Gastroenterology - Articles in Press

Unusual Thyroid Tumors in a Young Woman - Uncorrected Proof

Kentaro Yamashita, Yoshiaki Arimura, Yasuhisa Shinomura — 2012-01-30

Question: A 24-year-old woman was referred to our hospital because of thyroid nodules. Physical examination revealed a painless nodule in the right lobe of the thyroid but no abnormal findings in the abdomen. The patient has no remarkable past history and laboratory studies, including blood count, chemistry, and thyroid function tests, were all within normal limits. Computed tomography revealed 2 thyroid tumors (). With the monitor in place, upon ingesting a cold carbonated beverage, the patient developed presyncopal symptoms ) and fine needle aspiration from the right tumor suggested undifferentiated carcinoma. The patient underwent total thyroidectomy, which disclosed that both nodules were cancers with identical and unique histologic findings. They were composed of cribriform, morular, and papillary growth patterns (). Immunohistochemistry showed cytoplasmic and nuclear accumulation of beta-catenin (Figure E). The final diagnosis was cribriform-morular variant, a rare subtype of papillary thyroid carcinoma.

Abnormal Activation of Autophagy-Induced Crinophagy in Paneth Cells from Patients with Crohn's Disease Short title: Crinophagy in Crohn’s disease - Accepted Manuscript

2012-01-30

Abstract: ATG16L1, IRGM, and NOD2 regulate autophagy, and variants in these genes have been associated with predisposition to Crohn's disease (CD). However, little is known about the role of autophagy in CD. Intestinal biopsies from untreated pediatric patients with CD, celiac disease, or ulcerative colitis were analyzed by immunohistochemistry and electron microscopy. We observed that autophagy was specifically activated in Paneth cells from patients with CD, independently of mucosal inflammation or disease-associated variants of ATG16L1 or IRGM. In these cells, activation of autophagy was associated with a significant decrease in number of secretory granules and features of crinophagy. These observations might account for the disorganization of secretory granules previously reported in Paneth cells from patients with CD.

A Bad Streak - Uncorrected Proof

Seth Sweetser, Nataliya Razumilava, Patrick S. Kamath — 2012-01-27

Question: A 59-year-old Cambodian man, a resident of the United States for 25 years, presented with fatigue, early satiety, and intermittent abdominal discomfort. Physical examination revealed tender, firm hepatomegaly with a liver span of 16 cm and extending 6 cm below the right costal margin. There was no shifting dullness, lower extremity edema, or stigmata of chronic liver disease. Laboratory testing showed the following: hemoglobin, 10 g/dL with macrocytic indices; alkaline phosphatase, 525 U/L (normal, 50–130); aspartate aminotransferase, 513 U/L (normal, 8–43); alanine aminotransferase, 405 U/L (normal, 7–45); total bilirubin, 0.4 mg/dL; serum albumin, 2.2 g/dL (normal, 3.5–5); and International Normalized Ratio, 1.4. Hepatitis B surface antigen was positive, hepatitis B e antigen was negative, hepatitis B e antibody was positive, and HBV DNA 363,000 IU/mL. Hepatitis C RNA was negative. Ultrasonography revealed multiple masses in both liver lobes. Doppler studies revealed a thrombus in the main portal vein (PV) with extension into the right and left PVs. Heparin anticoagulation was initiated. Abdominal computed tomography demonstrated a mass in the right lobe of the liver (arrowheads) and an additional sign ().

Pigmentation Sparing on Melanosis Coli - Uncorrected Proof

Chien-Yuan Hung, Li-Rung Shyung, Ming-Jen Chen — 2012-01-27

Question: A 91-year man visited our outpatient clinic because of chronic constipation for decades and more recent tenesmus. For the chronic constipation, he had been taking sennosides laxatives for 40 years. The colonoscopy showed diffuse, dark brown pigmentation throughout the colon, which is grossly consistent with melanosis coli. One polypoid lesion of 1.5 cm ( A) seemed pale, with some flat tiny foci (Figure B) devoid of pigmentation in the descending colon. These lesions were underwent endoscopic submucosal resection. The course was unremarkable and the patient remained free of polyps after 3 years.

Forgotten Ileus - Uncorrected Proof

Vitale José, Edoardo Fesce, Giancarlo Schmidt — 2012-01-27

Question: A 26-year-old man was referred to our hospital for obstinate constipation unresponsive to chronic laxatives therapy. On admission he had no appetite, and experienced nausea, vomiting, and crampy abdominal pain. His family history included a sister who suffered from an unspecified thyroiditis. His history was not significant for any gastrointestinal, metabolic, neurologic, or connective tissue disease. On physical examination, the patient was alert and oriented with apparent slight slowing of speech without change in the tone of voice. He showed cool, pale extremities and his skin was dry. The external temperature was 36.1°C. Clinical examination of the head, neck, chest, and heart were normal. Neurologic examination was unremarkable. The abdomen was tender without guarding and bowel sounds were almost absent. Rectal examination was normal with traces of normal stool in the ampulla.

Hepatic Mass in a 73-Year-Old Man - Uncorrected Proof

Jaclyn F. Hechtman, Mohammad Raoufi, M. Isabel Fiel — 2012-01-27

Question: A 73-year-old man with history of hypertension and dyslipidemia was incidentally found to have a large liver mass on magnetic resonance imaging. He did not have a personal or family history of chronic liver disease, previously diagnosed malignancy, alcohol use, blood transfusion, or smoking. Physical examination revealed abdominal distention. A palpable mass and jaundice were absent. Comprehensive metabolic panel, complete blood count, alpha-fetoprotein, liver transaminases, and carcinoembryonic antigen were within reference range. Carbohydrate antigen 19-9 was elevated (45.8 U/mL). Serologic studies for hepatitis B surface antigen and hepatitis C core antigen were negative. Antibody to hepatitis B surface antigen was positive. Computed tomography (CT) was performed, revealing a large right hepatic lobe mass, >20 cm in greatest dimension (). The mass had predominantly fatty attenuation with interspersed wispy soft tissue attenuation, multiple scattered small round enhancing nodules, and prominent dilated irregular enhancing vessels.

An Unusual Cause of Acute Pancreatitis in a 6-Year-Old Boy - Uncorrected Proof

Shohei Honda, Hisayuki Miyagi, Tadao Okada — 2012-01-27

Question: A 6-year-old boy presented with periumbilical abdominal pain, nausea, and hematemesis. On physical examination, the abdomen was soft and mildly distended in the epigastric region, with local tenderness. He had undergone cyst excision and Roux-en-Y hepaticojejunostomy for choledochal cyst the previous year. Laboratory tests revealed an amylase level of 1043 U/L and lipase level of 1089 U/L, resulting in a diagnosis of acute pancreatitis.

Unusual Cause of a Massive Abdominal Cystic Tumor - Uncorrected Proof

Esther S.T. Ng, Sarika Gupta, Pei Jye Voon — 2012-01-27

Question: A 74-year-old Chinese woman presented to the gastroenterology unit with a 3-day history of abdominal distension. This was associated with intractable vomiting and an inability to tolerate food. There had been no bowel movement for the last 2 days. She had a history of total hysterectomy and bilateral salpingo-oopherectomy 19 years ago for ovarian granulosa theca cell tumor, but was otherwise healthy.

An Unusual Oral Mass - Uncorrected Proof

Lorenzo Mannelli, Mai Vi H. Hoang, Annette P. Sabath, Ken F. Linnau — 2012-01-27

Question: A 72-year-old man with a recent history of dental crown placement and a root canal procedure complaints of right-sided mouth pain, numbness, and lip paresthesia. A mandibular lytic lesion was noted on orthopantomogram (, arrow) and magnetic resonance imaging (MRI) was subsequently requested. The patient was claustrophobic and the MRI was interrupted after the acquisition of the T1 and diffusion-weighted images. The MRI showed a 4 × 3.5-cm mass in the right masticator space, centered at and eroding the right mandibular condyle. The mass was hyperintense on T1-weighted images (Figure B, arrow), and showed restricted diffusion on the apparent diffusion coefficient map obtained from diffusion weighted image (Figure C). A core biopsy was obtained (Figure D; H&E staining). Further, his past history revealed alcoholic cirrhosis and prostate carcinoma treated 10 years earlier with brachytherapy, remote history of basal cells carcinoma of the face.

Covering the Cover - Uncorrected Proof

Anson Lowe, Richard H. Moseley — 2012-01-27

Congenital short-bowel syndrome represents a developmental anomaly in which the intestinal tract is foreshortened to the extent that nutrient assimilation is compromised. This rare syndrome exhibits a recessive inheritance pattern that is associated with consanguinity. The specific cause of this syndrome was not known. In this issue of Gastroenterology, van der Werf et al identify CLMP as a candidate gene responsible for congenital short-bowel syndrome. The authors studied 7 patients from 5 different families. Genomic DNA derived from 5 patients was linkage mapped using single nucleotide polymorphism arrays, which resulted in a focus on the CLMP gene. Subsequent sequencing revealed mutations in the open reading frame in 5 of 7 of the afflicted subjects. Two afflicted siblings possessed a deletion in intron 1 that did not affect the coding sequence.

Is HCV Infection a Neurologic Disorder? - Uncorrected Proof

Cyrille Féray — 2012-01-27

See “Hepatitis C virus infects the endothelial cells of the blood-brain barrier,” by Fletcher NF, Wilson GK, Murray J, et al, on page 00.

Villin-Marked Gastric Progenitor Cells: Conveyors or Purveyors of Precancerous Change? - Uncorrected Proof

Deborah L. Gumucio, Jonathan P. Katz — 2012-01-27

See “Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice,” by Li Q, Jia Z, Wang L, et al, on page 000.

Curbside Consultation in IBS - Uncorrected Proof

Baha Moshiree — 2012-01-27

Designed as a reference guide for practitioners from primary care physicians to gastroenterologists, Curbside Consultation in IBS is designed for rapid reference and readability, addressing primary questions clinicians and patients would have in the diagnosis, pathophysiology, associations, and treatment of irritable bowel syndrome (IBS) and its related conditions. The book itself is organized in a highly intuitive fashion, moving from sections that focus on the epidemiology of IBS through to its treatment. Among this book's strengths are its comprehensiveness, expert opinions, and the brevity of its chapters, including even those that deal with the complex immunologic, biopsychosocial, and genetic mechanisms that account for the symptom complex and altered gut motility seen in IBS. Each chapter concludes with a summary section, providing a list of takeaways for diagnosis and treatment. Moreover, even chapters dealing with motor and sensory dysfunctions and disturbances of gut homeostasis are clearly and efficiently discussed.

Successful Training in Gastrointestinal Endoscopy - Uncorrected Proof

Herbert C. Wolfsen, Lesley A. houghton, Lois Hemminger — 2012-01-27

Successful Training in Gastrointestinal Endoscopy, edited by Jonathan Cohen, is a hard-bound textbook with accompanying DVD of instructional video clips that is designed to provide a comprehensive examination of the principles and specific components of training in endoscopy over nearly 400 pages in 34 chapters authored by a diverse, international list of contributors. This book addresses the limitations of traditional endoscopy teaching based on “unconscious competence,” whereby passive demonstration of endoscopy techniques is replaced by the identification of specific learning objectives and critical self-reflection. Cohen's text has identified and systematized important aspects of endoscopy teaching that should be important to all those performing endoscopy, from trainee to fellowship program director to veteran gastroenterologist in this new era dedicated to quality outcomes, as well as heightened efficiency, training, and credentialing issues.

Acing the Hepatology Questions on the GI Board Exam: The Ultimate Crunch-Time Resource - Uncorrected Proof

Mohammad S. Siddiqui, Richard K. Sterling — 2012-01-27

Preparing for the GI board examination is a daunting and overwhelming task, both for new graduates making the tough transition from fellowship to faculty, as well as busy clinicians preparing for the recertification examination. Burdened with clinical and research responsibilities, most test takers have limited time to devote to study for the challenging GI board examination. Many GI board review books are organized like textbooks and build topics from pathophysiology to clinical presentation to treatment and in doing so contain superfluous information. Because time is valuable and most preparing for the this examination already know the basics, the aim of a review book should be to focus on high-yield topics (ie, those that are likely to be on the examination). Acing the Hepatology Questions on the GI Board Exam does just that by focusing on high-yield topics while omitting low-yield or nontestable minutiae. Unlike the prior book by the same author (BMRS) that covered both GI and Hepatology topics (2009), this book focuses exclusively on liver diseases.

Hepatic Cell-Specific Gene Expression Better Predicts HCV Treatment Outcome than IL28B Genotype - Accepted Manuscript

2012-01-27

Abstract: Background: Cell-specific expression patterns of hepatic interferon-stimulated genes (ISGs) and single-nucleotide polymorphisms (SNPs) near the IL28B gene are associated with response to interferon-based therapy in patients with chronic hepatitis C virus (HCV) infection. It is not known how the IL28B genotype influences the ISG expression pattern or which is a better predictor of treatment response. Methods: Patients at the Toronto Western Hospital Liver Center with known outcome to interferon-based treatment for HCV infection were evaluated. We analyzed hepatic gene expression profiles using cDNA microarrays, genotypes of the IL28B SNP rs12979860, and levels of human myxovirus A protein 1 (MxA) in hepatocytes and macrophages by immunostaining. Results: The levels of ISG products in hepatic macrophages correlated inversely with those of hepatocytes and were strongly associated with treatment outcome. Gene expression profiles and the IL28B genotype were associated with treatment response, but only absence of MxA from macrophages accurately predicted non-response to treatment. The positive-predictive value (PPV) of the IL28B genotype was 94%; the negative predictive value (NPV) was 51% (n=209). For mRNA expression, the PPV was 94% and NPV was 54% (n=65). For detection of MxA in macrophages, the PPV was 60% and the NPV was 98% (n=110). Of 53 patients with undetectable levels of MxA in macrophage, only 1 had a sustained virologic response. IL28B genotype was strongly associated with cell-specific staining for MxA. There was a stepwise increase in macrophage staining and decrease in hepatocyte staining from the TT (lack of response) to CC SNP (associated with response) in IL28B. By logistic regression, after controlling for the presence of macrophage staining for MxA, the IL28B genotype was no longer associated with treatment response. Conclusion: The cell-type specific expression pattern of ISGs varies among patients with different IL28B genotypes and is a strong predictor of response to interferon-based treatment.

Gastric Sonic Hedgehog Acts as a Macrophage Chemoattractant During the Immune Response to Helicobacter pylori - Accepted Manuscript

2012-01-27

Abstract: Background & Aims: Macrophages mediate the epithelial response to Helicobacter pylori and are involved in the development of gastritis. Sonic Hedgehog (Shh) regulates gastric epithelial differentiation and function, but little is known about its immunoregulatory role in the stomach. We investigated whether gastric Shh acts as a macrophage chemoattractant during the innate immune response to H pylori infection. Methods: Mice with parietal cell-specific deletion of Shh (PC-ShhKO) and control mice were infected with H pylori. Levels of gastric Shh, cytokines, and chemokines were assayed by quantitative reverse-transcriptase PCR or by a Luminex®-based multiplex assay, 2, 7, or 180 days after infection. Circulating concentrations of Shh were measured by ELISA. Bone marrow chimera experiments were performed with mice that have myeloid cell-specific deletion of the Hedgehog signal transduction protein smoothened (LysMCre/SmoKO). Macrophage recruitment was measured in gastric tissue and peripheral blood by fluorescence-activated cell sorting analysis. Results: Control mice infected with H pylori for 6 months developed an inflammatory response characterized by infiltration of CD4+ T cells and increased levels of interferon-γ and interleukin (IL)-1β in the stomach. PC-ShhKO mice did not develop gastritis, even after 6 months of infection with H pylori. Control mice had increased concentrations of Shh, accompanied by the recruitment of CD11b+F4/80+Ly6Chigh macrophages 2 days after infection. Control mice that received bone marrow transplants from control mice had an influx of macrophages to the gastric mucosa in response to H pylori infection; this was not observed in H pylori-infected control mice that received bone marrow transplants from LysMCre/SmoKO mice. Conclusion: H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.

Risk for Immune-Mediated Graft Dysfunction in Liver Transplant Recipients with Recurrent HCV Infection Treated with Pegylated Interferon - Accepted Manuscript

2012-01-27

Abstract: Background & Aims: Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD), characterized by plasma cell hepatitis or rejection. Methods: We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG–IGD. Data from each case were compared with those from 2 matched patients that did not develop PEG–IGD (n=104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. Results: The overall incidence of PEG–IGD, over a 10-year study period, was 7.2%. Risk factors included no prior PEG therapy (odds ratio [OR]=5.3; P<.0001), therapy with PEGα-2a (OR=4.7; P=.03), and immune features (mainly plasma cell hepatitis) of liver biopsies collected before PEG therapy (OR=3.9; P=.005). PEG–IGD cases had lower long-term (61.5% vs. 91.3% of controls) and graft (38.5% vs. 85.6% of controls) survival and higher rates of re-transplantation (34.6% vs 6.7% of controls) (all P<.0001), without increases in sustained virologic response. Variables associated with increased mortality included acute graft rejection (hazard ratio [HR]=2.4; P=.002), a high level of alkaline phosphatase at PEG initiation (HR=1.003; P=.005), and lack of a sustained virologic response (HR=3.3; P=.04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR=1.002; P=0.04) and lack of a sustained virologic response (HR=2.1; P=.04). Conclusions: PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.

A Child With Diarrhea and Recurrent Otitis - Uncorrected Proof

Klaus Mönkemüller, Lucia C. Fry, Mattias Heiduk — 2012-01-25

Question: A 5-year-old boy presented with chronic diarrhea and recurrent otitis media for 3 years. His past medical history was otherwise unremarkable. On physical examination, the patient appeared chronically ill; his abdomen was distended with increased bowel sounds. His weight and height were in the 25th percentile for age. The hemoglobin, platelets, and white blood cell count were within reference ranges. However, the differential showed only 7% lymphocytes (normal, 25%–40%). The albumin level was 24.6 g/dL (normal, 35–52). The immunoglobulin (Ig) A and M levels were also decreased (IgA < 0.24 [normal, 0.4–1.8]; IgM, 0.38 [normal, 0.4–1.8]). Esophagogastroduodenoscopy and colonoscopy were unremarkable. An anal double balloon enteroscopy reaching the distal 35 cm of terminal ileum revealed diffuse mucosal edema with multiple white-yellowish submucosal cords and patchy pseudopolypoid mucosal lesions ().

An Unusual Etiology of Lower Abdominal Pain in a Young Adult - Uncorrected Proof

Kuo–Feng Hsu, Yuan–Ming Tsai, Yao–Chi Liu — 2012-01-25

Question: A 32-year-old man presented with intermittent lower abdominal pain of 2 weeks' duration. He was treated at a local medical clinic, but the symptom did not improve completely after medication. On the day of admission, he had an acute episode of lower abdominal pain followed by nausea and vomiting. He had no history of systemic disease or operation. On arrival in the emergency department, he had a temperature of 36.9°C, pulse of 76/min and, blood pressure of 148/91 mmHg. Physical examination showed tenderness in the right lower quadrant of the abdomen and a distended abdomen. Laboratory tests showed a white blood cell count of 10,100/μL with 80% segmented neutrophils; hemoglobin, 14.7 g/dL; and C-reactive protein, 2.93 mg/dL. Computed tomography (CT) demonstrated a tubular-like intraluminal mass with fatty density in the distant small bowel loop as a target-shaped lesion (, arrow). A tentative diagnosis of intussusception was made. He underwent emergent laparotomy. Exploration revealed a short section of distal small intestine (60 cm away from the ileocecal junction) was intussuscepted and contained a palpable intraluminal mass (, arrow). The segmental resection of small bowel with an end-to-to anastomosis was performed.

Can Surrogate Endpoints From a First-Round Screening Be Reliable for Colorectal Cancer Screening? - Uncorrected Proof

Alain Braillon — 2012-01-25

Wilschut et al use a simulation model that suggests that fecal immunochemical test was most effective with a 50 ng/mL cutoff level. Their simulation model used the detection rates obtained from robust randomized controlled trials comparing an immunologic test at various cutoff levels versus the guaiac test. These data reflect the results of first-round screenings, when the prevalence of adenoma or cancer is maximal in the screened population The sensitivity and the specificity may not be constant for subsequent rounds. The lower sensitivity of higher cutoff levels of the immunologic method or of the guaiac test during the first round may be compensated by repeating the test in subsequent rounds. In contrast, the lower specificity of the cutoff level of 50 ng during this first round may be worse when repeating the test at subsequent rounds The simulation model may not have accounted for variation in subsequent rounds of testing.

Environmental Contribution to Pathogenesis of Cyst Formation in Autosomal-Dominant Polycystic Liver Diseases - Uncorrected Proof

Vincenzo Cardinale, Domenico Alvaro — 2012-01-25

We read with interest the paper by Janssen et al, which elegantly demonstrating that, among patients with polycystic liver disease (PCLD) carrying a heterozygous germline mutation in PRKCSH gene, somatic mutations (second hits) are highly and widely detectable in the liver cyst epithelia; the loss of heterozygosity being the mechanism underling cyst formation through decreased hepatocystin expression in 67% of the cases. The authors conclude that autosomal-dominant PCLD is recessive at the cellular level, and loss of functional PRKCSH is an important step in cystogenesis. Regarding the liver involvement, the autosomal-dominantly inherited polycystic diseases, as PCLD or autosomal-dominant polycystic kidney disease (ADPKD), could be considered clinically homogenous entities being characterized by a massive liver derangement with multiple cysts, whose severity is greater in women than in men and correlates with the number of pregnancies and estrogens use. These observations are consistent with a role of estrogens in the development of PCLDs and support the similarity in the mechanism of liver cyst formation between ADPKD and PCLD. The recent findings by Janssen et al, together with several clinical observations, promote the need to elucidate the role of environment factors in the phenotypic manifestations of inherited autosomal dominant PCLDs. Second somatic mutations underlie the liver cyst formation both in PCLD and in ADPKD, with loss of heterozygosity being more frequent in PCLD. Posttrascriptional modifications of polycystins (PC) or hepatocystin could play a pivotal role in development and evolution of the PCLDs. Recently, we demonstrated that, in cholangiocytes, 17β-estradiol triggers PCs proteolysis associated with a proliferative cell response. Estrogens are able to regulate several cell proteolytic complexes. Epithelium lining the hepatic cysts of patients with ADPKD showed higher expression of receptors for estrogen and insulin-like growth factor 1 with respect to normal cholangiocytes and strong proliferative response to estrogen administration. These evidences provide a scientific basis for clinical observations that in ADPKD the formation and growth of liver cysts are faster in women than in men and are linked to estrogen stimulation. However, the expression of estrogen receptors in PCLD cyst epithelia has been demonstrated not to be increased with respect to normal cholangiocytes, suggesting a divergence in the mechanisms driving cyst formation between PCLD and ADPKD. Because lowering PKD1 expression by 13%–20% of functional transcripts is sufficient to cause polycystic disease, it was proposed that in patients heterozygous for PKD1 (ADPKD patients), reduction of the normal allele products below a critical level, owing to genetic factors, environmental agents and stochastic can determine the formation of cysts and clinical manifestations of the ADPKD. A high mutation rate might explain the high number of cysts observed in PCLD and ADPKD. The malfunction of PC-1 induces a premature transition from G1 phase to S phase, an increase of proliferation and apoptosis through activation of the mammalian target of rapamycin. In addition, we recently demonstrated how a reduction of PC-1 expression of 35% is associated with activation of cholangiocyte proliferation machinery. Previous investigations elucidated how, although the pathogenesis of PCLD involves overexpression of growth factor receptors and loss of adhesion, proliferation, or deregulated apoptosis do not seem to be implicated. However, it has been argued that, in PCLD, cysts grow in a nonlinear fashion. Therefore, the pathogenesis of liver cyst development and the cause of the high mutation rate in autosomal-dominant PCLDs are not completely elucidated. On the basis of our recent findings, we hypothesize that estrogens, by acting on heterozygote susceptible cells of ADPKD patients, reduces the functional levels of PC-1, through posttranscriptional proteolytic modifications, below a critical cutoff, thus determining an increased proliferation and finally a high probability of second somatic mutations. Cells undergoing a second mutation can further proliferate and form cysts, determining also a selection of cells sensitive to estrogens through a process of co-segregation of related features. Our speculations could apply in the ADPKD pathogenesis, although it is not immediately transposable in PCLD pathogenesis. However, in light of the common pathologic and clinical traits of PCLD and ADPKD, further investigations on posttranscriptional modifications of hepatocystin sustained by environmental stimuli could contribute to elucidate the complex pathogenesis of PCLD.

HLA-Cw1202-B5201-DRB1*1502 Haplotype Increases Risk for Ulcerative Colitis but Reduces Risk for Crohn's Disease - Uncorrected Proof

Hitoshi Asakura — 2012-01-25

In the September 2011 issue of Gastroenterology, Okada et al reported that the HLA-Cw*1202-B*5201-DRB1*1502 haplotype increased risk for ulcerative colitis, but reduced risk for Crohn's disease, based on a genome-wide association study of a Japanese population. Recently, a number of genome-wide association studies have identified numerous susceptibility loci for ulcerative colitis and Crohn's disease. A total of 22 HLA-C alleles, 39 HLA-B alleles, 32 HLA-DRB alleles, and 17 HLA-DPB1 alleles were genotyped in this study. Compared with the frequency of healthy controls, the HLA-Cw*1202- B*5201- DRB1*1502 haplotype had a significant susceptible effect on ulcerative colitis and a significant protective effect on noncolonic Crohn's disease, but had no effect on colonic Crohn's disease. It is an interesting report.

Comparing Fecal Immunochemical Testing: Improved Standardization Is Needed - Uncorrected Proof

James E. Allison, Callum G. Fraser, Stephen P. Halloran, Graeme P. Young — 2012-01-25

See “Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer,” by Denters MH, Deutkom M, Bossuyt PM, et al, on page 000.

Fast Routes to New Therapies: What Do Epilepsy And Inflammatory Bowel Disease Have In Common? - Uncorrected Proof

Ashish Nimgaonkar, Shamita B. Shah — 2012-01-25

Dudley JT, Sirota M, Shenoy M, et al. (Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California). Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease. Sci Transl Med 2011;3:96ra76.

Appendicitis: Can Immediate Antibiotic Treatment Still Be Withheld? - Uncorrected Proof

Hans-Dieter Allescher — 2012-01-25

Vons C, Barry C, Maitre S, et al. (Hôpital Antoine Béclère [Assistance Publique-Hôpitaux de Paris and Université Paris XI], Services de Chirurgie, Clamart, France). Amoxicillin plus clavulanic acid versus appendectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomized controlled trial. Lancet 2011;377:1573–1579.

Irritable Bowel Syndrome and Gluten Sensitivity Without Celiac Disease: Separating The Wheat From The Chafe - Uncorrected Proof

Courtney Ferch, William D. Chey — 2012-01-25

Biesiekierski JR, Newnham ED, Irving PM, et al. (Monash University, Victoria, Australia.) Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 2011;106:508–514.

Individualized Screening for Colorectal Cancer: One Size Does Not Fit All - Uncorrected Proof

Sameer D. Saini — 2012-01-25

Gross CP, Soulos PR, Ross JS, et al. (Yale School of Medicine, Section of General Internal Medicine, New Haven, Connecticut). Assessing the impact of screening colonoscopy on mortality in the Medicare population. J Gen Intern Med 2011;26:1441–1449.

Reply - Uncorrected Proof

Manoe J. Janssen, Joost P.H. Drenth — 2012-01-25

Vincenzo Cardinale and Domenico Alvaro hypothesize that autosomal-dominant polycystic kidney disease (ADPKD)cholangiocytes heterozygous for PKD1 or PKD2 respond to estrogens with increased cell proliferation and somatic mutations. We would like to reflect on the occurrence of somatic mutations in both polycystic liver disease (PCLD) and ADPKD, and propose an alternative model that takes into account the dynamic role of polycystin(PC)-1 levels in the cell.

Reply - Uncorrected Proof

Yukinori Okada, Michiaki Kubo — 2012-01-25

We thank Dr Hitoshi Asakura for his thoughtful comments on regarding our study for the comparative genetic association study between ulcerative colitis (UC) and Crohn's disease (CD), in which we reported that the haplotype in the MHC region consisting of HLA alleles (HLA-Cw*1202-B*5201-DRB1*1502) had opposite directions of genetic effects on UC and CD in the Japanese poulation.

Fibroblast Growth Factor 19, An Anticholestatic Drug Produced by Human Liver - Uncorrected Proof

Peter L.M. Jansen, Frank G. Schaap, Ulrich H.W. Beuers — 2012-01-25

In a remarkably lucid study, Modica et al conclude that activation of the nuclear farnesoid-x receptor (Fxr) in the intestine protects the liver from cholestatic injury. This seems to work fine in mice, but would it also work in humans? A word of caution seems warranted.

A Guide for Success as a Clinical Investigator - Uncorrected Proof

Dawn Provenzale — 2012-01-24

T here are several titles given to the academic clinical researcher. Clinician–researcher and clinician–scholar are among the few. Typically they describe an individual who spends approximately 50%–75% of his or her time engaged in clinical research. Clinical research in this context may include, but is not limited to, clinical trials, observational studies, outcomes or health services research, or translational research including development of biorepositories to link clinical findings with genomic, proteomic, or metabolomic research.

Autoimmunity, intestinal lymphoid hyperplasia, and Defects in Mucosal B-Cell Homeostasis in Patients with PTEN Hamartoma Tumor Syndrome - Accepted Manuscript

2012-01-24

Abstract: The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates the phosphoinositol-3-kinase (PI3K)– AKT signaling pathway. In a series of 34 patients with PTEN mutations we described gastrointestinal lymphoid hyperplasia, extensive hyperplastic tonsils, thymus hyperplasia, autoimmune lymphocytic thyroiditis, autoimmune hemolytic anemia, and colitis. Functional analysis of the gastrointestinal mucosa-associated lymphoid tissue revealed increased signaling via the PI3K–AKT pathway, including phosphorylation of S6 and increased cell proliferation, but also reduced apoptosis of CD20+CD10+ B cells. Reduced activity of PTEN therefore affects homeostasis of human germinal-center B cells, by increasing PI3K–AKT signaling via mammalian target of rapamycin (mTOR) as well as anti-apoptotic signals.

Requirements for Clinical Implementation of Biomarkers in Barrett's Esophagus - Uncorrected Proof

Sibu Varghese, Pierre Lao–Sirieix, Rebecca C. Fitzgerald — 2012-01-24

Abiomarker is a relatively recent term coined to describe a detectable indicator for the presence or future risk of disease. Biomarkers may be physiological measurements (eg, blood pressure), endoscopic motifs (eg, autofluorescence patterns), or more usually molecular measurements applied to tissue or body fluids. The role of a biomarker is defined by its clinical utility at a specific decision-making point in the clinical pathway of a condition from diagnosis to treatment. Hence, once validated a biomarker should aid or alter patient management.

Translational Approaches for Pharmacotherapy Development for Acute Diarrhea - Uncorrected Proof

2012-01-24

A report is presented of a National Institute of Diabetes and Digestive and Kidney Diseases–sponsored single topic conference designed to determine scientific advances needed to encourage development of pharmacotherapy for diarrheal diseases.

Continuing Medical Education (CME) Activities - Uncorrected Proof

2012-01-24

FXR Protects Hepatocytes from Injury by Repressing miR-199a-3p, which Increases Levels of LKB1 - Accepted Manuscript

2012-01-20

Abstract: Background & Aims: Hepatocyte injury occurs during liver fibrogenesis. Micro-(mi)RNAs regulate some of these processes, and some are regulated by the farnesoid X receptor (FXR). We investigated the effect of repression of specific miRNAs by FXR in hepatocyte injury using fibrotic liver tissue from patients and hepatocytes. Methods: We used immunohistochemistry or real-time PCR to analyze proteins and miRNAs in human and mouse liver samples. HepG2 cells were transfected with pre-miRNA, antisense oligonucleotides, small interfering RNAs, the 3’-untranslated region of LKB1 (STK11), or constructs for overepression and analyzed. Results: Liver tissue from patients with severe fibrosis had lower levels of FXR and greater amounts of hepatocyte death than samples from patients with mild disease. Levels of several miRNAs changed when FXR expression was disrupted in the liver; one of these, miR-199a-3p was significantly upregulated in patients with severe fibrosis. Activation of FXR by its ligand reduced the level of miR-199a-3p in HepG2 cells. LKB1 mRNA was identified as a target of miR-199a-3p, and its expression was reduced in human fibrotic liver tissue. Overexpression of FXR or incubation of cultured hepatocytes with the FXR ligand upregulated LKB1; LKB1 was not induced in cells transfected with miR-199a-3p. Incubation of HepG2 cells with FXR ligand, or injection of the ligand into mice, protected hepatocytes from injury and increased levels of LKB1; levels of miR-199a-3p were reduced compared to cells that were not incubated with the FXR ligand. Activation of FXR reduced mitochondrial dysfunction and oxidative stress and increased hepatocyte survival. Conclusions: In hepatocytes, FXR represses production of miR-199a-3p. In fibrotic livers of humans and mice, FXR expression is reduced, increasing levels of miR-199a-3p, which reduces levels of LKB1. FXR therefore protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1.

Increased Reprogramming Capacity of Mouse Liver Progenitor Cells, Compared with Differentiated Liver Cells, Requires the BAF Complex - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Ectopic expression of certain transcription factors can reprogram somatic cells to a pluripotent state. Hematopoietic stem cells can be more efficiently reprogrammed than differentiated blood cells, yet similar findings have not been demonstrated in other primary organ systems. Moreover, molecular characteristics of the cellular hierarchy of tissues that influence reprogramming capacities need to be delineated. We analyzed the effect of differentiation stage of freshly isolated, mouse liver cells on the reprogramming efficiency. Methods: Liver progenitor cell (LPC)-enriched cell fractions were isolated from adult (6–8 week old) and fetal (embryonic day 14.5) livers of mice and reprogrammed to become induced pluripotent stem (iPS) cells. Different transcription factors were expressed in cells, and markers of pluripotency were examined, along with the ability of cells to differentiate, in vitro, into different germ layers. Results: Fetal and adult LPC had significantly greater reprogramming efficiency after transduction with 3 or 4 reprogramming factors. Transfection efficiency-corrected reprogramming rates of fetal LPCs were 275-fold higher, compared to unsorted fetal liver cells, when 3 reprogramming factors were transfected. The increased reprogramming efficiency of LPCs, compared to differentiated liver cells, occurred independently of proliferation rate, but was associated with endogenous expression of reprogramming factors (Klf4 and c-Myc) and BAF (BRG1/brm-associated factor)-complex members Baf155 and Brg1, which mediate epigenetic changes during reprogramming. Knockdown of BAF complex members negated the increased reprogramming efficiency of LPCs, compared with non-LPCs. Conclusions: LPCs have intrinsic, cell proliferation-independent characteristics that allow them to be efficiently reprogrammed, compared to differentiated liver cells.

Frequent Detection of Pancreatic Lesions in Asymptomatic High-Risk Individuals - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, non-invasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRI). Methods: We screened 225 asymptomatic adult HRI at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. Results: Ninety-two of 216 HRI (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n=5) by any of the imaging modalities. Fifty-one of the 84 HRI with a cyst (60.7%) had multiple lesions, typically small (mean 0.55 cm, range 2–39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects <50 years old, 34% of subjects 50–59 years old, and 53% of subjects 60–59 years old (P<.0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRI, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRI (82 intraductal papillary mucinous neoplasms [IPMN] and 3 pancreatic endocrine tumors). Three of 5 HRI who underwent pancreatic resection had high-grade dysplasia in <3 cm IPMNs and in multiple intraepithelial neoplasias. Conclusions: Screening of asymptomatic HRI frequently detects small pancreatic cysts, including curable, non-invasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.

Disruption of Notch1 Induces Vascular Remodeling, Intussusceptive Angiogenesis, and Angiosarcomas in Livers of Mice - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Notch signaling mediates embryonic vascular development and normal vascular remodeling; Notch1 knockout mice develop nodular regenerative hyperplasia (NRH). The pathogenesis of NRH is unclear, but has been associated with vascular injury in the liver sinusoids in clinical studies. We investigated the role of Notch1 signaling in liver sinusoidal endothelial cells (LSECs). Methods: We studied MxCre Notch1lox/lox mice (conditional knockout mice without tissue-specific disruption of Notch1); mice with hepatocyte-specific knockout were created by crossing Notch1lox/lox with AlbCre+/- mice. Portal vein pressure was measured; morphology of the hepatic vasculature was assessed by histologic and scanning electron microscopy analyses. We performed functional and expression analyses of isolated liver cells. Results: MxCre-induced knockout of Notch1 led to NRH, in the absence of fibrosis, with a persistent increase in proliferation of LSECs. Notch1 deletion led to de-differentiation, vascular remodeling of the hepatic sinusoidal microvasculature, intussusceptive angiogenesis, and dysregulation of ephrinB2/EphB4 and Tek. Time course experiments revealed that vascular changes preceded node transformation. MxCre Notch1lox/lox mice had reduced endothelial fenestrae and developed portal hypertension and hepatic angiosarcoma over time. In contrast, mice with hepatocyte-specific disruption of Notch1 had a normal phenotype. Conclusions: Notch1 signaling is required for vascular homeostasis of hepatic sinusoids; it maintains quiescence and differentiation of LSECs in adult mice. Disruption of Notch1 signaling in LSECs leads to spontaneous formation of angiosarcoma, indicating its role as a tumor suppressor in the liver endothelium.

Duodenal Activation of cAMP-Dependent Protein Kinase Induces Vagal Afferent Firing and Lowers Glucose Production in Rats - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: The duodenum senses nutrients to maintain energy and glucose homeostasis, but little is known about the signaling and neuronal mechanisms involved. We tested whether duodenal activation of cAMP-dependent protein kinase (PKA) is sufficient and necessary for cholecystokinin (CCK) signaling to trigger vagal afferent firing and regulate glucose production. Methods: In rats, we selectively activated duodenal PKA and evaluated changes in glucose kinetics during the pancreatic (basal insulin) pancreatic clamps and vagal afferent firing. The requirement of duodenal PKA signaling in glucose regulation was evaluated, by inhibiting duodenal activation of PKA in the presence of infusion of the intraduodenal PKA agonist (Sp-CAMPS) or CCK1 receptor agonist (CCK-8). We also assessed the involvement of a neuronal network and the metabolic impact of duodenal PKA activation in rats placed on high-fat diets. Results: Intraduodenal infusion of Sp-CAMPS activated duodenal PKA and lowered glucose production, in association with increased vagal afferent firing in control rats. The metabolic and neuronal effects of duodenal Sp-CAMPS were negated by co-infusion with either the PKA inhibitor H89 or Rp-CAMPS. The metabolic effect was also negated by co-infusion with tetracaine, molecular and pharmacological inhibition of NR1-containing N -methyl-D-aspartate (NMDA) receptors within the dorsal vagal complex, or hepatic vagotomy in rats. Inhibition of duodenal PKA blocked the ability of duodenal CCK-8 to reduce glucose production in control rats, whereas duodenal Sp-CAMPS bypassed duodenal CCK resistance and activated duodenal PKA and lowered glucose production in rats on high-fat diets. Conclusions: We identified a neural gluco-regulatory function of duodenal PKA signaling.

Response of the Upper Esophageal Sphincter to Esophageal Distension is Affected by Posture, Velocity, Volume, and Composition of the Infusate - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Studies of the pressure response of the upper esophageal sphincter (UES) to simulated or spontaneous gastroesophageal reflux have shown conflicting results. These discrepancies could result from uncontrolled influence of variables such as posture, volume, and velocity of distension. We characterized in humans the effects of these variables on UES pressure response to esophageal distension. Methods: We studied 12 healthy volunteers (average 27±5 years old, 6 male) using concurrent esophageal infusion and high-resolution manometry to determine UES, lower esophageal sphincter, and intraesophageal pressure values. Reflux events were simulated by distal esophageal injections of room-temperature air and water (5, 10, 20, and 50 ml) in individuals in 3 positions (upright, supine and semi-supine). Frequencies of various UES responses were compared using γ2 analysis. Multi-nomial logistical regression analysis was used to identify factors that determine the UES response. Results: UES contraction and relaxation were the overriding responses to esophageal water and air distension, respectively, in a volume-dependent fashion (P<.001). Water-induced UES contraction and air-induced UES relaxation were the predominant responses among individuals in supine and upright positions, respectively (P<.001). The prevalence of their respective predominant response significantly decreased in the opposite position. Proximal esophageal dp/dt significantly and independently differentiated the UES response to infusion with water or air. Conclusions: The UES response to esophageal distension is affected by combined effects of posture (spatial orientation of the esophagus), physical properties, and volume of refluxate, as well as the magnitude and rate of increase in intraesophageal pressure. The UES response to esophageal distension can be predicted using a model that incorporates these factors.

CCL2-Induced Migration and SOCS3-Mediated Activation of Macrophages Are Involved in Cerulein-Induced Pancreatitis in Mice - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein– and L-arginine–induced acute pancreatitis in mice. Methods: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgeries to assess the hemodynamics of pancreatic macrophages. Results: Almost all types of immune cells, except for CD11bhighCD11c– cells, were detected in the pancreas of healthy mice. However, activated CD11bhighCD11c– cells, including Gr-1low macrophages and Gr-1high cells (granulocytes and myeloid-derived suppressor cells, MDSCs), were detected in damaged pancreas after cerulein administration. CCL2-/-mice given cerulein injections developed significantly less-severe pancreatitis, with less infiltration of CD11bhighCD11c– Gr-1low macrophages, but comparable infiltration of MDSCs, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11bhighCD11c– Gr-1low macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of SOCS3 given injections of cerulein developed less severe pancreatitis and Gr-1low macrophage produced less tumor necrosis factor-α by than wild-type mice given cerulein, although the absolute number of CD11bhighCD11c– Gr-1low macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. Conclusions: Cerulein induction of pancreatitis in mice involves migration of CD11bhighCD11c– Gr-1low macrophage from the bone marrow (mediated by CCL2 via CCR2) and SOCS3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

HCV Infection Induces a Unique Hepatic Innate Immune Response Associated with Robust Production of Type III Interferons - Accepted Manuscript

2012-01-16

Abstract: Background and Aims: Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity. Methods: We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. mRNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes. Results: HCV infection of primary human hepatocytes (PHHs) induced production of chemokines and type III IFNs including interleukin (IL)28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with upregulation of ISGs and minimal induction of type I IFNs. In liver biopsies from HCV-infected patients, hepatic expression of IL28 correlated with levels of ISGs, but not of type I IFNs. HCV infection produced extensive changes of gene expression in addition to ISGs in PHHs. The induction of type III IFNs is regulated by IFN regulatory factor 3- and NF-κB. Type III IFNs upregulate ISGs with a different kinetic profile than type 1 IFNs, and induce a distinct set of genes, which might account for their functional differences. Conclusions: HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association between IL28, level of ISGs, and recovery from HCV infection, and provide a therapeutic strategy for patients that do not respond to IFN therapy.

Effects of Fractionated Plasma Separation and Adsorption on Survival in Patients with Acute-On-Chronic Liver Failure - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. Methods: Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n=77) or only SMT (n=68). The Prometheus® liver support system was used to provide 8–11 rounds of FPSA (minimum of 4 h each) for 3 weeks. Primary endpoints were survival probabilities at days 28 and 90, irrespective of liver transplantation. Results: Baseline clinical parameters and number of transplanted patients were similar between study arms. Serum bilirubin decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMP group (p=0.70); on day 90, they were 47% and 38%, respectively (p=0.35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the two groups in the incidence of side effects. Conclusions: Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.

Effect of IL28B Genotype on Early Viral Kinetics during Interferon-Free Treatment of Patients with Chronic Hepatitis C - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Although IL28B genotype affects the response of patients with chronic hepatitis C (CHC) to peginterferon and ribavirin, little is known its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and hepatitis C virus (HCV) protease inhibitor danoprevir. Methods: We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment-naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts, then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hrs or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a bi-phasic model to describe first- and second-phase slopes of viral decay during therapy. Results: At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log10 IU/mL) than those without (4.59 log10 IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up. Conclusions: IL28B genotype appears to affect early VKs in patients with CHC receiving interferon-free treatment.

Folic Acid Increases Global DNA Methylation and Reduces Inflammation to Prevent Helicobacter-Associated Gastric Cancer in Mice - Accepted Manuscript

2012-01-16

Abstract: Background & Aims: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However the findings have varied and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. Methods: Hypergastrinemic mice (INS-GAS) infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements and immunohistochemistry (IHC) with anti-5-methylcytosine. We also profiled gene expression in the same tissues. Results: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and IHC for lymphocyte markers. Conclusions: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.

Cigarette Smoking Increases Risk of Barrett's Esophagus: an Analysis of the Barrett's and Esophageal Adenocarcinoma Consortium - Accepted Manuscript

2012-01-13

Abstract: Background & Aims: Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett’s esophagus (BE). We investigated whether tobacco smoking and other factors increase risk for BE. Methods: We analyzed data from 5 case-control studies included in the international Barrett’s and Esophageal Adenocarcinoma Consortium. We compared data from subjects with BE (n=1059) with those from subjects with gastroesophageal reflux disease (GERD controls, n=1332) and population-based controls (n=1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for BE. Results: Subjects with BE were significantly more likely to have ever-smoked cigarettes than the population-based controls (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.04–2.67) or GERD controls (OR=1.61; 95% CI, 1.33–1.96). Increasing pack-years of smoking increased the risk for BE. There was evidence for a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (0.25–0.52). Conclusions: Cigarette smoking is a risk factor for BE. The association strengthened with increased exposure to smoking until ~ 20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to the development of BE.

Body Mass Index Increases Risk for Colorectal Adenomas, Based on Meta-Analysis - Accepted Manuscript

2012-01-13

Abstract: Background & Aims: There have been inconsistent results published about the relationship between excess body weight, expressed as increased body mass index (BMI), and the risk of colorectal adenoma (CRA). We conducted a meta-analysis to explore this relationship. We focused on whether the relationship varied based on the sex of the study subjects, study design, features of the polyps, or potential confounders, including alcohol use, non-steroidal anti-inflammatory drug use, smoking, and exercise. Methods: We identified studies by performing a literature search of Medline, EMBASE, and ISI Web of Science through July 31, 2011 and by searching the reference lists of pertinent articles. We analyzed 36 independent studies, which included 29,860 incident cases of CRA. Summary relative risks (SRRs) with their 95% confidence intervals (CIs) were calculated with a random-effects model. Between-study heterogeneity was assessed using Cochran’s Q statistic and I2 analyses. Results: Overall, a 5-unit increase in BMI (in kg/m2) increased the risk for CRA (SRR=1.19; 95% CI, 1.13–1.26), although there was a high level of heterogeneity among studies (Pheterogeneity<.001, I2 = 76.8%). Subgroup analyses revealed that the increased risk of CRA in obese individuals was independent of race, geographic location, study design, sex, adenoma progression, and confounders. The association between increased BMI and risk for CRA was stronger for colon than rectal adenoma. Conclusions: Based on a meta-analysis, increased BMI increases the risk for colon, but not rectal adenoma. Unlike colorectal cancer, there is no sex difference in the relationship between increased BMI and risk of CRA.

Endoscopic Ultrasound-Guided Transmural and Percutaneous Transhepatic Gallbladder Drainage are Comparable for Acute Cholecystitis - Accepted Manuscript

2012-01-13

Abstract: Background & Aims: Endoscopic ultrasound (EUS)-guided transmural gallbladder drainage (EUS-GBD) is an alternative to percutaneous transhepatic gallbladder drainage (PTGBD) for patients with acute, high-risk, or advanced-stage cholecystitis who do not respond to initial medical treatment and cannot undergo emergency cholecystectomy. However, the technical feasibility, efficacy, and safety of EUS-GBD and PTGBD have not been compared. Methods: Fifty-nine patients with acute cholecystitis, who did not respond to initial medical treatment and were unsuitable for an emergency cholecystectomy, were randomly chosen to undergo EUS-GBD (n=30) or PTGBD (n=29). The technical feasibility, efficacy, and safety of EUS-GBD and PTGBD were compared. Results: EUS-GBD and PTGBD showed similar technical (97%, 29/30 vs 97%, 28/29; 95% 1-sided confidence interval [CI] lower limit, –7%; P=.001 for non-inferiority margin of 15%) and clinical (100%, 29/29 vs 96%, 27/28; 95% 1-sided CI lower limit, –2%; P=.0001 for non-inferiority margin of 15%) success rates, and similar rates of complications (7%, 2/30 vs 3%, 1/29; P=.492 in Fisher’s exact test) and conversions to open cholecystectomy (9%, 2/23 vs 12%, 3/26; P=.999 in Fisher’s exact test). The median post-procedure pain score was significantly lower after EUS-GBD than after PTGBD (1 vs 5; P<.001 in the Mann-Whitney U-test). Conclusions: EUS-GBD is comparable to PTGBD in terms of the technical feasibility and efficacy; there were no statistical differences in the safety. EUS-GBD is a good alternative for high-risk patients with acute cholecystitis who cannot undergo an emergency cholecystectomy.

Gastroenterology - Articles in Press

Unusual Thyroid Tumors in a Young Woman - Uncorrected Proof

Abnormal Activation of Autophagy-Induced Crinophagy in Paneth Cells from Patients with Crohn's Disease Short title: Crinophagy in Crohn’s disease - Accepted Manuscript

A Bad Streak - Uncorrected Proof

Pigmentation Sparing on Melanosis Coli - Uncorrected Proof

Forgotten Ileus - Uncorrected Proof

Hepatic Mass in a 73-Year-Old Man - Uncorrected Proof

An Unusual Cause of Acute Pancreatitis in a 6-Year-Old Boy - Uncorrected Proof

Unusual Cause of a Massive Abdominal Cystic Tumor - Uncorrected Proof

An Unusual Oral Mass - Uncorrected Proof

Covering the Cover - Uncorrected Proof

Is HCV Infection a Neurologic Disorder? - Uncorrected Proof

Villin-Marked Gastric Progenitor Cells: Conveyors or Purveyors of Precancerous Change? - Uncorrected Proof

Curbside Consultation in IBS - Uncorrected Proof

Successful Training in Gastrointestinal Endoscopy - Uncorrected Proof

Acing the Hepatology Questions on the GI Board Exam: The Ultimate Crunch-Time Resource - Uncorrected Proof

Hepatic Cell-Specific Gene Expression Better Predicts HCV Treatment Outcome than IL28B Genotype - Accepted Manuscript

Gastric Sonic Hedgehog Acts as a Macrophage Chemoattractant During the Immune Response to Helicobacter pylori - Accepted Manuscript

Risk for Immune-Mediated Graft Dysfunction in Liver Transplant Recipients with Recurrent HCV Infection Treated with Pegylated Interferon - Accepted Manuscript

A Child With Diarrhea and Recurrent Otitis - Uncorrected Proof

An Unusual Etiology of Lower Abdominal Pain in a Young Adult - Uncorrected Proof

Can Surrogate Endpoints From a First-Round Screening Be Reliable for Colorectal Cancer Screening? - Uncorrected Proof

Environmental Contribution to Pathogenesis of Cyst Formation in Autosomal-Dominant Polycystic Liver Diseases - Uncorrected Proof

HLA-Cw*1202-B*5201-DRB1*1502 Haplotype Increases Risk for Ulcerative Colitis but Reduces Risk for Crohn's Disease - Uncorrected Proof

Comparing Fecal Immunochemical Testing: Improved Standardization Is Needed - Uncorrected Proof

Fast Routes to New Therapies: What Do Epilepsy And Inflammatory Bowel Disease Have In Common? - Uncorrected Proof

Appendicitis: Can Immediate Antibiotic Treatment Still Be Withheld? - Uncorrected Proof

Irritable Bowel Syndrome and Gluten Sensitivity Without Celiac Disease: Separating The Wheat From The Chafe - Uncorrected Proof

Individualized Screening for Colorectal Cancer: One Size Does Not Fit All - Uncorrected Proof

Reply - Uncorrected Proof

Reply - Uncorrected Proof

Fibroblast Growth Factor 19, An Anticholestatic Drug Produced by Human Liver - Uncorrected Proof

A Guide for Success as a Clinical Investigator - Uncorrected Proof

Autoimmunity, intestinal lymphoid hyperplasia, and Defects in Mucosal B-Cell Homeostasis in Patients with PTEN Hamartoma Tumor Syndrome - Accepted Manuscript

Requirements for Clinical Implementation of Biomarkers in Barrett's Esophagus - Uncorrected Proof

Translational Approaches for Pharmacotherapy Development for Acute Diarrhea - Uncorrected Proof

Continuing Medical Education (CME) Activities - Uncorrected Proof

FXR Protects Hepatocytes from Injury by Repressing miR-199a-3p, which Increases Levels of LKB1 - Accepted Manuscript

Increased Reprogramming Capacity of Mouse Liver Progenitor Cells, Compared with Differentiated Liver Cells, Requires the BAF Complex - Accepted Manuscript

Frequent Detection of Pancreatic Lesions in Asymptomatic High-Risk Individuals - Accepted Manuscript

Disruption of Notch1 Induces Vascular Remodeling, Intussusceptive Angiogenesis, and Angiosarcomas in Livers of Mice - Accepted Manuscript

Duodenal Activation of cAMP-Dependent Protein Kinase Induces Vagal Afferent Firing and Lowers Glucose Production in Rats - Accepted Manuscript

Response of the Upper Esophageal Sphincter to Esophageal Distension is Affected by Posture, Velocity, Volume, and Composition of the Infusate - Accepted Manuscript

CCL2-Induced Migration and SOCS3-Mediated Activation of Macrophages Are Involved in Cerulein-Induced Pancreatitis in Mice - Accepted Manuscript

HCV Infection Induces a Unique Hepatic Innate Immune Response Associated with Robust Production of Type III Interferons - Accepted Manuscript

Effects of Fractionated Plasma Separation and Adsorption on Survival in Patients with Acute-On-Chronic Liver Failure - Accepted Manuscript

Effect of IL28B Genotype on Early Viral Kinetics during Interferon-Free Treatment of Patients with Chronic Hepatitis C - Accepted Manuscript

Folic Acid Increases Global DNA Methylation and Reduces Inflammation to Prevent Helicobacter-Associated Gastric Cancer in Mice - Accepted Manuscript

Cigarette Smoking Increases Risk of Barrett's Esophagus: an Analysis of the Barrett's and Esophageal Adenocarcinoma Consortium - Accepted Manuscript

Body Mass Index Increases Risk for Colorectal Adenomas, Based on Meta-Analysis - Accepted Manuscript

Endoscopic Ultrasound-Guided Transmural and Percutaneous Transhepatic Gallbladder Drainage are Comparable for Acute Cholecystitis - Accepted Manuscript

HLA-Cw1202-B5201-DRB1*1502 Haplotype Increases Risk for Ulcerative Colitis but Reduces Risk for Crohn's Disease - Uncorrected Proof