Les derniers abstracts de la revue Gastroenterology :

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Date de mise en ligne : Mercredi 01 février 2012
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http://www.gastrojournal.org/article/PIIS0016508511017203/abstract?rss=yes

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Date de mise en ligne : Lundi 19 décembre 2011
Anson W. Lowe, Richard H. Moseley
Covering the Cover
Tobacco remains the most preventable cause of death in the world. Evidence supporting a carcinogenic role for tobacco has now expanded to 18 cancers. In this issue of Gastroenterology, 2 studies provide evidence that tobacco use, mainly in the form of cigarette smoking, increases the risk of colorectal adenoma formation in patients with the Lynch syndrome, and the development of high-grade dysplasia and cancer among patients with Barrett's esophagus. The 2 studies indicate that lifestyle changes such as abstention from tobacco use can affect predisposed individuals.

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Date de mise en ligne : Lundi 19 décembre 2011
David Lieberman
How Good Is Your Dentist? How Good Is Your Endoscopist? The Quality Imperative
Recently, I polled my GI friends to determine how they selected their dentist, and whether their dentist practiced “high-quality� dentistry. Most had received recommendations from friends, and selected a dentist based on convenience of location. I asked if they were happy with their dentist, and if the dentist was “above average,� “average,� or “below average� in terms of dental skills and expertise. Every dentist who takes care of my friends and colleagues is “above average.� Apparently, dentistry is like Lake Wobegon, where “all of the children are above average.� Then, I asked, “How do you know if your dentist is above average?� Did the dentist use low-dose digital imaging to reduce radiation; monitor and report rates of infection; report the frequency of repeat fillings or crowns, root-canal experience, overall rates of complications, instrument sterilization, and more? Not one of my quality-conscious friends had considered these elements when selecting their dentist. If they had asked about these quality metrics, I suspect that most dentists would not be prepared with the answers.

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Date de mise en ligne : Lundi 19 décembre 2011
Hashem B. El–Serag
Writing and Publishing Scientific Papers
Published scientific papers are essential to disseminate research findings, and publications are a measure of academic productivity assessed for promotion and grant application. However, these are not perhaps the most important benefits of writing. As M. J. Mahoney once commented, “I would urge you to write not because it is a good thing, not because it is nice to see your name in print, but rather because you will really get to know a field only if you contribute to it� (Mahoney MJ, Psychology of the Scientist 1979). For most people, writing is an acquired skill, and success requires a continuum of self-discipline, basic rules and habits, and continuing practice. In addition to good writing, publishing in a scientific journal requires good science and a strategic approach that starts from idea generation to manuscript proofing. In this piece, I share with you my take on writing and publishing. The opinions expressed here reflect my experience with the process and represent advice from mentors and colleagues, reading books on writing, and attending a few workshops. Despite the frequent use of the word should, as I express my views and suggestions, I acknowledge that others may see things differently.

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Date de mise en ligne : Lundi 19 décembre 2011
Gregory S. Sayuk, Ikuo Hirano, James T. Fitzgerald, R. Brent Stansfield, Betty A. Armbruster, Tamara N. Jones, Joy Akinyi, Charles E. Willis, AGA Institute's GTE Subcommittee
AGA Gastroenterology Training Exam (GTE): A Progress Report
Subspecialty fellowship program directors (PDs) are keenly interested in monitoring and enhancing their trainees' academic progress throughout their fellowship experience. In addition to assessing trainee clinical acumen and knowledge base, PDs are required to demonstrate growth in clinical performance to validate advancement to subsequent training years, for which training programs have been confronted with increasing requirements by the Accreditation Council for Graduate Medical Education (ACGME). The ACGME has established core competency domains under which trainee progress can be objectively evaluated (medical knowledge, patient care, practice-based learning and improvement, systems-based practice, interpersonal and communication skills, and professionalism). These assessments potentially identify strengths and weaknesses at the individual level, prompting additional study and clinical exposures in these domains. Further, these evaluations facilitate the PDs' identification of potential strengths and deficiencies in fellowship training at the institution, such that one can optimize the focus of future didactic lectures, faculty and program development, and potentially even strategic faculty recruitment.

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Date de mise en ligne : Lundi 19 décembre 2011
Lisa L. Strate
Diverticulosis and Dietary Fiber: Rethinking the Relationship
See “A high-fiber diet does not protect against asymptomatic diverticulosis,� by Peery AF, Barrett PR, Park D, et al, on page 266.

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Date de mise en ligne : Lundi 26 décembre 2011
James F. Trotter, James E. Everhart
Outcomes Among Living Liver Donors
See “Estimates of early death, acute liver failure, and long-term mortality among live liver donors,� by Muzaale AD, Dagher NN, Montgomery RA, et al, on page 273.

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Date de mise en ligne : Mercredi 21 décembre 2011
Arnaud Galbois, Fabien Stenard, Dimitri Margetis
A Ghost Pancreas
Question: A 73-year-old man without medical history was admitted to the Intensive Care Unit (ICU) for shock. The day before ICU admission, he suddenly experienced nausea and abdominal pain, and vomited twice. On admission, core temperature was 37.9°C, heart rate was 86 beats/min, and blood pressure was 70/36 mmHg. Painful abdominal distension without occlusion was noticed. Arterial blood gases on room air showed: pH, 7.19; HCO3−, 9 mmol/L; PaCO2, 24 mmHg; PaO2, 105 mmHg; lactate, 9.3 mmol/L. Blood work showed: glycemia, 21.4 mmol/L; creatininemia, 306 μmol/L; hemoglobin, 16 g/dL; leukocytes, 9.4 g/L; platelets, 153 g/L; alanine aminotransferase, 412 IU/L; aspartate aminotransferase, 204 IU/L; lactate dehydrogenase, 1586 IU/L; alkaline phosphatase, 111 IU/L; total bilirubin, 42 μmol/L, and lipase, 1502 IU/L. A massive gas accumulation located in the pancreatic region was observed on abdominal radiography (, arrows). Abdominal computed tomography confirmed that the normal pancreatic parenchyma had totally disappeared and was infiltrated by gas (, C, arrows). Gas in the gallbladder and the biliary tract (arrowheads) and pneumoperitoneum (large arrows) were also visible ().

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Date de mise en ligne : Mercredi 21 décembre 2011
Ahmad ALHarbi, Majid Almadi, Andrew Szilagyi
An Unusual Cause of Upper Gastrointestinal Bleeding
Question: A 45-year-old man presented to the hospital with coffee ground emesis, melena, and syncope. Initial evaluation revealed signs of hemodynamic instability with a heart rate of 120 beats/min and a blood pressure of 88/62 mmHg. Initial laboratory investigations were normal except for a decreased hemoglobin level of 7.8 g/dL (normal, 13.0–17.0). After resuscitation, an evaluation for suspected upper gastrointestinal bleeding using an esophagogastroduodenoscope was performed; a focal area of mucosal erythema was noticed in the fundus with enlarged mucosal folds, no blood or active bleeding was seen. Endoscopic ultrasonography (EUS) was performed and revealed multiple, well-circumscribed, anechoic, tubular structures, that demonstrated vascular flow on color Doppler (), the appearance was consistent with that of isolated gastric fundal varices. A hypoechoic, heterogeneous, poorly defined mass lesion arising from the tail of the pancreas, measuring 25 × 19 mm, was identified by EUS. Fine needle aspiration was performed using a 22-gauge needle (), but did not yield a diagnosis. Computed tomography was performed and demonstrated splenomegaly of 13 cm, chronic splenic vein thrombosis with increased gastrosplenic collaterals, and focal enlargement of the mid pancreatic body. The patient underwent splenectomy for long-term control of variceal bleeding and the pancreatic mass was resected ().

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Date de mise en ligne : Mercredi 21 décembre 2011
Luc Biedermann, Ariana Gaspert, Christoph Gubler
The Way to a Man's Stomach Is Through His Heart
Question: A 74-year-old man underwent gastroscopy owing to severe nausea, vomitus, and fluctuating mild epigastric discomfort of 2 months' duration. He had known chronic renal failure with a creatinine clearance of 32 mL/min (Modification of Diet in Renal Disease formula), diabetes mellitus, and coronary heart disease with a history of myocardial infarction. The patient reported initiation of his current gastrointestinal (GI) symptoms within several hours after a coronary angiography with stent implantation in the right coronary artery owing to worsening chest pain. He attributed his new symptoms to the actual change of his cardiac medication after percutaneous coronary angiography. A marked deterioration in the patient's current renal function (glomerular filtration rate, 14 mL/min) was notable, which was attributed to possible contrast medium–induced nephropathy and prerenal exacerbation owing to ongoing vomiting and decreased liquid intake. Peripheral blood smear showed a slight eosinophilia (1860/μL; normal 0–700). Upper endoscopy revealed numerous macular non protuberant livid lesions in the corpus antrum transition of the stomach () as well as signs of gastritis in the antral mucosa. Biopsies of the livid lesions were obtained with noticeable friability of gastric mucosa.

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Date de mise en ligne : Mercredi 21 décembre 2011
Yang–Sheng Lin, Wei–Sheng Wang, Ming–Jen Chen
Emphysematous Changes of the Liver
Question: A 59-year-old woman presented to the emergency department with nausea and epigastric pain for 2 days preceded by 2 weeks of anorexia. Several years ago, she was diagnosed as glucose intolerant, but did not receive regular follow-up. On examination, her temperature was 34.8°C and her blood pressure was 81/53 mm Hg. She had icteric sclera, palpated tenderness in the upper right quadrant of the abdomen, and hepatomegaly (liver span of 14 cm at the midclavicular line). Blood tests showed a leukocyte count of 5700/mm3, (55% neutrophils; 19% lymphocytes), a glucose level of 347 mg/100 mL, an aspartate aminotransferase of 10,920 U/L, an alanine aminotransferase level of 3651 U/L, a total bilirubin of 4.8 mg/dL, and a creatinine level of 3.4 mg/100 mL. Plain film of the chest was normal, but plain film of the abdomen revealed a mottled appearance (, arrowheads) with branching radiolucencies (, arrows) in the liver. Hypotension persisted despite maximum inotropic support and the use of broad-spectrum antibiotics. She was hemodynamically unstable and died within 20 hours. A blood culture grew Klebsiella pneumoniae.

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Date de mise en ligne : Jeudi 22 décembre 2011
Stijn J.B. Van Weyenberg
To Snare a Snare, or Not to Snare?
Question: A 79-year-old man presented with a 1-year history of intermittent colicky abdominal pain, without rectal blood loss or fever. On physical examination, the abdomen was not distended, there were normal bowel sounds and no rebound tenderness or peritoneal guarding. The laboratory results were all normal. Colonoscopy revealed mild diverticulosis of the sigmoid colon. Additionally, we observed a thin, stalk-like lesion, the distal end of which seemed to be trapped in a peristaltic wave, resulting in considerable strain to the tissue, not unlike a stretched snare (). At that moment, the patient experienced abdominal pain. After the peristaltic wave had passed, the colicky pain resolved, and the entire lesion became visible (): Arising from a wide pseudo-pedicle, a 10-cm-long stalk with normal-appearing mucosa at its end, protruded in to the lumen. There was no hyperemia or congestion; neither did we observe adenomatous or hyperplastic changes.

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Date de mise en ligne : Jeudi 22 décembre 2011
Doerthe Kuester, Christian Schulz, Peter Malfertheiner
An Uncommon Cause of Epigastric Pain and Emesis
Question: A 35-year-old man presented to our gastrointestinal clinic with a 4-week history of sudden onset emesis and upper abdominal pain in the right epigastrium. Alarming symptoms, such as dysphagia, weight loss, vomiting, or gastrointestinal bleeding, were not reported. Physical examination revealed no abnormalities. Initial laboratory investigations showed elevation of alanine transaminase (54.6 U/L), alkaline phosphatase (147.6 U/L), and lactate dehydrogenase (353.4 U/L) levels. Upper gastrointestinal endoscopy revealed multiple nodular polypoid dark lesions of the esophagus (), the gastric antrum and corpus (), and the bulbus duodeni. The lesions measured 3–20 mm in diameter, were vulnerable, and were partly ulcerated. Multiple biopsy specimens of the esophagus () and gastric corpus () were sent to pathology for histologic examination.

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Date de mise en ligne : Jeudi 22 décembre 2011
Wan-Ling Miriam Wu, I-Ha Lao
A Rare but Important Cause of Acute Abdomen
Question: A 33-year-old man with history of right inguinal hernia presented with progressive abdominal pain for 1 week. On examination he had a soft right inguinal mass with diffuse peritonitis, and laboratory tests revealed an elevated white cell count (13 × 109/L). Abdominal computed tomography demonstrated a pathognomonic whirling fatty mass in the omentum (, black arrow) with diffuse abdominal/pelvic fatty infiltration (, arrowhead) extending into right inguinal canal next to the hernia (, white arrow).

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Date de mise en ligne : Jeudi 22 décembre 2011
Sumanth R. Daram, Elizabeth R. Paine, Amanda F. Swingley
Upper Gastrointestinal Bleeding in a Patient With Multiple Myeloma
Question: A 53-year-old African American woman was diagnosed with κ-light chain multiple myeloma in 2005. She underwent chemotherapy previously, and stem cell transplantation 4 months before the current hospitalization. She presented with acute upper gastrointestinal (GI) bleeding in the form of hematemesis. The patient underwent emergent esophagogastroduodenoscopy. There was no evidence of active bleeding. A multilobulated, submucosal mass, about 4 × 4 cm, with an overlying ulceration measuring about 10 mm was seen, occupying the proximal corpus along the greater curvature (). The ulcer had a nonbleeding visible vessel in its base (); this vessel was successfully ablated with bipolar cautery. Repeat GI endoscopy was performed 4 days later, which revealed the gastric mass, without evidence of bleeding or stigmata for recurrent bleeding. In addition, a small 1- to 2-mm erosion was seen on the lateral wall of the second portion of duodenum (). Biopsies were obtained from the duodenal lesion, as well as from the gastric mass. Sections from the gastric and duodenal biopsies showed dense submucosal infiltrates of highly atypical plasmacytic cells with Dutcher bodies and anaplasia. The CD138 immunohistochemical stain reacted positively with these submucosal infiltrates.

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Date de mise en ligne : Vendredi 23 décembre 2011
Sonia Radunz, Hideo A. Baba, Georgios C. Sotiropoulos
Large Tumor of the Liver and Hypoglycemic Shock in an 85-Year-Old Patient
Question: An 85-year-old woman was referred to our institution with a palpable mass in the upper abdomen. Her past medical history was unremarkable except for arterial hypertension and coronary artery disease. Lately, she had experienced frequent episodes of drenching sweats. On physical examination, a large mass was palpated in the upper abdomen. Computed tomography showed a large, heterogenous liver tumor of the left lobe measuring 17 cm in diameter (). The liver showed no signs of cirrhosis and no other lesions or pathologic findings were observed in the abdomen or the thorax. Before undergoing surgery the patient had to be treated in the intensive care unit for hypoglycemic shock (lowest blood glucose level, 32 mg/dL). Laparotomy showed an extensive, lobulated liver tumor of the left lobe with a pseudocapsule. Left hemihepatectomy was performed and the tumor was removed intact.

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Date de mise en ligne : Lundi 26 décembre 2011
Jiann–Hwa Chen, Chung–Tai Yue, Chieh–Wen Lai
Vague Abdominal Discomfort for 5 Years and a Large Upper Abdominal Mass in a 45-Year-Old Woman
Question: A 45-year-old woman with a history of a gastric ulcer 10 years ago presented to the outpatient department with vague upper abdominal discomfort for 5 years. She had no history of abdominal surgery. She denied having poor appetite and weight loss. Physical examination showed a moderately nourished lady, not anemic in appearance; a firm, large, nontender mass was distinguished in the left upper abdominal quadrant. All blood tests were normal, including tumors markers (carcinoembryonic antigen, alfa-fetoprotein, carbohydrate antigen 19-9, and carbohydrate antigen 125). Chest x-ray showed normal heart size with clear lung fields. The abdominal ultrasonography revealed a 10-cm hypoechoic heterogeneous mass at the left upper abdomen, which was located lateral to the left kidney and next to the spleen and pancreas. Abdominal computed tomography with enhancement disclosed an enhanced retroperitoneal solid tumor with contact to the left kidney and very close to the pancreas (, arrows). Endoscopic ultrasonography showed this heterogeneous tumor situated behind the stomach and it seemed to be unlikely that it originated from the stomach or pancreas.

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Date de mise en ligne : Vendredi 23 décembre 2011
Jagrati Mathur, David Limsui
Transient Ischemic Attack in a Patient With Cirrhosis
Question: A 63-year-old man presented with acute onset of slurred of speech that resolved within a few hours. He was recently diagnosed with cirrhosis secondary to hepatitis C and alcohol. He had lost 10 kg over the past year. He appeared thin and frail and was afebrile with normal vitals. Jaundice, hepatosplenomegaly, and ascites were not present. The abdomen was nondistended and nontender. His cardiac examination was normal, and he had no lymphadenopathy. Neurologic examination was normal with no asterixis. His laboratory tests showed: hemoglobin, 10 g/dL (normal, 14–18 g/dL); platelet count, 82 (normal, 140–440 K/UL); International Normalized Ratio, 1.2 (normal, 2–3); creatinine, 1 mg/dL (normal, 0.7–1.3 mg/dL); alkaline phosphatase, 127 IU/L (normal, 25–100 U/L); alanine aminotransferase, 178 IU/L (normal, 10–40 U/L); aspartate aminotransferase, 184 IU/L (normal, 8–40 U/L); and total bilirubin, 2.2 mg/dL (normal, 0.3–1.2 mg/dL). Blood cultures and carotid ultrasound were negative. Magnetic resonance imaging (MRI) of the brain showed 2 old, small, cortical-based infarcts in the frontal and left occipital lobes and was unremarkable for any acute or subacute changes. A transthoracic echocardiogram with bubble study showed a 2.5 × 2.5-cm mass in the right atrium (). Abdominal and pelvic computed tomography (CT) with contrast showed a nodular liver without mass lesions or thrombus ().

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Date de mise en ligne : Jeudi 22 décembre 2011
Jui-Shan Hsu, I-Hui Wu, Kao-Lang Liu
A Common Disease With an Unusual Complication of Acute Abdomen
Question: A previously healthy 64-year-old man presented to the emergency department with a 4-day duration of progressive and diffuse abdominal pain. The pain, seemingly unrelated to meals or postural change, began with intermittent cramps and progressed to a steady, constant ache. Physical examination revealed marked lower quadrant tenderness, diffuse peritoneal sign, and reduced bowel sounds. Deep tenderness at McBurney's point was not obvious. Laboratory investigation disclosed leukocytosis with a left shift, and the remaining tests were unremarkable. Contrast-enhanced computed tomography (CT) was performed ().

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Date de mise en ligne : Jeudi 22 décembre 2011
Ana Gonçalves, Teresa Antunes
Dysphagia in an HIV Patient: A Rare Culprit
Question: A 37-year-old Caucasian woman sought medical attention for intermittent dysphagia for both liquids and solids, loss of appetite, and a 5-kg weight loss in the past 3 months. She denied other symptoms such as fever, productive cough, or diarrhea. The patient history was significant for HIV-1; infection was diagnosed 15 years previously. She was noncompliant with medical follow-up or antiretroviral therapy for the last 5 years. On physical examination, the patient was visibly malnourished, with a body mass index of 15 kg/m2. Chest and heart examination were unremarkable. Abdominal examination revealed a diffusely tender abdomen without hepatosplenomegaly. There were no palpable lymph nodes. Laboratory assessment revealed a normocytic normochromic anemia of 11.6 g/dL, low platelet count of 120 × 109/L, and a normal white blood count. The CD4 count was inferior to 170 cells/μL. Upper endoscopy revealed that the distal third of the esophagus with profound circumferential and coalescent ulcers and friability of the mucosa (). Biopsies from the center and borders of the ulcers led us to the diagnosis (s).

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Date de mise en ligne : Vendredi 23 décembre 2011
Martin Wilhelmi, Pablo Munoz, Maria-Anna Ortner
Bleeding Polyps?
Question: A 60-year-old Caucasian woman presented with melena of 3 days' duration. It was the second episode of gastrointestinal (GI) bleeding. Fourteen days ago, colonoscopy done in another hospital revealed diverticulosis and 3 small polypoid lesions in the cecum without signs of acute bleeding. Biopsies of the lesions have been taken. Gastroscopy was normal. At admission to our hospital, the patient was hemodynamically stable. Laboratory findings showed hemoglobin level of 80 g/L (normal limits, 121–154 g/L) and thrombocytes of 34 g/L (normal limits, 140–380 g/L).

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Date de mise en ligne : Jeudi 22 décembre 2011
Javier G. Castillo, Dana Telem, Tomas M. Heimann
An Extremely Unusual and Large Cause of Anemia
Question: A 63-year-old man with a long-standing medical history of anemia presented to the gastroenterology outpatient clinic with diffuse abdominal pain, progressive dragging sensation in the left upper quadrant, and marked dizziness. Other prominent clinical symptoms included a weight loss of 15 lbs over 2 months, anorexia, and intermittent constipation. Clinical examination revealed tenderness in the left upper quadrant and massive splenomegaly. On further palpation, the spleen extended to the umbilicus, and had a smooth surface and a very firm consistency. The patient was hemodynamically stable with an arterial blood pressure of 111/56 mmHg and a heart rate of 90 beats/min. A complete blood cell count showed anemia (hemoglobin, 5.7 g/dL) and a normal platelet count. No abnormalities were found on the hemogram on a peripheral blood smear. After initial resuscitation, malignancy screenings, abdominal ultrasonography and computed tomography were performed. Ultrasonographic examination showed a large heterogeneous mass pattern measuring >30 cm ( A). The liver was mildly enlarged with no dilated intrahepatic ducts. Subsequent abdominal computed tomography confirmed the ultrasonographic findings ( B) and further revealed coarse calcifications, hypodense areas, and enhancing septations ( C).

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Date de mise en ligne : Lundi 19 décembre 2011
Marie–Annick Buendia, Ludovic Bourre, Stefano Cairo
Myc Target miRs and Liver Cancer: Small Molecules to Get Myc Sick
Primary liver cancer is a disease arising from malignant transformation of hepatocytes, which account for up to 80% of the liver tissue. In infants, the most common form of liver tumor is hepatoblastoma (HB), a rare childhood tumor that mostly affects kids <3 years old. In adults, hepatocellular carcinoma (HCC) is by far the most common form of liver malignancy.

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Date de mise en ligne : Vendredi 09 décembre 2011
Bryan D. White, Andy J. Chien, David W. Dawson
Dysregulation of Wnt/β-Catenin Signaling in Gastrointestinal Cancers
Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in gastrointestinal cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic.

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Date de mise en ligne : Lundi 07 novembre 2011
Helen G. Coleman, Shivaram Bhat, Brian T. Johnston, Damian McManus, Anna T. Gavin, Liam J. Murray
Tobacco Smoking Increases the Risk of High-Grade Dysplasia and Cancer Among Patients With Barrett's Esophagus
Background & Aims: Esophageal adenocarcinoma arises from Barrett's esophagus (BE); patients with this cancer have a poor prognosis. Identification of modifiable lifestyle factors that affect the risk of progression from BE to esophageal adenocarcinoma might prevent its development. We investigated associations among body size, smoking, and alcohol use with progression of BE to neoplasia. Methods: We analyzed data from patients with BE identified from the population-based Northern Ireland BE register, diagnosed between 1993 and 2005 with specialized intestinal metaplasia (n = 3167). Data on clinical, demographic, and lifestyle factors related to diagnosis of BE were collected from hospital case notes. We used the Northern Ireland Cancer Registry to identify which of these patients later developed esophageal adenocarcinoma, adenocarcinomas of the gastric cardia, or esophageal high-grade dysplasia. Cox proportional hazards models were used to associate lifestyle factors with risk of progression. Results: By December 31, 2008, 117 of the patients with BE developed esophageal high-grade dysplasia or adenocarcinomas of the esophagus or gastric cardia. Current tobacco smoking was significantly associated with an increased risk of progression (hazard ratio = 2.03; 95% confidence interval, 1.29−3.17) compared with never smoking, and across all strata of smoking intensity. Alcohol consumption was not related to risk of progression. Measures of body size were infrequently reported in endoscopy reports, and body size was not associated with risk of progression. Conclusions: Smoking tobacco increases the risk of progression to cancer or high-grade dysplasia 2-fold among patients with BE, compared with patients with BE that have never smoked. Smoking cessation strategies should be considered for patients with BE.

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Date de mise en ligne : Lundi 07 novembre 2011
Renate M. Winkels, Akke Botma, Fränzel J.B. Van Duijnhoven, Fokko M. Nagengast, Jan H. Kleibeuker, Hans F.A. Vasen, Ellen Kampman
Smoking Increases the Risk for Colorectal Adenomas in Patients With Lynch Syndrome
Background & Aims: Individuals with Lynch syndrome have a high risk of developing colorectal carcinomas and adenomas at a young age, due to inherited mutations in mismatch repair genes. We investigated whether modifiable lifestyle factors, such as smoking and alcohol intake, increase this risk. Methods: Using data from the GeoLynch cohort study, a prospective analysis of 386 subjects with Lynch syndrome, we calculated hazard ratios for the association between smoking and alcohol intake and development of colorectal adenoma. We used robust variance estimates in the calculation of 95% confidence intervals to account for dependency within families and adjusted for confounding by age, sex, smoking (in the analyses of alcohol intake), number of colonoscopies during the follow-up, colonic resection, and body mass index. Results: During a median follow-up of 10 months, 58 subjects developed a histologically confirmed colorectal adenoma. The hazard ratio for current smokers was 6.13 (95% confidence interval, 2.84−13.22) and for former smokers was 3.03 (95% confidence interval, 1.49−6.16) compared with never smokers. Among ever smokers, a higher number of pack-years was associated with an increased risk for colorectal adenoma (P for trend = .03). There was a trend of alcohol intake increasing the risk of colorectal adenomas, although this was not statistically significant; the hazard ratio for the highest tertile of intake (median, 22 g/day) vs the lowest tertile (median, 0.4 g/day) was 1.56 (95% confidence interval, 0.71−3.43). Conclusions: Among people with Lynch syndrome, current smokers have an increased risk of colorectal adenomas. Former smokers have a lower risk than current smokers, but greater risk than never smokers. Individuals with Lynch syndrome should be encouraged to avoid smoking.

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Date de mise en ligne : Lundi 07 novembre 2011
David A. Ahlquist, Hongzhi Zou, Michael Domanico, Douglas W. Mahoney, Tracy C. Yab, William R. Taylor, Malinda L. Butz, Stephen N. Thibodeau, Linda Rabeneck, Lawrence F. Paszat, Kenneth W. Kinzler, Bert Vogelstein, Niels Chr. Bjerregaard, Søren Laurberg, Henrik Toft Sørensen, Barry M. Berger, Graham P. Lidgard
Next-Generation Stool DNA Test Accurately Detects Colorectal Cancer and Large Adenomas
Background & Aims: Technical advances have led to stool DNA (sDNA) tests that might accurately detect neoplasms on both sides of the colorectum. We assessed colorectal neoplasm detection by a next-generation sDNA test and effects of covariates on test performance. Methods: We performed a blinded, multicenter, case-control study using archived stool samples collected in preservative buffer from 252 patients with colorectal cancer (CRC), 133 with adenomas ≥1 cm, and 293 individuals with normal colonoscopy results (controls); two-thirds were randomly assigned to a training set and one-third to a test set. The sDNA test detects 4 methylated genes, a mutant form of KRAS, and the α-actin gene (as a reference value) using quantitative, allele-specific, real-time target and signal amplification; it also quantifies hemoglobin. We used a logistical model to analyze data. Results: The sDNA test identified 85% of patients with CRC and 54% of patients with adenomas ≥1 cm with 90% specificity. The test had a high rate of detection for all nonmetastatic stages of CRC (aggregate 87% detection rate for CRC stages I−III). Detection rates increased with adenoma size: 54% ≥1 cm, 63% >1 cm, 77% >2 cm, 86% >3 cm, and 92% >4 cm (P < .0001). Based on receiver operating characteristic analysis, the rate of CRC detection was slightly greater for the training than the test set (P = .04), whereas the rate of adenoma detection was comparable between sets. Sensitivities for detection of CRC and adenoma did not differ with lesion site. Conclusions: Early-stage CRC and large adenomas can be detected throughout the colorectum and with high levels of accuracy by the sDNA test. Neoplasm size, but not anatomical site, affected detection rates. Further studies are needed to validate the findings in a larger population and optimize the sDNA test.

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Date de mise en ligne : Lundi 07 novembre 2011
William J. Sandborn, Gert van Assche, Walter Reinisch, Jean–Frederic Colombel, Geert D'Haens, Douglas C. Wolf, Martina Kron, Mary Beth Tighe, Andreas Lazar, Roopal B. Thakkar
Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis
Background & Aims: Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. Methods: Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti–TNF-α) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. Results: Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P = .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004). Among anti–TNF-α naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P = .017); corresponding values for week 52 were 22% and 12.4% (P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P = .559); corresponding values for week 52 were 10.2% and 3% (P = .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. Conclusions: Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.

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Date de mise en ligne : Lundi 07 novembre 2011
Anne F. Peery, Patrick R. Barrett, Doyun Park, Albert J. Rogers, Joseph A. Galanko, Christopher F. Martin, Robert S. Sandler
A High-Fiber Diet Does Not Protect Against Asymptomatic Diverticulosis
Background & Aims: The complications of diverticulosis cause considerable morbidity in the United States; health care expenditures for this disorder are estimated to be $2.5 billion per year. Many physicians and patients believe that a high-fiber diet and frequent bowel movements prevent the development of diverticulosis. Evidence for these associations is poor. We sought to determine whether low-fiber or high-fat diets, diets that include large quantities of red meat, constipation, or physical inactivity increase risk for asymptomatic diverticulosis. Methods: We performed a cross-sectional study of 2104 participants, 30–80 years old, who underwent outpatient colonoscopy from 1998 to 2010. Diet and physical activity were assessed in interviews using validated instruments. Results: The prevalence of diverticulosis increased with age, as expected. High intake of fiber did not reduce the prevalence of diverticulosis. Instead, the quartile with the highest fiber intake had a greater prevalence of diverticulosis than the lowest (prevalence ratio = 1.30; 95% confidence interval, 1.13–1.50). Risk increased when calculated based on intake of total fiber, fiber from grains, soluble fiber, and insoluble fiber. Constipation was not a risk factor. Compared to individuals with <7 bowel movements per week, individuals with >15 bower movements per week had a 70% greater risk for diverticulosis (prevalence ratio = 1.70; 95% confidence interval, 1.24–2.34). Neither physical inactivity nor intake of fat or red meat was associated with diverticulosis. Conclusions: A high-fiber diet and increased frequency of bowel movements are associated with greater, rather than lower, prevalence of diverticulosis. Hypotheses regarding risk factors for asymptomatic diverticulosis should be reconsidered.

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Date de mise en ligne : Lundi 21 novembre 2011
Abimereki D. Muzaale, Nabil N. Dagher, Robert A. Montgomery, Sarah E. Taranto, Maureen A. Mcbride, Dorry L. Segev
Estimates of Early Death, Acute Liver Failure, and Long-term Mortality Among Live Liver Donors
Background & Aims: We sought to estimate the risk of perioperative mortality or acute liver failure for live liver donors in the United States and avoid selection or ascertainment biases and sample size limitations. Methods: We followed up 4111 live liver donors in the United States between April 1994 and March 2011 for a mean of 7.6 years; deaths were determined from the Social Security Death Master File. Survival data were compared with those from live kidney donors and healthy participants of the National Health and Nutrition Examination Survey (NHANES) III. Results: Seven donors had early deaths (1.7 per 1000; 95% confidence interval [CI], 0.7–3.5); risk of death did not vary with age of the liver recipient (1.7 per 1000 for adults vs 1.6 per 1000 for pediatric recipients; P = .9) or portion of liver donated (2.0 per 1000 for left lateral segment, 2.8 per 1000 for left lobe, and 1.5 per 1000 for right lobe; P = .8). There were 11 catastrophic events (early deaths or acute liver failures; 2.9 per 1000; 95% CI, 1.5–5.1); similarly, risk did not vary with recipient age (3.1 per 1000 adult vs 1.6 per 1000 pediatric; P = .4) or portion of liver donated (2.0 per 1000 for left lateral segment, 2.8 per 1000 for left lobe, and 3.3 per 1000 for right lobe; P = .9). Long-term mortality of live liver donors was comparable to that of live kidney donors and NHANES participants (1.2%, 1.2%, and 1.4% at 11 years, respectively; P = .9). Conclusions: The risk of early death among live liver donors in the United States is 1.7 per 1000 donors. Mortality of live liver donors does not differ from that of healthy, matched individuals over a mean of 7.6 years.

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Date de mise en ligne : Lundi 07 novembre 2011
Christine Varon, Pierre Dubus, Frédéric Mazurier, Corinne Asencio, Lucie Chambonnier, Jonathan Ferrand, Alban Giese, Nathalie Senant–Dugot, Martina Carlotti, Francis Mégraud
Helicobacter pylori Infection Recruits Bone Marrow−Derived Cells That Participate in Gastric Preneoplasia in Mice
Background & Aims: Studies in animal models have shown that bone marrow−derived cells (BMDC) could be involved in the formation of carcinomas of the upper gastrointestinal tract, including gastric carcinoma. Most gastric carcinomas in humans have been associated with chronic infection with Helicobacter pylori; we investigated the bacteria's potential to induce premalignant lesions in mice and studied the kinetics of BMDC settlement in the gastric epithelium. Methods: C57BL/6J female chimeric mice with BMDCs from male donors that express green fluorescent protein were infected with human-derived and mouse-adapted strains of H pylori and followed. We assessed development of pathologic features and recruitment of BMDC to the gastric mucosa using immunohistochemistry and fluorescent in situ hybridization analyses of gastric tissue sections. Results: Infection of mice with different strains of H pylori led to the development of chronic inflammation, hyperplasia, and mucinous metaplasia, and, later in life, of pseudointestinal metaplasia and dysplasia. After 1 year, gastric glands that contained green fluorescent protein−positive male cells were detected in 50%−90% of female chimeric mice infected with H pylori strains; the presence of these glands correlated with the development of pseudointestinal metaplasia. Twenty-two percent of H pylori−induced dysplastic lesions were composed of glands that contained epithelial BMDCs. Conclusions: H pylori infection leads to development of chronic inflammation, hyperplasia, metaplasia, and dysplasia, as well as the recruitment and accumulation of BMDC in the gastric epithelial mucosa. Nearly 25% of dysplastic lesions include cells that originate from the BM.

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Date de mise en ligne : Vendredi 11 novembre 2011
Daisuke Hayashi, Atsushi Tamura, Hiroo Tanaka, Yuji Yamazaki, Shin Watanabe, Koya Suzuki, Kazuo Suzuki, Kazuhiro Sentani, Wataru Yasui, Hiromi Rakugi, Yoshitaka Isaka, Sachiko Tsukita
Deficiency of Claudin-18 Causes Paracellular H+ Leakage, Up-regulation of Interleukin-1β, and Atrophic Gastritis in Mice
Background & Aims: Although defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. Methods: We generated knockout mice of stomach-type claudin-18, a major component of TJs in the stomach. Results: Cldn18−/− mice were afflicted with atrophic gastritis that started on postnatal day 3. This coincided with a decrease in intragastric pH due to H+ secretion from parietal cells and concomitant up-regulation of the cytokines, interleukin-1β, cyclooxygenase-2, and KC, resulting in spasmolytic polypeptide-expressing metaplasia (SPEM). Oral administration of hydrochloric acid on postnatal day 1 induced the expression of these cytokines in Cldn18−/− infant stomach, but not in Cldn18+/+ mice. A paracellular H+ leak in Cldn18−/− stomach was detected by electrophysiology and H+ titration, and freeze-fracture electron microscopy showed structural defects in the TJs, in which the tightly packed claudin-18 (stomach-type)-based TJ strands were lost, leaving a loose meshwork of strands consisting of other claudin species. Conclusions: These findings provide evidence that claudin-18 normally forms a paracellular barrier against H+ in the stomach and that its deficiency causes paracellular H+ leak, a persistent up-regulation of proinflammatory cytokines, chronic recruitment of neutrophils, and the subsequent development of SPEM in atrophic gastritis.

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Date de mise en ligne : Lundi 31 octobre 2011
Lei Ding, Zhe Lu, Oded Foreman, Rodney Tatum, Qun Lu, Randall Renegar, Jian Cao, Yan–Hua Chen
Inflammation and Disruption of the Mucosal Architecture in Claudin-7–Deficient Mice
Background & Aims: Integrity of the intestinal epithelium is required for nutrition absorption and defense against pathogens. Claudins are cell adhesion molecules that localize at tight junctions (TJs); many are expressed in the intestinal tract, but little is known about their functions. Claudin-7 is unique in that it has a stronger basolateral membrane distribution than other claudins, which localize primarily to apical TJs in the intestinal epithelium. We investigated the basolateral functions of claudin-7 and assessed the effects of disruption of Cldn7 in intestines of mice. Methods: We generated Cldn7−/− mice and examined their intestines by histology, molecular and cellular biology, and biochemistry approaches. We performed gene silencing experiments in epithelial cell lines using small interfering RNAs (siRNAs). Results: The Cldn7−/− mice had severe intestinal defects that included mucosal ulcerations, epithelial cell sloughing, and inflammation. Intestines of Cldn7−/− mice produced significantly higher levels of cytokines, the nuclear factor κB p65 subunit, and cyclooxygenase 2; they also up-regulated expression of matrix metalloproteinases (MMPs)-3 and -7. siRNA in epithelial cell lines showed that the increased expression of MMP-3 resulted directly from claudin-7 depletion, whereas that of MMP-7 resulted from inflammation. Electron microscopy analysis showed that intestines of Cldn7−/− mice had intercellular gaps below TJs and cell matrix loosening. Deletion of Cldn7 reduced expression and altered localization of the integrin α2 subunit in addition to disrupting formation of complexes of claudin-7, integrin α2, and claudin-1 that normally form in epithelial basolateral compartments of intestines. Conclusions: In mice, claudin-7 has non-TJ functions, including maintenance of epithelial cell–matrix interactions and intestinal homeostasis.

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Date de mise en ligne : Vendredi 11 novembre 2011
Maud Pinier, Gregor Fuhrmann, Heather J. Galipeau, Nathalie Rivard, Joseph A. Murray, Chella S. David, Hana Drasarova, Ludmila Tuckova, Jean–Christophe Leroux, Elena F. Verdu
The Copolymer P(HEMA-co-SS) Binds Gluten and Reduces Immune Response in Gluten-Sensitized Mice and Human Tissues
Background & Aims: Copolymers of hydroxyethyl methacrylate and styrene sulfonate complex with isolated gliadin (the toxic fraction of gluten) and prevent damage to the intestinal barrier in HLA-HCD4/DQ8 mice. We studied the activity toward gluten and hordein digestion and biologic effects of poly(hydroxyethyl methacrylate-co-styrene sulfonate (P(HEMA-co-SS)). We also investigated the effect of gliadin complex formation in intestinal biopsy specimens from patients with celiac disease. Methods: We studied the ability of P(HEMA-co-SS) to reduce digestion of wheat gluten and barley hordein into immunotoxic peptides using liquid chromatography–mass spectrometry. The biodistribution and pharmacokinetic profile of orally administered P(HEMA-co-SS) was established in rodents using tritium-labeled polymer. We assessed the capacity of P(HEMA-co-SS) to prevent the immunologic and intestinal effects induced by a gluten-food mixture in gluten-sensitized HLA-HCD4/DQ8 mice after short-term and long-term administration. We measured the effects of gliadin complex formation on cytokine release ex vivo using intestinal biopsy specimens from patients with celiac disease. Results: P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein in vitro, thereby decreasing formation of toxic peptides associated with celiac disease. After oral administration to rodents, P(HEMA-co-SS) was predominantly excreted in feces, even in the presence of low-grade mucosal inflammation and increased intestinal permeability. In gluten-sensitized mice, P(HEMA-co-SS) reduced paracellular permeability, normalized anti-gliadin immunoglobulin A in intestinal washes, and modulated the systemic immune response to gluten in a food mixture. Furthermore, incubation of P(HEMA-co-SS) with mucosal biopsy specimens from patients with celiac disease showed that secretion of tumor necrosis factor-α was reduced in the presence of partially digested gliadin. Conclusions: The copolymer P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein and attenuated the immune response to gluten in a food mixture in rodents. It might be developed to prevent or reduce gluten-induced disorders in humans.

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Date de mise en ligne : Jeudi 03 novembre 2011
Chia–Min Liao, Michael I. Zimmer, Sharmila Shanmuganad, Hon–Tsen Yu, Susanna L. Cardell, Chyung–Ru Wang
Dysregulation of CD1d-Restricted Type II Natural Killer T Cells Leads to Spontaneous Development of Colitis in Mice
Background & Aims: CD1d-restricted natural killer (NK) T cells are a subset of immunoregulatory T cells that comprise type I (express the semi-invariant T-cell receptor [TCR] and can be detected using the α-galactosylceramide/CD1d tetramer) and type II (express diverse TCRs and cannot be directly identified). Studies in mouse models of inflammatory bowel disease revealed a complex role for type I NKT cells in the development of colitis. Type II NKT cells have been associated with intestinal inflammation in patients with ulcerative colitis. Methods: To investigate whether dysregulation of type II NKT cells, caused by increased expression of CD1d, can contribute to colitis, we generated transgenic mice that express high levels of CD1d and a TCR from an autoreactive, type II NKT cell (CD1dTg/24αβTg mice). Results: CD1dTg/24αβTg mice had reduced numbers of 24αβ T cells compared with 24αβTg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24αβ T cells in CD1dTg/24αβTg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24αβTg mice. Interestingly, CD1dTg/24αβTg mice spontaneously developed colitis; adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic. Conclusions: Aberrant type II NKT cell responses directly contribute to intestinal inflammation in mice, indicating the importance of CD1d expression levels in the development and regulation of type II NKT cells.

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Date de mise en ligne : Jeudi 03 novembre 2011
Alexander F. Heiseke, Antonia C. Faul, Hans–Anton Lehr, Irmgard Förster, Roland M. Schmid, Anne B. Krug, Wolfgang Reindl
CCL17 Promotes Intestinal Inflammation in Mice and Counteracts Regulatory T Cell–Mediated Protection From Colitis
Background & Aims: Priming of T cells by dendritic cells (DCs) in the intestinal mucosa and associated lymphoid tissues helps maintain mucosal tolerance but also contributes to the development of chronic intestinal inflammation. Chemokines regulate the intestinal immune response and can contribute to pathogenesis of inflammatory bowel diseases. We investigated the role of the chemokine CCL17, which is expressed by conventional DCs in the intestine and is up-regulated during colitis. Methods: Colitis was induced by administration of dextran sodium sulfate (DSS) to mice or transfer of T cells to lymphopenic mice. Colitis activity was monitored by body weight assessment, histologic scoring, and cytokine profile analysis. The direct effects of CCL17 on DCs and the indirect effects on differentiation of T helper (Th) cells were determined in vitro and ex vivo. Results: Mice that lacked CCL17 (Ccl17E/E mice) were protected from induction of severe colitis by DSS or T-cell transfer. Colonic mucosa and mesenteric lymph nodes from Ccl17-deficient mice produced lower levels of proinflammatory cytokines. The population of Foxp3+ regulatory T cells (Tregs) was expanded in Ccl17E/E mice and required for long-term protection from colitis. CCR4 expression by transferred T cells was not required for induction of colitis, but CCR4 expression by the recipients was required. CCL17 promoted Toll-like receptor–induced secretion of interleukin-12 and interleukin-23 by DCs in an autocrine manner, promoted differentiation of Th1 and Th17 cells, and reduced induction of Foxp3+ Treg cells. Conclusions: The chemokine CCL17 is required for induction of intestinal inflammation in mice. CCL17 has an autocrine effect on DCs that promotes production of inflammatory cytokines and activation of Th1 and Th17 cells and reduces expansion of Treg cells.

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Date de mise en ligne : Vendredi 11 novembre 2011
Marcelo A. Catalán, Carlos A. Flores, Mireya González–Begne, Yan Zhang, Francisco V. Sepúlveda, James E. Melvin
Severe Defects in Absorptive Ion Transport in Distal Colons of Mice That Lack ClC-2 Channels
Background & Aims: The fluid secretion model predicts that intestinal obstruction disorders can be alleviated by promoting epithelial Cl− secretion. The adenosine 3′,5′-cyclic monophosphate (cAMP)-activated anion channel CFTR mediates Cl−-dependent fluid secretion in the intestine. Although the role of the ClC-2 channel has not been determined in the intestine, this voltage-gated Cl− channel might compensate for the secretory defects observed in patients with cystic fibrosis and other chronic constipation disorders. We investigated whether mice that lack ClC-2 channels (Clcn2−/−) have defects in intestinal ion transport. Methods: Immunolocalization and immunoblot analyses were used to determine the cellular localization and the amount of ClC-2 expressed in mouse early distal colon (EDC) and late distal colon (LDC). Colon sheets from wild-type and Clcn2−/− littermates were mounted in Ussing chambers to determine transepithelial bioelectrical parameters and Na+, K+, and Cl− fluxes. Results: Expression of ClC-2 was higher in the basolateral membrane of surface cells in the EDC compared with the LDC, with little expression in crypts. Neither cAMP nor Ca2+-induced secretion of Cl− was affected in the EDC or LDC of Clcn2−/− mice, whereas the amiloride-sensitive short-circuit current was increased approximately 3-fold in Clcn2−/− EDC compared with control littermates. Conversely, electroneutral Na+, K+, and Cl− absorption was dramatically reduced in colons of Clcn2−/− mice. Conclusions: Basolateral ClC-2 channels are required for colonic electroneutral absorption of NaCl and KCl. The increase in the amiloride-sensitive short-circuit current in Clcn2−/− mice revealed a compensatory mechanism that is activated in the colons of mice that lack the ClC-2 channel.

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Date de mise en ligne : Jeudi 03 novembre 2011
Salvatore Modica, Michele Petruzzelli, Elena Bellafante, Stefania Murzilli, Lorena Salvatore, Nicola Celli, Giuseppe Di Tullio, Giuseppe Palasciano, Tarek Moustafa, Emina Halilbasic, Michael Trauner, Antonio Moschetta
Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis
Background & Aims: Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BAs and protecting the liver from cholestasis in mice. Methods: We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-of-function models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. Results: Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BAs and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis after bile duct ligation or administration of α-naphthylisothiocyanate. In Mdr2−/− mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. Conclusions: Activation of FXR transcription in the intestine protects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients.

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Date de mise en ligne : Vendredi 11 novembre 2011
Nobuhiro Nakamoto, Hirotoshi Ebinuma, Takanori Kanai, Po–Sung Chu, Yuichi Ono, Yohei Mikami, Keisuke Ojiro, Martin Lipp, Paul E. Love, Hidetsugu Saito, Toshifumi Hibi
CCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis
Background & Aims: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. Methods: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. Results: After injection of con A, we detected CCR9+CD11b+CD11c– macrophages that express tumor necrosis factor (TNF)-α in livers of mice, whereas CCR9+Siglec–H+CD11b–CD11clow plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9+ macrophages were also detected in the livers of RAG-2−/− mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9+ macrophages induced naive CD4+ T cells to become interferon gamma–producing Th1 cells in vivo and in vitro. CCR9−/− mice injected with con A did not develop hepatitis unless they also received CCR9+ macrophages from mice that received con A; more CCR9+ macrophages accumulated in their inflamed livers than CCR9+ pDCs, CCR9– pDCs, or CCR9– macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9+ macrophages and their production of TNF-α. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-α–producing CCR9+CD14+CD16high monocytes than controls. Conclusions: CCR9+ macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

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Date de mise en ligne : Lundi 31 octobre 2011
Claudia Nitsche, Mouad Edderkaoui, Ryan M. Moore, Guido Eibl, Noriyuki Kasahara, Janet Treger, Paul J. Grippo, Julia Mayerle, Markus M. Lerch, Anna S. Gukovskaya
The Phosphatase PHLPP1 Regulates Akt2, Promotes Pancreatic Cancer Cell Death, and Inhibits Tumor Formation
Background & Aims: The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). Methods: We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. Results: PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. Conclusions: PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.

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Date de mise en ligne : Vendredi 11 novembre 2011
Sandra Baumgart, Elisabeth Glesel, Garima Singh, Nai–Ming Chen, Kristina Reutlinger, Jinsan Zhang, Daniel D. Billadeau, Martin E. Fernandez–Zapico, Thomas M. Gress, Shiv K. Singh, Volker Ellenrieder
Restricted Heterochromatin Formation Links NFATc2 Repressor Activity With Growth Promotion in Pancreatic Cancer
Background & Aims: Transcriptional silencing of the p15INK4b tumor suppressor pathway overcomes cellular protection against unrestrained proliferation in cancer. Here we show a novel pathway involving the oncogenic transcription factor nuclear factor of activated T cells (NFAT) c2 targeting a p15INK4b-mediated failsafe mechanism to promote pancreatic cancer tumor growth. Methods: Immunohistochemistry, real-time polymerase chain reaction, immunoblotting, and immunofluorescence microscopy were used for expression studies. Cancer growth was assessed in vitro by [3H]thymidine incorporation, colony formation assays, and in vivo using xenograft tumor models. Protein-protein interactions, promoter regulation, and local histone modifications were analyzed by immunoprecipitation, DNA pull-down, reporter, and chromatin immunoprecipitation assays. Results: Our study uncovered induction of NFATc2 in late-stage pancreatic intraepithelial neoplasia lesions with increased expression in tumor cell nuclei of advanced cancers. In the nucleus, NFATc2 targets the p15INK4b promoter for inducible heterochromatin formation and silencing. NFATc2 binding to its cognate promoter site induces stepwise recruitment of the histone methyltransferase Suv39H1, causes local H3K9 trimethylation, and allows docking of heterochromatin protein HP1γ to the repressor complex. Conversely, inactivation of NFATc2 disrupts this repressor complex assembly and local heterochromatin formation, resulting in restoration of p15INK4b expression and inhibition of pancreatic cancer growth in vitro and in vivo. Conclusions: Here we describe a novel mechanism for NFATc2-mediated gene regulation and identify a functional link among its repressor activity, the silencing of the suppressor pathway p15INK4b, and its pancreatic cancer growth regulatory functions. Thus, we provide evidence that inactivation of oncogenic NFATc2 might be an attractive strategy in treatment of pancreatic cancer.

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Date de mise en ligne : Mercredi 14 décembre 2011
Exam 1: Next-Generation Stool DNA Test Accurately Detects Colorectal Cancer and Large Adenomas
Exam 1: Next-Generation Stool DNA Test Accurately Detects Colorectal Cancer and Large Adenomas
http://www.gastrojournal.org/article/PIIS0016508511016404/abstract?rss=yes

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Date de mise en ligne : Mercredi 21 décembre 2011
Eileen F. Murphy, Eamonn M.M. Quigley
The Microbiota and Bariatric Surgery: It's a Bug's Life
Li J, Ashrafian H, Bueter M, et al. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut 2011;60:1214–1223. Obesity, one of the great pandemics of our time, is a major threat to public health and a challenge to health care resources. This complex syndrome is influenced by host susceptibility and by environmental or lifestyle factors, such as diet and physical activity. Obesity is associated with a number of serious health consequences, including type 2 diabetes, cardiovascular disease, pulmonary hypertension, obstructive sleep apnea, gastroesophageal reflux disease, musculoskeletal disorders, and a variety of cancers (Mayo Clin Proc 2006;81[suppl]:S5–S10) and has been repeatedly shown to be associated with an increased risk of mortality (Gastroenterology 2007;132:2087–2210).

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Date de mise en ligne : Lundi 19 décembre 2011
Julian R. Marchesi, Jia Li, Elaine Holmes, Hutan Ashrafian, Thanos Athanasiou, Ara Darzi, Jeremy K. Nicholson
Reply
We welcome the authors' comments in relation to our article published in Gut (2011;60:1214–1223) and wish to reiterate the point that referring to the role of gut microbiota as potentially being “mere epiphenomenon� needs to be strongly reconsidered. The whole field has moved beyond this notion and we should be thinking of where on the continuum of microbiome–host interactions this change in the composition falls. In the last 10 years, we have slowly begun to reintegrate the functions in the gut microbiome into host biology and there are many notable examples where they influence host; for example, bacterial glucuronidases impact chemotherapeutic treatments for colorectal cancer (Science 2010;330:831–835). In RYGB, there is a profound impact on the composition of the gut microbiota and we believe that there will be significant implications for how the gut microbiome interacts with the host. For example, we see significant shifts in the ability to produce butyrate and this correlates with survival of cells incubated with fecal water from RYGB animals (Front Microbiol 2011;2:183). There is also a proposed reduction, yet to be confirmed, in the ability of the colonic microbiota to process bile salts, because the bile salt hydrolases that catalyze this task are not found in the genera enriched in RYGB humans and animals. We are just starting to explore the ramifications of altering the gut microbiome by RYGB and other bariatric procedures (Obese Rev 2010;11:907–920). Although the short-term gain, owing to direct metabolic (BRAVE) effects in addition to calorific restriction is evident and most probably does not involve the microbiome, it is the long-term consequences of altering or removing these functions that need further consideration. To this end, we need to implement a more integrated set of systems biology investigations with “-omic� tools assessing samples from a large cohort of humans and over several time points. Such an approach would allow us to determine the changes in the gut microbiome and establish which interactions between the gut microbiota and the host are most affected.

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Date de mise en ligne : Mercredi 21 décembre 2011
Darren M. Brenner
Stimulant Laxatives for the Treatment of Chronic Constipation: Is it Time to Change the Paradigm?
Kamm MA, Mueller-Lissner S, Wald A, et al. Oral bisacodyl is effective and well-tolerated in patients with chronic constipation. Clin Gastroenterol Hepatol 2011;9:577–583. Chronic constipation (CC) is a common gastrointestinal disorder with a varying prevalence depending on the definition used to establish the diagnosis. Overall, 12%–19% of Americans are affected (Am J Gastroenterol 2004;9:750–759), and CC is the second most common ambulatory diagnosis made by gastroenterologists. Its pathogenesis derives from a heterogeneous combination of secondary causes—age, medications, electrolyte imbalances, endocrinopathies, and musculoskeletal disorders—as well as primary causes including normal and slow transit constipation and evacuation disorders. Despite the variety of etiologies, recent consensus guidelines recommend against the use of diagnostic testing in the majority of patients and laxatives are used as both diagnostic and therapeutic interventions. Classically, physicians and patients alike have had access to multiple over-the-counter formulations, including bulking agents, osmotic, and stimulant laxatives. More recently, however, newer classes of agents including chloride channel activators and guanylate cyclase agonists have also proven beneficial for treating this disorder. Unfortunately, even with this diverse cache of therapeutics, the incidence of complicated constipation has surged with outpatient and hospital diagnosis doubling and quadrupling, respectively (Gastroenterol 2009;136:741–754). It has yet to be determined whether this is due to increasing rates of refractory constipation and/or a lack of evidence-based data and, consequently, limitations in our understanding of how to use these agents.

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Date de mise en ligne : Mercredi 21 décembre 2011
Joshua Max, Akbar K. Waljee
Inflammatory Bowel Disease and Thromboembolism: A C‘Lot’ to Worry About
Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011;60:937–943.

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Date de mise en ligne : Mercredi 21 décembre 2011
Martin Storr, Hans–Dieter Allescher
Irritable Bowel Syndrome: A Dysfunction of the Endocannabinoid System?
Park JM, Choi MG, Cho YK. Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study. J Clin Gastroenterol 2011;45:45–49.

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Date de mise en ligne : Jeudi 22 décembre 2011
Paul Y. Kwo
Controversies in Hepatology: The Experts Analyze Both Sides
The field of hepatology has grown exponentially over the past 40 years both in the clinical and research arenas. This has accompanied the world-wide recognition of the burden of chronic liver disease including alcoholic liver disease, hepatitis B, hepatitis C, nonalcoholic liver disease, and end-stage liver disease and hepatocellular cancer. Major advances in our understanding of these diseases along with major therapeutic advances including treatments for viral hepatitis; autoimmune, cholestatic, and metabolic liver diseases; alcoholic hepatitis; end-stage liver disease; and the ultimate therapy for end-stage liver disease, liver transplantation, have allowed hepatologists to improve the lives of those with chronic liver disease while extending survival and in many instances, curing our patients of their ailment. In Controversies in Hepatology, editor Donald Jensen assembles an internationally distinguished group of authors to address conundrums that hepatologists and gastroenterologists routinely face on a day-to-day basis.

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Date de mise en ligne : Lundi 19 décembre 2011
Michael J. Levy
Endoscopic Ultrasound: An Introductory Manual and Atlas, 2nd edition
Endoscopic ultrasound (EUS) has emerged as a valuable diagnostic imaging modality since its introduction >30 years ago. There remains a need for enhanced EUS training that is not fully met by dedicated EUS training programs. Although technical skills are most readily acquired within a formal EUS fellowship, the education is facilitated by having a thorough knowledge of normal and abnormal EUS anatomy and a clear understanding of the concepts that apply to therapeutic EUS. Such educational material also benefits persons completing training to allow skill maintenance and continued intellectual and procedural growth.

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Date de mise en ligne : Jeudi 22 décembre 2011
Neil Gupta, Sreenivasa Jonnalagadda
Curbside Consultation in GI Cancer for the Gastroenterologist: 49 Clinical Questions
This is another issue of the successful “Curbside Consultation� textbook series published by SLACK Incorporated. This new addition to the series focuses on the area of gastrointestinal cancers and is a timely release considering the growing complexities and nuances related to the management of colorectal cancer, esophageal adenocarcinoma, pancreatic cancer, and hepatocellular cancer. Colorectal cancer is the third leading cause of cancer and second leading cause of cancer-related death, causing an estimated 50,000 deaths in 2011. Esophageal adenocarcinoma is 1 of the few cancers with a rising incidence and has a poor 5-year survival rate. Pancreatic cancer continues to carry a dismal prognosis and has become increasingly publicized by the media as more celebrities such as Patrick Swayze and Luciano Pavarotti succumb to the condition. Hepatocellular cancer is expected to have an increasing incidence over the next several years as the large population of patients suffering from hepatitis C and fatty liver disease ages. This issue of the “Curbside Consultation� series addresses the field of gastrointestinal cancers from the perspective of gastroenterologists. This perspective on gastrointestinal cancers is exceedingly important as gastroenterology continues its shift from a specialty that provides only cancer diagnosis to a specialty that is an integral component of a multidisciplinary approach to cancer prevention, diagnosis, and treatment.

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Date de mise en ligne : Lundi 09 janvier 2012
Correction
Correction
Polyak SJ, Morishima C, Scott JD, et al. A summary of the 18th international symposium on hepatitis C virus and related viruses. Gastroenterology 2012;142:e1–e5. In the above article, Pablo Gastaminza, PhD, Departamento de Biología Celular y Molecular, Centro Nacional de Biotecnología-CSIC, Madrid, Spain, should be listed as the 4th author in the article's byline.

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Date de mise en ligne : Mercredi 21 décembre 2011
Srijit Das, R. Sakthiswary
Estrogen Regulates the Human Duodenal Bicarbonate Secretion: Interesting Facts
We enjoyed reading the recently published article “Estrogen Regulation of Duodenal Bicarbonate Secretion and Sex-Specific Protection of Human Duodenum� by Tuo et al. We congratulate the investigators for carrying out the first ever human study on the effects of estrogen on human duodenal bicarbonate secretion (DBS). The previous studies were all murine based. Perhaps the only disadvantage is that the present results cannot be compared with the findings of earlier studies.

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Date de mise en ligne : Mercredi 21 décembre 2011
Biguang Tuo, Hui Dong
Reply
We thank Drs Das and Rajalingham for their interests and thoughtful comments on our article, and also would like to answer their questions and concerns on our paper. Peptic ulcers, especially duodenal ulcers, are common alimentary diseases with high prevalence. Although it has been clinically observed for many years that duodenal ulcer occurs more often in men than in women, the reason for these gender differences is not clear. Our present study demonstrates for the first time that estrogen regulates human duodenal bicarbonate secretion (DBS), which could reduce the risk for duodenal ulcer in women and contribute to gender differences in the prevalence of duodenal ulcer. We would like to stress here that the present experimental results obtained from the humans are consistent with the findings of our earlier studies from animals. Second, although the epidemiologic investigation was from patients with dyspepsia, all studies for effect of estrogen on DBS were from healthy Helicobacter pylori-negative volunteers, not in dyspeptic patients. The results showed that basal and acid-stimulated DBS was significantly higher in healthy premenopausal volunteers compared with age-matched men, but this difference was not observed in postmenopausal women. In premenopausal women, basal and acid-stimulated DBS was higher during the pre-ovulatory phase, when serum estrogen levels are higher, compared with during the premenstrual phase. A direct role for estrogen in DBS, independent of gender and age, was supported by the finding of stimulation of DBS by the administration of 17β-estradiol into the duodenal lumen. Taken together, we believe that the effect of estrogen on normal subjects is clearly addressed in the present study.

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Date de mise en ligne : Mercredi 21 décembre 2011
Jeremy Hugh Baron
Estrogen Regulation of Duodenal Bicarbonate Secretion
In the September 2011 issue of Gastroenterology, Tuo et al demonstrated that the well-known rarity of duodenal ulcer in premenopausal women was associated with decreased duodenal bicarbonate secretion (DBS), that serum levels of estradiol changed in parallel with basal and acid-stimulated DBS during the menstrual cycle, and that estrogen receptors were detected in human duodenal cells.

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Date de mise en ligne : Lundi 19 décembre 2011
Biguang Tuo, Hui Dong
Reply
We thank Dr Baron for his interest in our article “Estrogen Regulation of Duodenal Bicarbonate Secretion and Sex-Specific Protection of Human Duodenum� published recently in Gastroenterology.

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Date de mise en ligne : Lundi 19 décembre 2011
Antonio Colecchia, Davide Festi, Anna Rita di Biase
Noninvasive Parameters for Predicting Esophageal Varices in Children: Their Sequential Use Provides the Best Accuracy
We read with great interest the paper by Gana et al regarding the prognostic value of the clinical predictive rule (CPR) in children at risk of esophagogastric varices (EGV). The authors studied 108 children with chronic liver disease or portal vein obstruction who underwent esophagogastroduodenoscopy (EGD) to assess the presence of esophageal or gastric varices. The aim of the study was to evaluate the predictive value of the noninvasive clinical prediction rule and other noninvasive parameters, such as splenomegaly on physical examination, spleen length z score measured by ultrasound, platelet count, and platelet:spleen size z-score ratio (P/SSAZ). The authors observed that, in their population (in which there was a prevalence of EGV of 69%), 87% of the children with a positive CPR had varices on EGD, whereas 21% were classified incorrectly (including 18% of those with varices). Furthermore, 86% of the children with a positive P/SSAZ and 79% with a low platelet count had varices, 22% being classified incorrectly. The authors concluded that the preferred noninvasive tests were CPR and platelet count despite the slightly higher area under the receiver operating characteristic curve (AUROC) for P/SSAZ (0.84) and that these tests can assist in triaging children for EGD to evaluate the presence of varices.

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Date de mise en ligne : Mercredi 21 décembre 2011
Juan Cristóbal Gana, Dan Turner, Simon C. Ling
Reply
We thank Colecchia et al for their comments in connection with our study, in which we demonstrated that common blood work and imaging variables can be utilized for estimating the likelihood of the presence of varices in children and thereby help determine which children should undergo esophagogastroduodenoscopy (EGD). There is a notable lack of pediatric data regarding the diagnosis and management of esophageal varices. It is therefore not surprising that we have previously shown a significant variation in practice amongst pediatric hepatologists, many of whom perform screening endoscopies in selected children at risk of varices.

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Date de mise en ligne : Mercredi 01 février 2012
Editorial Board
Editorial Board
http://www.gastrojournal.org/article/PIIS0016508511017227/abstract?rss=yes

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Date de mise en ligne : Mercredi 01 février 2012
Table of Contents
Table of Contents
http://www.gastrojournal.org/article/PIIS0016508511017239/abstract?rss=yes

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Date de mise en ligne : Mercredi 01 février 2012
Information for Authors and Readers
Information for Authors and Readers
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

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Date de mise en ligne : Mercredi 01 février 2012
Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship
Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship
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.)

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