%–66.6%; P > .1), respectively. The overall SVR rate was 50.4% (278 of 551; 95% CI, 46.2%–54.7%), including 115 of 150 patients with an RVR treated for 24 weeks and 4 of 78 patients without an EVR.Conclusions: Extending therapy with peginterferon alfa-2a/ribavirin to 72 weeks decreases the probability of relapse in patients with an EVR. If they can be maintained on extended-duration therapy, SVR rates also may improve.

Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression

2009-10-26

Background & Aims: The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications.Methods: We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy.Results: Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred. The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy.Conclusions: Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.

Screening and Early Treatment of Migrants for Chronic Hepatitis B Virus Infection Is Cost-Effective

2009-10-30

Background & Aims: Persons with chronic hepatitis B virus (HBV) infection are at risk of developing cirrhosis and hepatocellular carcinoma. Early detection of chronic HBV infection through screening and treatment of eligible patients has the potential to prevent these sequelae. We assessed the cost-effectiveness in The Netherlands of systematically screening migrants from countries that have high and intermediate HBV infection levels.Methods: Epidemiologic data of the expected numbers of patients with active chronic HBV infection in the target population and information about the costs of a screening program were used in a Markov model and used to determine costs and quality-adjusted life years (QALY) for patients who were and were not treated.Results: Compared with the status quo, a 1-time screen for HBV infection can reduce mortality of liver-related diseases by 10%. Using base case estimates, the incremental cost-effectiveness ratio (ICER) of screening, compared with not screening, is euros (€) 8966 per QALY gained. The ICER ranged from €7936 to €11,705 based on univariate sensitivity analysis, varying parameter values of HBV prevalence, participation rate, success in referral, and treatment compliance. Using multivariate sensitivity analysis for treatment effectiveness, the ICER ranged from €7222 to €15,694; for disease progression, it ranged from €5568 to €60,418.Conclusions: Early detection and treatment of people with HBV infection can have a large impact on liver-related health outcomes. Systematic screening for chronic HBV infection among migrants is likely to be cost-effective, even using low estimates for HBV prevalence, participation, referral, and treatment compliance.

Asymptomatic Pancreatic Cystic Neoplasms: Maximizing Survival and Quality of Life Using Markov-Based Clinical Nomograms

Benjamin M. Weinberg, Brennan M.R. Spiegel, James S. Tomlinson, James J. Farrell — 2009-10-09

Background & Aims: The natural history and management of pancreatic cysts, especially for branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), remain uncertain. We developed evidence-based nomograms to assist with clinical decision making.Methods: We used decision analysis with Markov modeling to compare competing management strategies in a patient with a pancreatic head cyst radiographically suggestive of BD-IPMN, including the following: (1) initial pancreaticoduodenectomy (PD), (2) yearly noninvasive radiographic surveillance, (3) yearly invasive surveillance with endoscopic ultrasound, and (4) “do nothing.” We derived probability estimates from a systematic literature review. The primary outcomes were overall and quality-adjusted survival. We depicted the results in a series of nomograms accounting for age, comorbidities, and cyst size.Results: Initial PD was the dominant strategy to maximize overall survival for any cyst greater than 2 cm, regardless of age or comorbidities. In contrast, surveillance was the dominant strategy for any lesion less than 1 cm. However, when measuring quality-adjusted survival, the do-nothing approach maximized quality of life for all cysts less than 3 cm in patients younger than age 75. Once age exceeded 85 years, noninvasive surveillance dominated. Initial PD did not maximize quality of life in any age group or cyst size.Conclusions: Management of pancreatic cysts can be guided using novel Markov-based clinical nomograms, and depends on age, cyst size, comorbidities, and whether patients value overall survival vs quality-adjusted survival. For patients focused on overall survival, regardless of quality of life, surgery is optimal for lesions greater than 2 cm. For patients focused on quality-adjusted survival, a 3-cm threshold is more appropriate for surgery except for the extreme elderly.

History of Peptic Ulcer Disease and Pancreatic Cancer Risk in Men

2009-10-09

Background & Aims: Peptic ulcer disease has been associated with an increased risk of pancreatic cancer, but findings on this topic are inconsistent. We investigated the association between pancreatic cancer and the occurrence of gastric or duodenal ulcer in a large US cohort.Methods: We analyzed data collected from 51,529 male health professionals in a prospective cohort study. History of peptic ulcer disease was assessed at baseline in 1986 and updated biennially thereafter. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models adjusting for smoking, body mass index, diabetes, and physical activity.Results: During 18 years of follow-up evaluation, we observed 274 incident pancreatic cancer cases. Compared with those with report of no peptic ulcer disease, men with gastric ulcer had an increased risk of pancreatic cancer (RR, 1.83; 95% CI, 1.13–2.97). Although the risk was highest for those with a diagnosis of gastric ulcer that was close in time to the cancer diagnosis (RR, 3.66; 95% CI, 1.45–9.24), the risk remained significantly increased 10–19 years after the gastric ulcer diagnosis (RR, 2.89; 95% CI, 1.26–6.64). In contrast, duodenal ulcer was not associated with pancreatic cancer risk (RR, 1.15; 95% CI, 0.78–1.71).Conclusions: Gastric ulcer increases the risk of pancreatic cancer, whereas there does not appear to be an association between duodenal ulcers and pancreatic cancer.

Loss of Parietal Cell Expression of Sonic Hedgehog Induces Hypergastrinemia and Hyperproliferation of Surface Mucous Cells

2009-11-11

Background & Aims: Sonic Hedgehog (Shh) is expressed in the adult stomach, but its role as a gastric morphogen is unclear. We sought to identify mechanisms by which Shh might regulate gastric epithelial cell function and differentiation.Methods: Mice with a parietal cell–specific deletion of Shh (HKCre/ShhKO) were created. Gastric morphology and function were studied in control and HKCre/ShhKO mice between 1 and 8 months of age.Results: In contrast to control mice, HKCre/ShhKO mice developed gastric hypochlorhydria, hypergastrinemia, and a phenotype that resembled foveolar hyperplasia. The fundic mucosa of HKCre/ShhKO mice had an expanded surface pit cell lineage that was documented by increased incorporation of bromodeoxyuridine and was attributed to the hypergastrinemia. Compared with controls, numbers of total mucous neck and zymogen cells were significantly decreased in stomachs of HKCre/ShhKO mice. In addition, zymogen and neck cell markers were coexpressed in the same cell populations, indicating disrupted differentiation of the zymogen cell lineage from the mucous neck cells in the stomachs of HKCre/ShhKO mice. Laser capture microdissection of the surface epithelium, followed by quantitative reverse-transcription polymerase chain reaction, revealed a significant increase in expression of Indian Hedgehog, glioma-associated oncogene homolog 1, Wnt, and cyclin D1. Laser capture microdissection analysis also showed a significant increase in Snail with a concomitant decrease in E-cadherin.Conclusions: In the stomachs of adult mice, loss of Shh from parietal cells results in hypochlorhydria and hypergastrinemia. Hypergastrinemia might subsequently induce increased Hedgehog and Wnt signaling in the surface pit epithelium, resulting in hyperproliferation.

Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog

2009-11-02

Background & Aims: In both human subjects and rodent models, Helicobacter infection leads to a decrease in Shh expression in the stomach. Sonic Hedgehog (Shh) is highly expressed in the gastric corpus and its loss correlates with gastric atrophy. Therefore, we tested the hypothesis that proinflammatory cytokines induce gastric atrophy by inhibiting Shh expression.Methods: Shh-LacZ reporter mice were infected with Helicobacter felis for 3 and 8 weeks. Changes in Shh expression were monitored using β-galactosidase staining and immunohistochemistry. Gastric acidity was measured after infection, and interleukin (IL)-1β was quantified by quantitative reverse-transcription polymerase chain reaction. Mice were injected with either IL-1β or omeprazole before measuring Shh mRNA expression and acid secretion. Organ cultures of gastric glands from wild-type or IL-1R1 null mice were treated with IL-1β then Shh expression was measured. Primary canine parietal or mucous cells were treated with IL-1β. Shh protein was determined by immunoblot analysis. Changes in intracellular calcium were measured by Fura-2.Results: All major cell lineages of the corpus including surface pit, mucous neck, zymogenic, and parietal cells expressed Shh. Helicobacter infection reduced gastric acidity and inhibited Shh expression in parietal cells by 3 weeks. IL-1β produced during Helicobacter infection inhibited gastric acid, intracellular calcium, and Shh expression through the IL-1 receptor. Suppression of parietal cell Shh expression by IL-1β and omeprazole was additive. IL-1β did not suppress Shh expression in primary gastric mucous cells.Conclusions: IL-1β suppresses Shh gene expression in parietal cells by inhibiting acid secretion and subsequently the release of intracellular calcium.

Protease-Activated Receptor-1 Down-regulates the Murine Inflammatory and Humoral Response to Helicobacter pylori

2009-08-25

Background & Aims: Helicobacter pylori infection results in a diversity of pathologies, from asymptomatic gastritis to adenocarcinoma. The reason for these diverse outcomes is multifactorial and includes host factors that regulate severity of Helicobacter-induced gastritis. Protease-activated receptors (PAR) are environmental sensors that can detect tissue damage and pathogens. Whereas PAR-2 has proinflammatory activity and PAR-1 can protect the gastric mucosa against chemical damage, neither has previously been examined for their potential roles in regulating Helicobacter pathogenesis.Methods: PAR-1−/−, PAR-2−/−, and wild-type mice were infected with H pylori for up to 2 months then colonization levels determined by colony-forming assay, gastritis by histology, and serum antibody levels by enzyme-linked immunosorbent assay. Responsiveness of primary epithelial cells to PAR-1 activation was assessed by calcium mobilization assay. Primary epithelial cells, macrophages, and dendritic cells were cocultured with H pylori and nuclear factor (NF)-κB, and cytokine secretion was determined by enzyme-linked immunosorbent assay.Results: Two months postinfection, H pylori levels were significantly reduced in PAR-1−/− and increased in PAR-2−/− mice. This effect on colonization was inversely correlated with inflammation severity. Infection of PAR-1−/− mice induced an increased serum antibody response. Primary epithelial cells were activated by a PAR-1-activating peptide. H pylori stimulation of primary epithelial cells, but not macrophages or dendritic cells, from PAR-1−/− mice induced increased levels of NF-κB and the proinflammatory cytokine macrophage-inflammatory protein (MIP)-2. PAR-1 also down-regulated MIP-2 secretion in response to cag pathogenicity island activity.Conclusions: PAR-1 protects the host against severe Helicobacter-induced gastritis. This may be mediated by suppressing the production of proinflammatory cytokines such as MIP-2.

Inhibition of HDAC9 Increases T Regulatory Cell Function and Prevents Colitis in Mice

2009-10-30

Background & Aims: Foxp3+ T regulatory cells (Tregs) help prevent autoimmunity, and increases in their numbers of functions could decrease the development of inflammatory bowel disease. Like other cells, Foxp3+ Tregs express histone/protein deacetylases (HDACs), which regulate chromatin remodeling and gene expression. We investigated whether disruption of a specific class IIa HDAC, HDAC9, activity in Tregs affects the pathogenesis of colitis in mice.Methods: We tested the effects of various HDAC inhibitors (HDACi) in models of colitis using wild-type mice. We also transferred Tregs and non-Treg cells from HDAC9−/− or wild-type mice to immunodeficient mice. HDAC9 contributions to the functions of Tregs were determined during development and progression of colitis.Results: Pan-HDACi, but not class I-specific HDACi, increased the functions of Foxp3+ Tregs, prevented colitis, and reduced established colitis in mice, indicating the role of class II HDACs in controlling Treg function. The abilities of pan-HDACi to prevent/reduce colitis were associated with increased numbers of Foxp3+ Tregs and their suppressive functions. Colitis was associated with increased local expression of HDAC9; HDAC9−/− mice resistant to development of colitis. HDAC9−/− Tregs expressed increased levels of the heat shock protein (HSP) 70, compared with controls. Immunoprecipitation experiments indicated an interaction between HSP70 and Foxp3. Inhibition of HSP70 reduced the suppressive functions of HDAC9−/− Tregs; Tregs that overexpressed HSP70 had increased suppressive functions.Conclusions: Strategies to decrease HDAC9 expression or function in Tregs or to increase expression of HSP70 might be used to treat colitis and other autoimmune disorders.

Mesalamine Inhibits Epithelial β-Catenin Activation in Chronic Ulcerative Colitis

2009-10-30

Background & Aims: Mesalamine is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) in which condition it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that mesalamine reduces β-catenin-associated progenitor cell activation, Akt-phosphorylated β-cateninSer552 (P-β-catenin), and colitis-induced dysplasia (CID).Methods: Effects of mesalamine on P-β-catenin staining and function were assessed by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in biopsy specimens of CUC in mild or “refractory” severe mucosal inflammation. Effects of mesalamine on epithelial proliferation and activation of Akt and β-catenin were assessed in interleukin (IL)-10−/− colitis and CID by immunohistochemistry and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon.Results: Data from IL-10−/− and human colitis samples show that mesalamine reduced Akt activation and P-β-catenin levels in the middle and upper crypt. Reductions in P-β-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-β-catenin levels in tissue refractory to mesalamine's anti-inflammatory effects. In IL-10−/− mice, mesalamine reduced CID concordant with inhibition of crypt Akt and β-catenin signaling.Conclusions: The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing β-catenin signaling within intestinal progenitors.

Prolyl Hydroxylase-3 Is Down-regulated in Colorectal Cancer Cells and Inhibits IKKβ Independent of Hydroxylase Activity

Jing Xue, Xuebing Li, Shi Jiao, Ye Wei, Guohao Wu, Jing Fang — 2009-09-27

Background & Aims: Prolyl hydroxylase (PHD) hydroxylates hypoxia inducible factor (HIF) α, leading to HIFα degradation. The PHD family comprises PHD1, PHD2, and PHD3. The enzymatic activity of PHDs is O2-dependent, so PHDs are believed to be oxygen sensors as well as tumor suppressors. However, the expression pattern of PHDs in colorectal cancer and the correlation between their expression level and tumorigenesis is unclear.Methods: We determined the expression of PHDs in 60 human primary colorectal carcinoma tissues, paired with normal colorectal tissues. PHD3 expression levels were knocked down using small interfering RNA (siRNA); cells were analyzed by immunoblotting, immunoprecipitation, and histochemical analyses. In vivo tumor growth was analyzed in nu/nu mice.Results: Expression of PHD3 is decreased in colorectal cancer tissues. Decreased expression of PHD3 is associated with higher tumor grade and metastasis. PHD3 inhibits phosphorylation of inhibitor of κB (IκB) kinase (IKK) β and activation of (NF) κB, independent of its hydroxylase activity. PHD3 associates with IKKβ but does not target it for destruction; instead, PHD3 blocks the interaction between IKKβ and Hsp90 that is required for phosphorylation of IKKβ. Knockdown of PHD3 increased resistance of colorectal cancer cells to the effects of tumor necrosis factor-α and tumorigenesis.Conclusions: PHD3 appears to be a tumor suppressor in colorectal cancer cells that inhibits IKKβ/NF-κB signaling, independent of its hydroxylase activity. Activation of NF-κB has been observed in colon cancer. Determination of PHD3 status could aid targeted therapy selection for patients with colorectal tumors that have increased NF-κB activity.

Reg IV Regulates Normal Intestinal and Colorectal Cancer Cell Susceptibility to Radiation-Induced Apoptosis

2009-11-09

Background & Aims: Regenerating (Reg) gene IV is predominantly expressed in gastrointestinal cells and highly up-regulated in many gastrointestinal malignancies, including colorectal cancer (CRC). Human CRC cells expressing higher levels of Reg IV gene and its protein product (Reg IV) are resistant to conventional therapies, including irradiation (IR). However, the underlying mechanism is not well defined.Methods: A murine model of IR-induced intestinal injury and in vitro and in vivo models of human CRC were used to determine the role of Reg IV in regulation of normal intestinal and colorectal cancer cell susceptibility to IR-induced apoptosis.Results: Treatments of recombinant human Reg IV (rhR4) protein protected normal intestinal crypt cells from IR-induced apoptosis by increasing the expression of antiapoptotic genes Bcl-2, Bcl-XL, and survivin. However, overexpression of Reg IV in human CRC cells was associated with increased resistance to IR-induced apoptosis. Therefore, we used antagonism of Reg IV as a tool to increase CRC cell susceptibility to IR-induced cell death. Two complementary approaches using specific monoclonal antibodies and small interfering RNAs were tested in both in vitro and in vivo models of human CRC. Both approaches resulted in increased apoptosis and decreased cell proliferation, leading to decreased tumor growth and increased animal survival. Furthermore, these approaches increased CRC cell susceptibility to IR-induced apoptosis.Conclusions: These results implicate Reg IV as an important modulator of gastrointestinal cell susceptibility to IR; hence, it is a potential target for adjunctive treatments for human CRC and other gastrointestinal malignancies.

CDX Transcription Factors Positively Regulate Expression of Solute Carrier Family 5, Member 8 in the Colonic Epithelium

2009-11-09

Background & Aims: Caudal-related homeodomain transcription factors CDX1 and CDX2 regulate gut development and differentiation of intestinal epithelial cells; they are candidate tumor suppressors of colorectal carcinomas. Because the functions of CDX1 and CDX2 in the colonic epithelium are not fully understood, we sought to identify genes that they target.Methods: We conducted a chromatin immunoprecipitation (ChIP) screen to identify genes that bind the CDX transcription factors. Expression of target genes was analyzed in colon cells and tissues from Cdx1−/−, Cdx2+/−, Apc+/Δ716, and wild-type (control) mice.Results: Using the ChIP screen, we identified solute carrier family 5, member 8 (SLC5A8, also known as SMCT1) as a direct target of CDX1 and CDX2. CDX transcription factors bind to the promoter region of SLC5A8 and transactivate SLC5A8 reporter constructs. Overexpression of Cdx1 or Cdx2 in human colon cancer cell lines induced expression of endogenous SLC5A8, whereas CDX1 and CDX2 knockdowns reduced its level. Consistently, Slc5a8 expression was significantly reduced in colons of Cdx1−/− or Cdx2+/− mice compared with wild-type mice. Slc5a8 levels were also reduced in colonic adenomatous polyps and hamartomas from Apc+/Δ716 and Cdx2+/− mutant mice, respectively, compared with adjacent normal colon tissues.Conclusions: CDX1 and CDX2 bind the promoter region of SLC5A8 and up-regulate its expression in cultured cells and in colonic epithelium. SLC5A8 transports monocarboxylates such as pyruvate, lactate, and butyrate; CDX1 and CDX2 might therefore regulate the uptake of these substances in the colon.

The Intestinal Nuclear Receptor Signature With Epithelial Localization Patterns and Expression Modulation in Tumors

2009-10-09

Background & Aims: The WNT–adenomatous polyposis coli system controls cell fate in the intestinal epithelium, where compartment-specific genes tightly regulate proliferation, migration, and differentiation. Nuclear receptors are transcription factors functioning as sensors of hormones and nutrients that are known to contribute to colon cancer progression. Here we mapped the messenger RNA (mRNA) abundance and the epithelial localization of the entire nuclear receptor family in mouse and human intestine.Methods: We used complementary high-resolution in situ hybridization and systematic real-time quantitative polymerase chain reaction in samples of normal distal ileum and proximal colon mucosa and tumors obtained from mouse and human adenomatous polyposis coli–initiated tumor models (ie, ApcMin/+ mice and familial adenomatous polyposis patients) and in cellular models of human colon cancer.Results: We first defined for each receptor an expression pattern based on its transcript localization in the distal ileum and the proximal colon. Then, we compared the mRNA levels between normal intestinal epithelium and neoplastic intestinal tissue. After analyzing the correspondence between mouse and human tumor samples plus genetically modified human colon cancer cells, we used complementary graphic and statistical approaches to present a comprehensive overview with several classification trees for the nuclear hormone receptor intestinal transcriptome.Conclusions: We defined the intestinal nuclear hormone receptor map, which indicates that the localization pattern of a receptor in normal intestine predicts the modulation of its expression in tumors. Our results are useful to select those nuclear receptors that could be used eventually as early diagnostic markers or targeted for clinical intervention in intestinal polyposis and cancer.

Lysophosphatidic Acid Stimulates the Intestinal Brush Border Na+/H+ Exchanger 3 and Fluid Absorption via LPA5 and NHERF2

2009-10-05

Background & Aims: Diarrhea results from reduced net fluid and salt absorption caused by an imbalance in intestinal absorption and secretion. The bulk of sodium and water absorption in the intestine is mediated by Na+/H+ exchanger 3 (NHE3), located in the luminal membrane of enterocytes. We investigated the effect of lysophosphatidic acid (LPA) on Na+/H+ exchanger activity and Na+-dependent fluid absorption in the intestine.Methods: We analyzed the effects of LPA on fluid absorption in intestines of wild-type mice and mice deficient in Na+/H+ exchanger regulatory factor 2 (NHERF2; Nherf2−/−) or LPA2 (Lpa2−/−). Roles of LPA5 and NHERF2 were determined by analysis of heterologous expression.Results: Under basal conditions, LPA increased fluid absorption in an NHE3-dependent manner and restored the net fluid loss in a mouse model of acute diarrhea. Expression of the LPA receptor LPA5 was necessary for LPA-induced stimulation of NHE3 activity in colonic epithelial cells. Stimulation of NHE3 by the LPA-LPA5 signaling required coexpression of NHERF2, which interacted with LPA5. LPA-mediated intestinal fluid absorption was impaired in Nherf2−/− mice, demonstrating the requirement for NHERF2 in LPA5 activity. However, fluid absorption was unaltered in Lpa2−/− mice. LPA stimulated NHE3 and fluid absorption in part by increasing NHE3 protein abundance at the brush border membrane of intestinal epithelial cells.Conclusions: LPA is a potent stimulant of NHE3 and fluid absorption in the intestine, signaling through LPA5. Regulation by LPA5 depends on its interaction with NHERF2. LPA might be useful in the treatment of certain diarrheal diseases.

Release of 5-Hydroxytryptamine From the Mucosa Is Not Required for the Generation or Propagation of Colonic Migrating Motor Complexes

Damien J. Keating, Nick J. Spencer — 2009-09-25

Background & Aims: The pacemaker mechanism that underlies the cyclic generation of colonic migrating motor complexes (CMMCs) is unknown, although studies have suggested that release of 5-hydroxytryptamine (5-HT) from enterochromaffin cells in the mucosa is essential. However, no recordings of 5-HT release from the colon have been made to support these suggestions.Methods: We used real-time amperometry to record 5-HT release directly from the mucosa in mouse isolated colon to determine whether 5-HT release from enterochromaffin cells was required for CMMC generation.Results: We found that 5-HT was released from mucosal enterochromaffin cells during many, but not all, CMMC contractions. However, spontaneous CMMCs still were recorded even after removal of the mucosa, and submucosa and submucosal plexus when all release of 5-HT had been abolished. CMMC pacemaker frequency was slower in the absence of the mucosa, an effect reversed by focal application of exogenous 5-HT onto the myenteric plexus. Despite the absence of the mucosa and all detectable release of 5-HT, ondansetron significantly reduced CMMC frequency, suggesting that 5-HT3 receptor blockade slows the CMMC pacemaker via a mechanism independent of 5-HT release from enterochromaffin cells.Conclusions: Our results show that 5-HT can be released dynamically during CMMCs. However, the intrinsic pacemaker and pattern generator underlying CMMC generation lies within the myenteric plexus and/or muscularis externa and does not require any release of 5-HT from enterochromaffin cells. Endogenous release of 5-HT from enterochromaffin cells plays a modulatory role, not an essential role, in CMMC generation.

Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection

2009-09-25

Background & Aims: Silymarin, an extract from the seeds of the milk thistle plant Silybum marianum, has been used for centuries for the treatment of chronic liver diseases. Despite common use by patients with hepatitis C in the United States, its clinical efficacy remains uncertain. The goal of this study was to determine whether silymarin has in vitro effects on immune function that might have implications for its potential effect on hepatitis C virus (HCV)-induced liver disease.Methods: Freshly isolated peripheral blood mononuclear cells (PBMC) and T cells from HCV-infected and uninfected subjects were tested in vitro for responses to nonspecific and antigenic stimulation in the presence and absence of a standardized preparation of silymarin (MK001).Results: Minimal MK001 toxicity on PBMC was found at concentrations between 5 and 40 μg/mL. MK001 dose dependently inhibited the proliferation and secretion of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 by PBMC stimulated with anti-CD3. In addition, MK001 inhibited proliferation by CD4+ T cells to HCV, Candida, and tetanus protein antigens and by HLA-A2/HCV 1406–1415-specific CD8+ T cells to allogeneic stimulation. MK001 inhibited T-cell TNF-α and IFN-γ cytokine secretion to tetanus and Candida protein antigens. Finally, MK001 inhibited nuclear factor-κB transcriptional activation after T-cell receptor-mediated stimulation of Jurkat T cells, consistent with its ability to inhibit Jurkat T-cell proliferation and secretion of IL-2.Conclusions: Silymarin's ability to inhibit the proliferation and proinflammatory cytokine secretion of T cells, combined with its previously described antiviral effect, suggests a possible mechanism of action that could lead to clinical benefit during HCV infection.

Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

2009-10-05

Background & Aims: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B.Methods: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8+ T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-γ and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies.Results: Intrahepatic HBV-specific CD8+ cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8+ cell proliferation and IFN-γ and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells.Conclusions: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

Heme Oxygenase-1 Protects Against Steatohepatitis in Both Cultured Hepatocytes and Mice

2009-10-09

Background & Aims: Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. We investigated the role of HO-1 in nutritional steatohepatitis in vitro and in vivo.Methods: AML-12 hepatocytes were cultured in methionine- and choline-deficient (MCD) medium. Cells were transfected with an adenovirus vector that expressed HO-1 (Ad-HO-1) or incubated with the HO-1 inducer hemin or the HO-1 inhibitor stannic mesoporphyrin for 24 hours. C57BL6 mice and db/db mice were fed MCD or control diets, with or without hemin, for up to 4 weeks.Results: AML-12 cells exposed to MCD medium developed significant steatosis, increased release of alanine aminotransferase, and showed signs of oxidative injury. Incubation with hemin induced HO-1 protein, suppressed steatosis, and reduced levels of alanine aminotransferase and lipid peroxidation. A comparable effect was observed in cells transfected with Ad-HO-1, whereas incubation of these cells with stannic mesoporphyrin completely abolished the Ad-HO-1− or hemin-mediated protection of hepatocytes. Mice injected with hemin significantly attenuated MCD-induced steatohepatitis and increased HO-1 protein and activity. This effect was associated with up-regulation of antioxidant chaperones and enzymes, down-regulation of proinflammatory cytokines, and up-regulation of the anti-inflammatory interleukin-22. Moreover, the reduction in steatosis caused by hemin was affected by up-regulation of peroxisome proliferator−activated receptor-α and by down-regulation of sterol regulatory element binding protein-1c.Conclusions: HO-1 can interrupt progression of nutritional steatohepatitis by inducing an antioxidant pathway, suppressing production of cytokines, and modifying fatty acid turnover. Induction of HO-1 might provide a new approach for treatment of steatohepatitis.

MeCP2 Controls an Epigenetic Pathway That Promotes Myofibroblast Transdifferentiation and Fibrosis

2009-10-19

Background & Aims: Myofibroblast transdifferentiation generates hepatic myofibroblasts, which promote liver fibrogenesis. The peroxisome proliferator-activated receptor γ (PPARγ) is a negative regulator of this process. We investigated epigenetic regulation of PPARγ and myofibroblast transdifferentiation.Methods: Chromatin immunoprecipitation (ChIP) assays assessed the binding of methyl-CpG binding protein 2 (MeCP2) to PPARγ and chromatin modifications that silence this gene. MeCP2−/y mice and an inhibitor (DZNep) of the epigenetic regulatory protein EZH2 were used in the carbon tetrachloride model of liver fibrosis. Liver tissues from mice were assessed by histologic analysis; markers of fibrosis were measured by quantitative polymerase chain reaction (qPCR). Reverse transcription PCR detected changes in expression of the microRNA miR132 and its target, elongated transcripts of MeCP2. Myofibroblasts were transfected with miR132; PPARγ and MeCP2 expressions were analyzed by qPCR or immunoblotting.Results: Myofibroblast transdifferentiation of hepatic stellate cells is controlled by a combination of MeCP2, EZH2, and miR132 in a relay pathway. The pathway is activated by down-regulation of miR132, releasing the translational block on MeCP2. MeCP2 is recruited to the 5′ end of PPARγ, where it promotes methylation by H3K9 and recruits the transcription repressor HP1α. MeCP2 also stimulates expression of EZH2 and methylation of H3K27 to form a repressive chromatin structure in the 3′ exons of PPARγ. Genetic and pharmacologic disruptions of MeCP2 or EZH2 reduced the fibrogenic characteristics of myofibroblasts and attenuated fibrogenesis.Conclusions: Liver fibrosis is regulated by an epigenetic relay pathway that includes MeCP2, EZH2, and miR132. Reagents that interfere with this pathway might be developed to reduce fibrogenesis in chronic liver disease.

Biliary Acute Pancreatitis in Mice is Mediated by the G-Protein−Coupled Cell Surface Bile Acid Receptor Gpbar1

George Perides, Johanna M. Laukkarinen, Galya Vassileva, Michael L. Steer — 2009-11-09

Background & Aims: The mechanisms by which reflux of bile acids into the pancreas induces pancreatitis are unknown. We reasoned that key events responsible for this phenomenon might be mediated by Gpbar1, a recently identified and widely expressed G-protein−coupled, cell surface bile acid receptor.Methods: Acute pancreatitis was induced in wild-type and Gpbar1−/− mice by either retrograde ductal infusion of taurolithocholic acid-3-sulfate (TLCS) or supramaximal secretagogue stimulation with caerulein. In vitro experiments were performed in which acini obtained from wild-type and Gpbar1−/− mice were exposed to either submicellar concentrations of TLCS (200−500 μM) or a supramaximally stimulating concentration of caerulein (10 nM).Results: Gpbar1 is expressed at the apical pole of acinar cells and its genetic deletion is associated with reduced hyperamylasemia, edema, inflammation, and acinar cell injury in TLCS-induced, but not caerulein-induced, pancreatitis. In vitro, genetic deletion of Gpbar1 is associated with markedly reduced generation of pathological calcium transients, intracellular activation of digestive zymogens, and cell injury when these responses are induced by exposure to TLCS, but not when they are induced by exposure to caerulein.Conclusions: Gpbar1 may play a critical role in the evolution of bile-acid−induced pancreatitis by coupling exposure to bile acids with generation of pathological intracellular calcium transients, intra-acinar cell zymogen activation, and acinar cell injury. Acute biliary pancreatitis may be a “receptor-mediated” disease and interventions that interfere with Gpbar1 function might prove beneficial in the treatment and/or prevention of biliary acute pancreatitis.

Cathepsin L Inactivates Human Trypsinogen, Whereas Cathepsin L-Deletion Reduces the Severity of Pancreatitis in Mice

2009-11-09

Background & Aims: Acute pancreatitis is characterized by an activation cascade of digestive enzymes in the pancreas. The first of these, trypsinogen, can be converted to active trypsin by the peptidase cathepsin B (CTSB). We investigated whether cathepsin L (CTSL) can also process trypsinogen to active trypsin and has a role in pancreatitis.Methods: In CTSL-deficient (Ctsl−/−) mice, pancreatitis was induced by injection of cerulein or infusion of taurocholate into the pancreatic duct. Human tissue, pancreatic juice, mouse pancreatitis specimens, and recombinant enzymes were studied by enzyme assay, immunoblot, N-terminal sequencing, immunocytochemistry, and electron microscopy analyses. Isolated acini from Ctsl−/− and Ctsb−/− mice were studied.Results: CTSL was expressed in human and mouse pancreas, colocalized with trypsinogen in secretory vesicles and lysosomes, and secreted into pancreatic juice. Severity of pancreatitis was reduced in Ctsl−/− mice, whereas apoptosis and intrapancreatic trypsin activity were increased. CTSL-induced cleavage of trypsinogen occurred 3 amino acids toward the C-terminus from the CTSB activation site and resulted in a truncated, inactive form of trypsin and an elongated propeptide (trypsinogen activation peptide [TAP]). This elongated TAP was not detected by enzyme-linked immunosorbent assay (ELISA) but was effectively converted to an immunoreactive form by CTSB. Levels of TAP thus generated by CTSB were not associated with disease severity, although this is what the TAP-ELISA is used to determine in the clinic.Conclusions: CTSL inactivates trypsinogen and counteracts the ability of CTSB to form active trypsin. In mouse models of pancreatitis, absence of CTSL induces apoptosis and reduces disease severity.

February CME Exam 1 Questions

2009-12-21

February CME Exam 2 Questions

2009-12-21

IBD Guide 2009 CME Exam 3

2009-12-23

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

2010-02-01

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC).

AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

Francis A. Farraye, Robert D. Odze, Jayne Eaden, Steven H. Itzkowitz — 2010-02-01

Podcast interview: www.gastro.org/gastropodcast.

Antidepressants for Irritable Bowel Syndrome: Reappraisal for the Nondepressed

Lauren B. Gerson — 2009-12-21

Ford AC, Talley NJ, Schoenfeld PS, et al. (Gastroenterology Division, McMaster University, Ontario, Canada; Department of Medicine, Mayo Clinic, Jacksonville, Florida; Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, Michigan; Department of Medicine, Cork University Hospital, Cork, Ireland). Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–378.

Reply

Alexander C. Ford — 2009-12-21

I am very grateful to Dr Gerson for drawing attention to our recent systematic review and meta-analysis (Gut 2009;58:367–378). This was the first published study to conclude that antidepressants were effective as primary therapy for the treatment of irritable bowel syndrome (IBS). A previous systematic review and meta-analysis had examined this issue (Cochrane Database Syst Rev 2005;2:CD003460). However, errors in its conduct, including failure to identify published eligible studies available at the time the review was conducted, inclusion of ineligible studies, and errors in dichotomous data extraction, led the authors to erroneously conclude that these drugs were of no benefit for treatment of patients who had IBS (Am J Gastroenterol 2009;doi:10.1038/ajg.2009.658). A limitation of some of the randomized, controlled trials (RCTs) identified by both these meta-analyses was the lack of any adjustment for the presence of coexistent anxiety or depression among the patients they recruited.

Failure of Interferon to Prevent Disease Progression and Liver Cancer in Hepatitis C Virus Infection: Proof of Absence or Absence of Proof?

Carlos Rodríguez de Lope, Jordi Bruix — 2009-12-21

Di Bisceglie AM, Shiffman ML, Everson GT, et al, HALT-C trial investigators. (Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri). Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429–2441.

Gut Microbiota Control Gut Permeability Through GLP-2

Alastair J.M. Watson, Carrie A. Duckworth — 2009-12-21

Cani PD, Possemiers S, Van de Wiele T, et al. (Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Louvain Drug Research Unit, Université catholique de Louvain, Brussels, Belgium). Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–1103.

Reply

Patrice D. Cani, Nathalie M. Delzenne — 2009-12-21

We appreciate the interest that our work has generated. We would like to thank Professors Watson and Duckworth for raising the relevant question whether other mechanisms and/or tight junction proteins are involved in the control of the gut permeability through the gut microbiota and endogenous GLP-2 production. We would like to specifically focus our response on the following comment: “Further studies are warranted to determine whether the observed changes in barrier function are mediated by occludin and/or ZO-1 alone or in combination with other tight junction associated molecules such as the claudins and JAMs, and whether these other molecules are implicated in barrier response to GLP-2 with occludin and ZO-1 having bystander roles only.”

Are Immunoglobulin G4-Positive Multiorgan Lymphoproliferative Syndrome and Autoimmune Pancreatitis Different Manifestations of a Common Clinicopathologic Entity?

Tsutomu Chiba — 2009-12-21

Masaki Y, Dong L, Kurose N, et al. (Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan). Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009;68:1310–1315.

Reply

Yasufumi Masaki, Hisanori Umehara — 2009-12-21

We appreciated the Selected Summary entitled “Are IgG4-positive multiorgan lymphoproliferative syndrome and autoimmune pancreatitis different manifestations of a common clinicopathological entity?” by Dr Chiba. As Dr Chiba mentioned, our concept of IgG4-positive multiorgan lymphoproliferative syndrome (IgG4+MOLPS; Ann Rheum Dis 2009;68:1310–1315) shares many similar clinical features and laboratory findings observed in AIP (J Gastoenterol 2008;43:409–418), especially in LPSP (Am J Dig Dis 1961;6:688–698). In general, we agree with Dr Chiba that IgG4+MOLPS and AIP are the same disease entity, although several differences in histopathologic features and frequencies of affected organs still exist between the 2 diseases. Beside “IgG4+MOLPS,” there are many synonyms, such as multifocal idiopathic fibrosclerosis (Ann Intern Med 1967;66:884–892), IgG4-related autoimmune disease (J Gastroenterol 2003;38:982–984), systemic IgG4-related plasmacytic disease (Mod Rheumatol 2006;16:335–340), IgG4-related sclerosing disease (J Gastroenterol 2006;41:613–625), and IgG4-associated systemic disease (Pancreas 2009;38:523–526), all of which may refer to the same conditions. To evaluate these IgG4-related features and establish the new clinical entity, specialists in various clinical fields need to share the common concept of “IgG4-related diseases.”

Probiotics in Pediatric Medicine

Jeffry A. Katz — 2009-12-21

If you Google “probiotics,” you get >2 million hits; PubMed yields >5000 scientific articles on the topic; and both Time and Newsweek ran pieces on probiotics and gut flora in 2008. Lots of patients take probiotics, lots of physicians recommend probiotics for the management of various gastrointestinal symptoms, and more and more companies are marketing probiotic foods and supplements. Despite all this intense interest in the field of probiotics and gut health, it can be challenging for the clinician to find an unbiased, evidence-based, and comprehensive evaluation of probiotics. Probiotics in Pediatric Medicine, a 352-page, 24-chapter, multi-author book, fills this role quite nicely, providing an excellent, thorough, and complete reference text focused on the normal physiology of gut microbiota in children and the role of probiotic bacteria in childhood health and disease.

Understanding the Irritable Gut

Monthira Maneeratanaporn, William D. Chey — 2009-12-21

The functional gastrointestinal disorders (FGIDs) encompass a diverse group of conditions that are defined by the presence of characteristic symptoms. Because no reliable or reproducible biomarkers are currently available, these disorders are defined on the basis of symptom clusters. The Rome Foundation is an “independent not for profit organization that provides support for activities designed to create scientific data and educational information to assist in the diagnosis and treatment of functional gastrointestinal disorders.” (http://www.romecriteria.org/about/). The stated mission of the Rome Foundation is to “improve the lives of people with functional GI disorders.” The Rome Foundation has provided leadership and direction in the development of diagnostic criteria for the various FGIDs. In fact, the Rome criteria have become the de facto gold standard for defining FGIDs in clinical research trials. Unfortunately, the Rome criteria have not met with the same level of acceptance in the offices of every day clinicians. In recent years, the Rome Foundation has been making efforts to bridge the gap between clinical research and clinical practice.

Gastrointestinal Cancer Atlas for Endoscopic Therapy

Ravi N. Sharaf, Jacques Van Dam — 2009-12-21

Early diagnosis of cancer is the key to cure. With small (<1 cm) and minute (<5 mm) lesions, gastroenterologists have an essential role not only in endoscopic cancer detection but also in treatment through endoscopic mucosal resection and endoscopic submucosal dissection. The technical expertise of the Cancer Institute Hospital of JFCR, Tokyo, Japan, in managing such small malignancies is succinctly presented in the Gastrointestinal Cancer Atlas for Endoscopic Therapy.

Role of Viral Factors in Modifying Weight-Related Effects on Disease Progression of Chronic Hepatitis C Patients

Ching–Sheng Hsu, Jia–Horng Kao — 2009-12-21

We read with great interest the article by Everhart et al. Their analyses were based on the data from the Hepatitis C Anti-viral Long-term Treatment Against Cirrhosis (HALT-C) trail, a prospective, randomized trial to evaluate the histologic and clinical outcomes of long-term, maintenance pegylated interferon on patients with chronic hepatitis C (CHC) infection who failed to have a sustained virologic response to initial therapy. The authors examined the effects of weight-related conditions on disease outcomes, and demonstrated that insulin resistance, the presence of Mallory bodies, as well as weight change between baseline and 1 year after randomization were associated with outcomes of CHC patients, implying that improvement in weight-related factors might modify disease progression. Although their findings provide additional information to this area of active investigation, several issues deserve further discussion.

Reply

James E. Everhart, Anna S. Lok — 2009-12-21

We appreciate the interest of Dr Hsu and Dr Kao in our paper. Our response to the several comments in the order they were provided is as follows. Insulin resistance, as estimated by HOMA2, was the dominant weight-related risk factor for liver disease progression. However, we made no claim that insulin resistance caused clinical outcomes. We agree that interventions to reduce insulin resistance and related metabolic abnormalities should be evaluated in those with advanced hepatitis C disease.

The American College of Gastroenterology Irritable Bowel Syndrome Monograph: Translating Systematic Review Data to Clinical Practice

2009-12-21

We write in response to the article by Drs Camilleri and Mayer in a recent issue of Gastroenterology. The article raises some concerns about the interpretation of systematic reviews and evidence-based medicine, in particular with regard to the recently updated American College of Gastroenterology (ACG) monograph on the management of irritable bowel syndrome (IBS). We agree with their general point of view and indeed have discussed these same issues in a recent article with a curiously similar title. There are, however, specific points they raise that need further clarification.

Reply

Michael Camilleri, Emeran A. Mayer — 2009-12-21

The comments on our article by Moayyedi et al show that there is a great deal of agreement in the need for more high-quality, large-scale, randomized, controlled trials for the treatment of irritable bowel syndrome (IBS). Moayyedi et al do not disagree with many specific weaknesses identified in our commentary in individual trials included in many meta-analyses.

Correction

2010-02-01

Lindley RM, Hawcutt DB, Connell MG, et al. Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon. Gastroenterology 2008;135:205–216.

Correction

2010-02-01

Wong RC. Nonvariceal upper gastrointestinal hemorrhage: probing beneath the surface. Gastroenterology 2009;137:1897–1902. On page 1900 in the above article, the final sentence of the 3rd paragraph incorrectly notes a 0.7 mm gastric ulcer as a cause of recurrent GI bleeding. The sentence should correctly read, “Finally, it is also uncertain whether current EUS imaging has sufficient resolution to reliably detect blood flow in subsurface vessels associated with bleeding peptic ulcers, which, in a seminal study on recurrently bleeding gastric ulcers (Swain et al17), the bleeding artery had a mean external diameter of 0.7 mm (range 0.1–1.8 mm).” to denote that the bleeding artery, (not ulcer) was the cause of recurrent GI bleeding.

Correction

2010-02-01

Colletti M, Cicchini C, Conigliaro A, et al. Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology 2009;137:660–672.

Information for Authors

2010-02-01

Gastroenterology publishes clinical and basic studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The types of articles Gastroenterology publishes include original papers, review articles, and special category manuscripts. Manuscripts must be prepared in accordance with the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” developed by the International Committee of Medical Journal Editors (http://www.icmje.org). Gastroenterology is a member of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org.uk).

Cover 1

2010-02-01

Editorial Board

2010-02-01

Information for Authors and Readers

2010-02-01

Gastroenterology is the premiere journal in the field of gastrointestinal disease and is led by an internationally renowned board of editors. As the official journal of the AGA Institute, Gastroenterology delivers up-to-date and authoritative coverage of both basic and clinical gastroenterology and hepatology. Regular features include research and perspectives by leading authorities, reports on the latest technologies for diagnosing and treating digestive diseases, images illustrating important clinical findings, reviews of scholarly media, medical news, meeting summaries, video abstracts, and monthly podcasts. Gastroenterology also bridges the gap between basic and clinical science by publishing comprehensive reviews on important topics such as pancreatitis and liver disease.

Forthcoming Articles 1

2010-02-01

Comparison of Probe Based Confocal Laser Endomicroscopy With Virtual Chromoendoscopy for Classification of Colon Polyps Anna M. Buchner, Muhammad W. Shahid, Michael G. Heckman, Murli Krishna, Marwan Ghabril, Muhammad Hasan, Julia E. Crook, Victoria Gomez, Massimo Raimondo, Timothy Woodward, HerbertC. Wolfsen, and Michael B. Wallace

Forthcoming Articles 2

2010-02-01

Adverse Outcomes in Alaska Natives Who Recovered From or Have Chronic Hepatitis C Infection Brian J. McMahon, Dana Bruden, Michael G. Bruce, Stephen Livingston, Carol Christensen, Chriss Homan, Thomas W. Hennessy, James Williams, Daniel Sullivan, Hugo R. Rosen, and David Gretch

Forthcoming Articles 3

2010-02-01

Conditional Deletion of Ikappab-Kinase Beta (Ikkβ) Accelerates Helicobacter-Dependent Gastric Apoptosis, Proliferation and Preneoplasia Wataru Shibata, Shigeo Takaishi, Sureshkumar Muthupalani, D. Mark Pritchard, Mark T. Whary, Arlin B. Rogers, James G. Fox, Kelly S. Betz, Klaus H. Kaestner, Michael Karin, and Timothy C. Wang

Forthcoming Articles 4

2010-02-01

Cell-Type Specific Gene Expression Signature in Liver Underlies Response to Interferon Therapy in Chronic Hepatitis C Infection Limin Chen, Ivan Borozan, Jing Sun, Maha Guindi, Sandra Fischer, Jordan Feld, Nitasha Anand, Jenny Heathcote, Aled M. Edwards, and Ian D. McGilvray

Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship

2010-02-01

Copyright Assignment. In consideration of the American Gastroenterological Association (AGA) Institute (the “AGA Institute”) taking action to review and credit the below-identified submission (the “Manuscript”), and for other valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the undersigned authors and/or creators (the “Authors”), jointly and severally, hereby transfer, convey, and assign to the AGA Institute, free and clear of any liens, licenses or encumbrances, the entire right, title, and interest in and to the Manuscript throughout the world, including without limitation in and to any and all copyrights for the Manuscript (including but not limited to rights to copy, publish, excerpt, collect royalties and make derivative works) in print, electronic, Internet, broadcast, and all other forms and media now or hereafter known, and for any and all causes of action heretofore accrued in Authors' favor for infringement of the aforesaid copyrights, to have and to hold the same unto the AGA Institute, its successors and assigns, for and during the existence of the aforesaid copyrights, and all renewals and extensions thereof. At any time and from time to time hereafter, the Authors shall upon the AGA Institute's written request take any and all steps and execute, acknowledge and deliver to the AGA Institute any and all further instruments and assurances necessary or expedient in order to vest the aforesaid copyrights and causes of action more effectively in the AGA Institute. The Authors retain the nonexclusive permission to use all or part of the Manuscript in future works of their own in a noncompeting way, provided proper copyright credit is given to the AGA Institute. Should the AGA Institute finally determine that it will not publish the Manuscript, the AGA Institute agrees to assign its rights therein back to the Authors. (Note: material prepared by employees of the federal government in the course of their official duties may not be copyrightable.)

Gastroenterology

This Month in Gastroenterology

More Than $500 Million Spent for Lobbying by Health Care Interest Groups in 2009

GINA, Imperfect But Official

Sustained Virologic Response to Hepatitis C Virus Therapy and Spontaneous Viral Clearance Found Linked to Genotype

New Appointments to the Board of Editors

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

The Development of Clinical Guidelines by the American Gastroenterological Association

Optical Molecular Imaging Approaches in Colorectal Cancer

IV or Not IV? Just One of the Antibiotic Questions in Whipple's Disease

Sonic Hedgehog: A Link Between Inflammation, Gastric Atrophy, and Acid Suppression?

The Role of Bile Acids in Gallstone-Induced Pancreatitis

Colonoscopy: An Unusual Complication

Recurrent Nausea, Vomiting, and Abdominal Pain

Esophageal Blebs and Blisters

A Georgian Woman With Dysphagia and Stridor

An Unusual Liver Mass

In Vivo Molecular Imaging of Colorectal Cancer With Confocal Endomicroscopy by Targeting Epidermal Growth Factor Receptor

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Postprandial Changes in Small Bowel Water Content in Healthy Subjects and Patients With Irritable Bowel Syndrome

Efficacy of Ceftriaxone or Meropenem as Initial Therapies in Whipple's Disease

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands

Des-γ-Carboxy Prothrombin and α-Fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma

Peginterferon Alfa-2a/Ribavirin for 48 or 72 Weeks in Hepatitis C Genotypes 1 and 4 Patients With Slow Virologic Response

Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression

Screening and Early Treatment of Migrants for Chronic Hepatitis B Virus Infection Is Cost-Effective

Asymptomatic Pancreatic Cystic Neoplasms: Maximizing Survival and Quality of Life Using Markov-Based Clinical Nomograms

History of Peptic Ulcer Disease and Pancreatic Cancer Risk in Men

Loss of Parietal Cell Expression of Sonic Hedgehog Induces Hypergastrinemia and Hyperproliferation of Surface Mucous Cells

Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog

Protease-Activated Receptor-1 Down-regulates the Murine Inflammatory and Humoral Response to Helicobacter pylori

Inhibition of HDAC9 Increases T Regulatory Cell Function and Prevents Colitis in Mice

Mesalamine Inhibits Epithelial β-Catenin Activation in Chronic Ulcerative Colitis

Prolyl Hydroxylase-3 Is Down-regulated in Colorectal Cancer Cells and Inhibits IKKβ Independent of Hydroxylase Activity

Reg IV Regulates Normal Intestinal and Colorectal Cancer Cell Susceptibility to Radiation-Induced Apoptosis

CDX Transcription Factors Positively Regulate Expression of Solute Carrier Family 5, Member 8 in the Colonic Epithelium

The Intestinal Nuclear Receptor Signature With Epithelial Localization Patterns and Expression Modulation in Tumors

Lysophosphatidic Acid Stimulates the Intestinal Brush Border Na+/H+ Exchanger 3 and Fluid Absorption via LPA5 and NHERF2

Release of 5-Hydroxytryptamine From the Mucosa Is Not Required for the Generation or Propagation of Colonic Migrating Motor Complexes

Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection

Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B

Heme Oxygenase-1 Protects Against Steatohepatitis in Both Cultured Hepatocytes and Mice

MeCP2 Controls an Epigenetic Pathway That Promotes Myofibroblast Transdifferentiation and Fibrosis

Biliary Acute Pancreatitis in Mice is Mediated by the G-Protein−Coupled Cell Surface Bile Acid Receptor Gpbar1

Cathepsin L Inactivates Human Trypsinogen, Whereas Cathepsin L-Deletion Reduces the Severity of Pancreatitis in Mice

February CME Exam 1 Questions

February CME Exam 2 Questions

IBD Guide 2009 CME Exam 3

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

Antidepressants for Irritable Bowel Syndrome: Reappraisal for the Nondepressed

Reply

Failure of Interferon to Prevent Disease Progression and Liver Cancer in Hepatitis C Virus Infection: Proof of Absence or Absence of Proof?

Gut Microbiota Control Gut Permeability Through GLP-2

Reply

Are Immunoglobulin G4-Positive Multiorgan Lymphoproliferative Syndrome and Autoimmune Pancreatitis Different Manifestations of a Common Clinicopathologic Entity?

Reply

Probiotics in Pediatric Medicine

Understanding the Irritable Gut

Gastrointestinal Cancer Atlas for Endoscopic Therapy

Role of Viral Factors in Modifying Weight-Related Effects on Disease Progression of Chronic Hepatitis C Patients

Reply

The American College of Gastroenterology Irritable Bowel Syndrome Monograph: Translating Systematic Review Data to Clinical Practice

Reply

Correction

Correction

Correction

Information for Authors

Cover 1

Editorial Board

Table of Contents

Information for Authors and Readers

Forthcoming Articles 1

Forthcoming Articles 2

Forthcoming Articles 3

Forthcoming Articles 4

Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship