Gastroenterology - Articles in Press

March CME Exam 1 Questions - Uncorrected Proof

2010-02-08

Correction - Uncorrected Proof

2010-02-08

Buchman AL, Howard LJ, Guenter P, et al. Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future. Gastroenterology 2009;137(5 Suppl):S1–S6.

Correction - Uncorrected Proof

2010-02-08

Shiffman ML, Morishima C, Dienstag JL, et al. Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial. Gastroenterology 2009;137:1986–1994.

Correction - Uncorrected Proof

2010-02-08

Dassopoulos T, Inadomi JM, Lewis JD, et al. The Development of Clinical Guidelines by the American Gastroenterology Association. Gastroenterology 2010;138:417–418. In the above article, the author affiliations appeared transposed for John M. Inadomi, MD and John I. Allen, MD, MBA, AGAF. The correct affiliations are as follows: John M. Inadomi, MD, San Francisco General Hospital University of California, San Francisco. John I. Allen, MD, MBA, AGAF, Minnesota Gastroenterology PA, University of Minnesota School of Medicine.

Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic Infection - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: Hyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection.Methods:: Resistant (BALB/c, C57BL/6), susceptible (AKR), and Muc2-deficient mouse strains were infected with the nematode, Trichuris muris and worm expulsion, energy status of the whipworms, changes in mucus/mucins, and inflammatory and immune responses were investigated following infection.Results:: The increase in Muc2 production, observed exclusively in resistant mice, correlated with worm expulsion. Moreover, expulsion of the worms from the intestine was significantly delayed in the Muc2-deficient mice. Although a marked impairment in the development of PAS-stained intestinal goblet cells was observed in Muc2-deficient mice, as infection progressed a significant increase in the number of PAS-positive goblet cells was observed in these mice. Surprisingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, was observed following infection of only the resistant animals. Overall, the mucus barrier in the resistant mice was less permeable than that of susceptible mice. Furthermore, the worms isolated from the resistant mice had a lower energy-status.Conclusions:: Mucins are an important component of innate defence in enteric infection; this is the first demonstration of the important functional contribution of mucins to host protection from nematode infection.

α-cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: The tumor suppressor menin is recognized as a key regulator of pancreatic islet development, proliferation and β-cell function, whereas its role in α-cells remains poorly understood. The purpose of the current study was to address this issue in relation to islet tumor histogenesis.Methods:: We generated α-cell-specific Men1 mutant mice using Cre/loxP technology and carried out analyses of pancreatic lesions developed in the mutant mice during ageing.Results:: We showed that, in spite of the α-cell specificity of the GluCre transgene, both glucagonomas and a large amount of insulinomas developed in mutant mice older than six months of age, accompanied by mixed islet tumors. Interestingly, the cells sharing characteristics of both α- and β-cells were identified shortly after the appearance of menin-deficient α-cells, but well before the tumor onset. Using a genetic cell lineage tracing analysis, we demonstrated that insulinoma cells were directly derived from transdifferentiating glucagon-expressing cells. Furthermore, our data indicated that the expression of Pdx1, MafA, Pax4 and Ngn3 did not seem to be required for the initiation of this transdifferentiation.Conclusions:: Our work reveals cell transdifferentiation as a novel mechanism involved in islet tumor development, and provides evidence showing that menin regulates the plasticity of differentiated pancreatic α-cells in vivo, shedding new light on the mechanisms of islet tumorigenesis.

Does Capsule Endoscopy Improve Outcomes in Obscure Gi Bleeding: Randomized Trial Vs. Dedicated Small Bowel Radiography - Accepted Manuscript

Loren Laine, Amandeep Sahota, Abbid Shah — 2010-02-04

Abstract: Background & Aims:: Capsule endoscopy improves the diagnostic yield in patients with obscure GI bleeding but whether it improves outcomes is uncertain.Methods:: Patients with obscure GI bleeding and negative upper endoscopy, colonoscopy, and push enteroscopy were randomly assigned to capsule endoscopy or dedicated small bowel contrast radiography. Patients returned at 1, 2, 3, 6, 9, and 12 months for follow-up visits and hemoglobin. The primary endpoint was further bleeding.Results:: The predefined sample size of 136 patients (54 overt bleeding, 82 occult bleeding) was enrolled. Diagnostic yield was 20 (30%) with capsule vs. 5 (7%) with radiography (difference=23%, 95% CI 11 to 36%). Further bleeding with capsule vs. radiography occurred in 20 (30%) vs. 17 (24%) (difference=6%, -9 to 21%), subsequent diagnostic or therapeutic interventions for bleeding were performed in 17 (26%) vs. 15 (21%) (difference=4%, -10 to 19%), subsequent hospitalizations for bleeding were required in 8 (12%) vs. 4 (6%) (difference=6%, -3 to 16%), and subsequent blood transfusions were given in 5 (8%) vs. 4 (6%) (difference=2%, -7 to 10%). Further bleeding was more common in patients presenting with overt bleeding than in those with occult bleeding (21/54 (39%) vs. 16/82 (20%); difference=19%, 4 to 35%).Conclusions:: The significant improvement in diagnostic yield with capsule endoscopy may not translate into improved outcomes in a population with obscure GI bleeding. Most patients do well whether or not abnormalities are identified, and additional diagnostic or therapeutic interventions may be required whether or not capsule endoscopy identifies a source of bleeding.

Interferon α Induces TRAIL on Natural Killer cells is Associated with Control of Hepatitis C Virus Infection - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: Pegylated interferon-α (PEG-IFNa), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, PEG-IFNα is believed to affect natural killer (NK) cells, which have been associated with control of HCV infection. We examined the effects of IFNα on human NK cells from patients with HCV infection.Methods:: We performed gene expression profiling studies of peripheral blood monocytes from patients with acute or chronic HCV infection that had received PEG-IFNa therapy. Samples from healthy subjects were used as controls. We evaluated IFNa-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using PCR and flow cytometry analyses of NK cells isolated from patients.Results:: TRAIL was among the most upregulated genes 4 h after IFNα stimulation of NK cells from patients with HCV infection. After in vitro stimulation with IFNα, CD56dim NK cells from patients who had responded to PEG-IFNα therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNα therapy. In patients with acute hepatitis C, TRAIL expression on CD56bright NK cells increased significantly compared with cells from controls. In in vitro studies, IFNα-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism.Conclusions:: IFNα-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV RNA levels during PEG-IFNα therapy.

Glucose-dependent insulinotropic polypeptide (GIP) is expressed in pancreatic islet α-cells and promotes insulin secretion - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: Glucose-dependent insulinotropic polypeptide (GIP) and the proglucagon product glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones that are released in response to nutrient intake and promote insulin secretion. Interestingly, a subset of enteroendocrine cells express both GIP and GLP-1. We sought to determine whether GIP might also be co-expressed with proglucagon in pancreatic ą-cells.Methods:: We assessed GIP expression via reverse transcription PCR, in situ hybridization, and immunohistochemistry. We developed a novel bioassay to measure GIP release from isolated islets, compared the biological activities of full-length and truncated GIP, and assessed the impact of immunoneutralization of islet GIP on glucose-stimulated insulin secretion in isolated islets.Results:: GIP mRNA was present in mouse islets; GIP protein localized to islet ą-cells of mouse, human, and snake pancreas, based on immunohistochemical analyses. However, using a C-terminal antibody GIP, immunoreactivity was detected in islets from PC2 knockout but not wild-type mice. Bioactive GIP was secreted from mouse and human islets following arginine stimulation. In the perfused mouse pancreas, GIP1-42 and amidated GIP1-30 had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion.Conclusions:: GIP is expressed and secreted from pancreatic islets; in ą-cells, PC2 processes proGIP to yield a truncated but bioactive form of GIP that differs from the PC1/3-derived form from K-cells. Islet-derived GIP promotes islet glucose competence and could also support islet development and/or survival.

A novel Gastrokine in mammals marks gastric atrophy and shows evidence of adaptive gene loss in humans - Accepted Manuscript

2010-02-04

Abstract: Background & Aims: Gastrokines are a family of gastric mucus cell-secreted proteins, consisting of two known members, GKN1 and GKN2. Gastrokines show loss of expression in gastric cancer and may act as tumour suppressors. Here, we identify a third gastrokine gene in mammals.Methods: Gkn3 was characterised by studies of molecular structure, evolutionary conservation and tissue expression as well as transcriptional/translational outcome in mouse genetic models of gastric pathology. The functional consequences of Gkn3overexpression were evaluated in transfected cell lines.Results: Gkn3 encodes a secreted (~19kDa) protein, co-expressed with trefoil factor (Tff)2 in gastric epithelium and Brunner’s glands, and discriminates a GS -II positive mucus neck cell (MNC) subpopulation. In humans, widespread homozygosity for a premature stop codon polymorphism, W59X, has likely rendered GKN3non-functional. Population genetic analysis revealed an ancestral GKN3read-through allele, predominating in Africans, arguing for rapid expansion of W59X in non-Africans during recent evolution. Gkn3expression is strongly induced in Tff2-deficient murine gastric atrophy, marking a non-proliferative GS -II positive, metaplastic lineage showing features of spasmolytic polypeptide-expressing metaplasia (SPEM). Gkn3overexpression inhibits proliferation in gastric epithelial cell lines, independently of recombinant human TFF2 treatment or apoptosis.Conclusions: Gkn3 encodes a novel, functionally distinct gastrokine that is overexpressed in gastric atrophy and limits epithelial cell proliferation. Spread of the human GKN3W59X stop allele may have been favoured in non-Africans owing to selective pressures influencing pre-neoplastic outcomes in the stomach.

Interferon α Induces TRAIL on Natural Killer cells is Associated with Control of Hepatitis C Virus Infection - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: Pegylated interferon-α (PEG-IFNa), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, PEG-IFNα is believed to affect natural killer (NK) cells, which have been associated with control of HCV infection. We examined the effects of IFNα on human NK cells from patients with HCV infection.Methods:: We performed gene expression profiling studies of peripheral blood monocytes from patients with acute or chronic HCV infection that had received PEG-IFNa therapy. Samples from healthy subjects were used as controls. We evaluated IFNa-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using PCR and flow cytometry analyses of NK cells isolated from patients.Results:: TRAIL was among the most upregulated genes 4 h after IFNα stimulation of NK cells from patients with HCV infection. After in vitro stimulation with IFNα, CD56 dim NK cells from patients who had responded to PEG-IFNα therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNα therapy. In patients with acute hepatitis C, TRAIL expression on CD56 bright NK cells increased significantly compared with cells from controls. In in vitro studies, IFNα-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism.Conclusions:: IFNα-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV RNA levels during PEG-IFNα therapy.

Adjunctive Functional Pharyngeal Electrical Stimulation Reverses Swallowing Disability following Brain Lesions - Accepted Manuscript

2010-02-04

Abstract: Background & Aims:: Oropharyngeal dysphagia is an important disability that occurs following stroke; it contributes to aspiration pneumonia and death, and current modalities for rehabilitation of dysphagia have uncertain efficacy. We therefore examined the role of pharyngeal electrical stimulation (PES) in expediting human swallowing recovery after experimental (virtual) and actual (stroke) brain lesions.Methods:: First, healthy subjects (n=13) were given 1Hz repetitive transcranial magnetic stimulation to induce a unilateral virtual lesion in pharyngeal motor cortex followed by active or sham (control) PES. Motor-evoked potentials and swallow accuracy were recorded before and after the lesion to assess PES response. Thereafter, 50 acute dysphagic stroke patients underwent either a dose response study, to determine optimal parameters for PES (n=22), or were randomly assigned to groups given either active or sham (control) PES (n=28). The primary endpoint was the reduction of airway aspiration at 2 weeks post intervention.Results:: In contrast to sham PES, active PES reversed the cortical suppression induced by the virtual lesion ( F 7, 70=2.7, p=0.015) and was with associated improvement in swallowing behavior ( F 3, 42=5, p=0.02). Following stroke, 1 PES treatment each day ( U =8·0, p=0.043) for 3 days ( U =10·0) produced improved airway protection, compared with controls (p=0.038). Active PES also reduced aspiration, ( U =54·0, p=0·049), improved feeding status ( U =58.0, p=0.040), and resulted in a shorter time to hospital discharge (Mantel-Cox log rank test p=0.038).Conclusion:: This pilot study of PES confirms that it is a safe neurostimulation intervention which reverses swallowing disability following virtual lesion or stroke.

Glowing in the Dark: Not Always a Bad Thing - Uncorrected Proof

Sasan Sakiani, Christopher Koh, Theo Heller — 2010-02-01

Question: A 55-year-old male long-distance runner of many years' underwent evaluation for an unusual movement disorder of the right lower extremity. During the evaluation, a magnetic resonance angiogram of the abdomen, pelvis, and lower extremities was performed to rule out intimal thickening and kinking of pelvic arteries that could have contributed to some of his symptoms. An incidental finding of a 1.7-cm lesion on the right lobe of the liver was identified (, arrow).

The Death of the Pen - Uncorrected Proof

Michael B. Wallace — 2010-02-01

As I rounded on our inpatient service recently, I realized simultaneously that I had forgotten my pen—and that it didn't matter. I am uncertain whether to lament or marvel as we move beyond one of the great technological developments of our time: the use of pen and paper. As physicians, we have come to expect a pen in our pocket and a stethoscope around our neck. Both habits are changing, but I will focus on the pen. This change will have important implications for how we practice and discover new knowledge in medicine.

This Month in Gastroenterology - Uncorrected Proof

By Jan Tack, John M. Carethers — 2010-02-01

Chronic constipation is a highly prevalent condition characterized by infrequent bowel movements with hard stool consistency, straining during evacuation, and abdominal discomfort and bloating. Traditionally, chronic constipation is managed by life style and dietary modifications, with addition of laxatives and stool softeners in many cases. More recently, lubiprostone, a chloride channel activator, was shown to be effective in the treatment of chronic constipation. Despite these modalities, a large proportion of patients remains incompletely relieved with currently available therapeutic approaches.

Prevalence of Uninvestigated Dyspepsia 8 Years After a Large Waterborne Outbreak of Bacterial Dysentery: Cohort Study - Accepted Manuscript

2010-02-01

Abstract: Background & aims:: Symptoms of dyspepsia may occur following an episode of acute gastroenteritis, but data are conflicting. We assessed prevalence of uninvestigated dyspepsia in a cohort of individuals, some of whom were exposed to bacterial dysentery in May 2000, as well as risk factors for dyspepsia in exposed individuals.Methods:: This was a cohort study conducted in the town of Walkerton, Ontario. Involved individuals were recruited into the Walkerton Health Study between 2002 and 2003, and were attending for annual assessment in 2008. Exposed individuals were subdivided into those with self-reported gastroenteritis, with acute illness unconfirmed by health records, and those with clinically confirmed gastroenteritis, with substantiation of acute illness by health record review. Presence of dyspepsia at 8 years, according to a broad definition (any symptom referable to the upper gastrointestinal tract), and the Rome II criteria was compared between exposed and non-exposed individuals.Results:: Of 2597 subjects eligible, 1088 (41.9%) provided data for analysis, 706 (64.9%) had reported acute gastroenteritis. Multivariate odd ratios for dyspepsia at 8 years in exposed individuals using a broad definition and the Rome II definition were 2.09 (95% CI 1.58 to 2.78) and 2.30 (95% CI 1.63 to 3.26) respectively. Prevalence of dyspepsia was higher in females, smokers, those with pre-morbid irritable bowel syndrome, anxiety, or depression, and those reporting > 7 days of diarrhea or abdominal cramps during the acute illness.Conclusions:: Symptoms of dyspepsia 8 years after an outbreak of acute gastroenteritis were significantly more prevalent in exposed compared with non-exposed individuals.

Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity - Accepted Manuscript

2010-02-01

Abstract: Background & Aims:: Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid intake; it regulates pancreatic digestive enzymes that are required for absorption of nutrients. We proposed that mice with a disruption in the CCK gene (CCK-KO mice) that were fed a diet of 20% butter fat would have altered fat metabolism.Methods:: We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK-KO mice using an automated measurement system. Intestinal fat absorption and energy expenditure were determined using a noninvasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively.Results:: After consuming a high-fat diet for 10 weeks, CCK-KO mice had reduced body weight gain and body fat mass and enlarged adipocytes, despite the same level of food intake as wild-type mice. CCK-KO mice also had defects in fat absorption, especially of long-chain saturated fatty acids, but pancreatic triglyceride lipase (PTL) did not appear to have a role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type mice and CCK-KO mice had greater oxidation of carbohydrates while on the high-fat diet. Plasma leptin levels in the CCK-KO mice fed the high-fat diet were markedly lower than in wild-type mice, although levels of insulin, gastric-inhibitory polypeptide, and glucagon-like peptide-1 were normal.Conclusion:: CCK is involved in regulating the metabolic rate and is important for lipid absorption and control of body weight in mice placed on a high-fat diet.

A 79-Year-Old Patient With Yellow Sputum - Uncorrected Proof

Sebastian Weis, Joachim Mössner, Konrad Schoppmeyer — 2010-01-29

Question: A 79-year-old woman was admitted with a 2-day history of vomiting, malaise, and nocturnal yellowish stained cough. She denied having fever or pain. One month earlier she has had an episode of Escherichia coli pneumonia and sepsis. Her history included a cholecystectomy 9 months ago. Postoperatively, a benign bile duct stenosis had caused recurrent episodes of cholangitis and was treated by repeated endoscopic stenting. Furthermore, paroxysmal atrial fibrillation, coronary artery disease, and type 2 diabetes mellitus were present.

The Role of Iron in Nonalcoholic Fatty Liver Disease: The Story Continues - Uncorrected Proof

Kris V. Kowdley — 2010-01-29

See “HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease,” by Valenti L, Ludovica FA, Elisabetta B, et al, on page •••.

Cooperation between the Thyroid hormone receptor TRα1 and the WNT pathway in the induction of intestinal tumorigenesis - Accepted Manuscript

2010-01-29

Abstract: Background and aim.: Colorectal tumorigenesis is a multistep process involving the alteration of oncogenes and tumor suppressor genes, leading to the deregulation of molecular pathways that govern intestinal homeostasis. We have previously shown that the thyroid hormone receptor α1 controls intestinal development and homeostasis through the WNT pathway. More precisely, TRα1 directly enhances the transcription of several components of this pathway, allowing the increased expression of β-catenin/Tcf4 target genes and stimulation of cell proliferation. Since the WNT pathway is a major player in controlling intestinal homeostasis, we addressed whether the TRα1 receptor has tumor-inducing potential.Methods.: We generated mice overexpressing TRα1 specifically in the intestinal epithelium in a wild-type (vil-TRα1) or a WNT-activated (vil-TRα1/Apc+/1638N) genetic background.Results.: The intestine of vil-TRα1 mice presents aberrant intestinal mucosal architecture, increased cell proliferation and develop adenoma at low rate. However, TRα1 overexpression per se is unable to induce cancer development. On the contrary, we observed accelerated tumorigenesis in vil-TRα1/Apc+/1638N mice, compared with the Apc+/1638N mutants.In conclusion, our results suggest that this phenotype is due to cooperation between the activated TRα1 and WNT pathways. This is the first report describing the tumor-inducing function of the TRα1 in the intestine.

Carriers of Inactive Hepatitis B Virus Are Still at Risk for Hepatocellular Carcinoma and Liver-Related Death - Accepted Manuscript

2010-01-29

Abstract: Background & Aims:: The risk and the predictors of liver disease progression in carriers of inactive hepatitis B virus (HBV) are unclear.Methods:: Participants in the REVEAL HBV study who were seronegative for hepatitis B e antigen; had serum levels of HBV DNA <10,000 copies/mL; and did not have cirrhosis, hepatocellular carcinoma, or increased serum levels of alanine aminotransferase were classified as carriers of inactive HBV (n=1,932). Study participants who were seronegative for HB surface antigen and antibodies against HCV, yet had similar clinical liver features, were the controls (n=18,137). Liver-related death and new cases of hepatocellular carcinoma were ascertained through computerized data linkage with National Cancer Registry and Death Certification profiles. The disease progression rates were estimated. The multivariate-adjusted hazard ratios for risk predictors were derived from Cox regression models.Results:: There were 20,069 participants, contributing a total of 262,122 person-years, with a mean follow-up of 13.1 years. The annual incidence rates of hepatocellular carcinoma and liver-related death were 0.06% and 0.04%, respectively, for inactive HBV carriers; the rates were 0.02%, and 0.02% for controls, respectively. The multivariate-adjusted hazard ratios for the carriers of inactive HBV, compared to controls, were 4.6 (95% confidence interval [CI] 2.5–8.3) for hepatocellular carcinoma and 2.1 (95% CI 1.1–4.1) for liver-related death. Older age and alcohol drinking habits were independent predictors of risk for carriers of inactive HBV to develop hepatocellular carcinoma.Conclusions:: Carriers of inactive HBV have a substantial risk of hepatocellular carcinoma and liver-related death, compared with individuals not infected with HBV.

Unusual Tumor That Presented With Rectal Bleeding - Uncorrected Proof

Hung-Hua Liang, Weu Wang, Po-Li Wei — 2010-01-28

Question: A 53-year-old man received a health check-up and showed a positive occult blood in the stool. He has no tenesmus, no abdominal pain, no bowel habit changes, and no small-caliber stool. There was also no palpitation, no hot flushes, and no loss of body weight. Colonoscopy revealed a rectal polyp with a broad base, found proximally 6 cm from the anal verge ( and ). Biopsy was performed and the pathologic examination showed tubulovillous adenoma with focal malignant change. A low anterior resection was performed. Two separate parts of the tumor were seen on the cut surface ().

March CME Exam 2 Questions - Uncorrected Proof

2010-01-28

Taking a Lesson From Microbial Diarrheagenesis in the Management of Chronic Constipation - Uncorrected Proof

Adil E. Bharucha, Scott A. Waldman — 2010-01-28

See “Linaclotide is effective for patients with chronic constipation,” by Lembo AJ, Kurtz CR, MacDougall JE, et al, on page •••.

An Unusual Cause of Abdominal Pain in a Cirrhotic Patient - Uncorrected Proof

Hung-Hsu Hung, Tseng-Shing Chen, Gar-Yang Chau — 2010-01-27

Question: A 57-year-old woman presented to the emergency department (ED) with fever, chills, and right upper-quadrant abdominal pain for further evaluation. She had a history of chronic hepatitis C–related liver cirrhosis and a gallbladder stone. Sclerotherapy was previously applied for gastric varices bleeding. In the ED, the blood counts were the following: white blood cells, 10,700/mm3 (normal, 4,800–10,800/mm3), hemoglobin, 13 g/dL (normal, 12–16), and platelets 34,000/mm3 (normal, 130,000–400,000/mm3). The differential count of white blood cell was neutrophils, 95%; lymphocytes, 2%; monocytes, 3%; eosinophils, 0%; and basophils, 0%. Serum biochemistry test results were as follows: alanine aminotransferase, 16 IU/L (normal, 0–40), γ-glutamyltransferase, 26 U/L (normal, 8–61), total bilirubin, 2.07 mg/dL (normal, 0.2–1.6), and C-reactive protein, 9.54 mg/dL (normal, 0–0.5). Acute cholecystitis was suspected and abdominal computed tomography (CT) was arranged (). As compared with the previous CT scan from 2 years previously (), gallstone dislocation and perihepatic fluid accumulation was disclosed. What is the possible diagnosis?

An Unusual Case of Rectal Bleeding and Hemospermia - Uncorrected Proof

Jia Liu Stevens, Katherine Schon, Hasan Mukhtar — 2010-01-25

Question: A 29-year-old man presented to the colorectal clinic complaining of a 1-month history of mild fresh rectal bleeding. Over the past 5 months, he also noticed blood in his semen. This subsequently became yellow, discolored, and developed a lumpy texture before presentation. No additional symptoms were reported. He also had no significant past medical history and was not on any regular medications. His family history revealed cancers of the bladder and prostate; however, no colonic polyposis or bowel cancer was reported. He smokes and drinks alcohol occasionally and works as an architect. On examination his abdomen was soft and nontender with no palpable masses. Digital rectal examination revealed a roughened and thickened fold of mucosa palpated in the lower rectum. A rigid sigmoidoscopy was performed and an irregular flat mucosal lesion with multiple polyps was visualized. His basic laboratory blood tests revealed a normal full blood count and urea and electrolytes. Examining the urine on microscopy, inflammatory infiltrates were seen suggestive of infection. However, no organism was isolated on urine or semen culture. An urgent colonoscopy with colonic biopsy was arranged. The endoscopic view of the rectum can be seen in . Biopsies were taken and sent for hematoxylin and eosin staining (), demonstrating a high-powered view.

Controversies Involving the Role of 5-Hydroxytryptamine in Generating Colonic Migrating Motor Complexes: What Is Spontaneous? - Uncorrected Proof

2010-01-25

It is important to understand and elucidate the mechanisms underlying the colonic migrating motor complex (CMMC), because it is a primary motor event in the large bowel that assists in the movement of fecal contents. Recently, Keating and Spencer used tension recordings and real-time amperometry to determine the role of 5-hydroxytryptamine (5-HT) in generating CMMCs in the isolated mouse colon. They make a number of conclusions that seem to contradict our recent study.

Proliferative suppression by CDK4/6 inhibition: complex function of the RB-pathway in liver tissue and hepatoma cells - Accepted Manuscript

2010-01-25

Abstract: Background and Aims:: Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide and current chemotherapeutic interventions for this disease are largely ineffective. The retinoblastoma tumor suppressor (RB) is functionally inactivated at relatively high frequency in hepatocellular carcinoma and hepatoma cell lines. Here we interrogated the ability of CDK4/6-inhibition to inhibit hepatocyte proliferation and the impact of RB-status on this process.Methods:: Hepatoma cell lines and xenograft models harboring RB knockdown and mice harboring liver specific Rb deletion were utilized to define the role of RB function in response to CDK4/6 inhibition.Results:: Our study shows that CDK4/6-dependent, cell cycle progression in hepatoma cells was readily arrested by inhibition of CDK4/6 by PD-0332991 or p16ink4a irrespective of RB status. Interestingly, upon CDK4/6 inhibition, p107 protein stability was dramatically increased as a function of RB loss. This engagement of compensatory mechanisms was critical for cell cycle inhibition in the absence of RB, as both the E1A oncoprotein and overexpression of E2F proteins were capable of overcoming the impact of CDK4/6 inhibition. These findings were recapitulated in xenograft models. Furthermore, to determine how these findings relate to hepatocyte proliferation in vivo, mice were exposed to carbon tetrachloride to induce liver regeneration followed by treatment with PD-0332991. This treatment significantly inhibited hepatocyte proliferation. Strikingly, this facet of PD-0332991 function was retained even in RB-deficient livers.Conclusions:: These data demonstrate that CDK4/6 inhibition is a potent mediator of cytostasis, and RB loss can be readily compensated for in the context of both hepatoma cell lines and in liver tissue.

Meta-Analysis Shows that Detection of Circulating Tumor Cells Indicates Poor Prognosis in Patients with Colorectal Cancer - Accepted Manuscript

2010-01-25

Abstract: Background & Aims: The prognostic significance of circulating (CTC) and disseminated tumor cells (DTC) in patients with colorectal cancer (CRC) is controversial. We performed a meta-analysis of available studies to assess whether the detection of tumor cells in the blood and bone marrow of patients diagnosed with primary CRC can be used as a prognostic factor.Methods: We searched the Medline, Biosis, Science Citation Index and Embase databases and reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB), mesenteric/portal blood (MPB) or bone marrow (BM) of patients with CRC. Meta-analyses were carried out using a random effects model, with hazard ratio (HR) and 95% confidence intervals (95% CI) as effect measures.Results: A total of 36 studies including 3094 patients were eligible for final analyses. Pooled analyses that combined all sampling sites (PB, MPB, and BM) associated the detection of tumor cells with poor recurrence-free survival (RFS) (HR 3.24, 95% CI 2.06–5.10, n=26, I2=77%) and overall survival (OS) (2.28, 1.55–3.38, n=21, I2=66%). Stratification by sampling site revealed that detection of tumor cells in the PB compartment was a statistically significant prognostic factor (RFS: 3.06, 1.74–5.38, n=19, I2=78%; OS: 2.70, 1.74–4.20, n=16, I2=59%), but not in the MPB (RFS: 4.12, 1.01–16.83, n=8, I2=75%; OS: 4.80, 0.81–28.32, n=5, I2=82%) or in the BM (RFS: 2.17, 0.94–5.03, n=4, I2=78%; OS: 1.50, 0.52–4.32, n=3, I2=84%).Conclusion: Detection of CTC in the peripheral blood indicates poor prognosis in patients with primary CRC.

Recent Advances in Gastroenterology - Uncorrected Proof

Mark Osterman — 2010-01-25

Chris Probert's Recent Advances in Gastroenterology provides a review of recent “hot topics” in gastroenterology. The primary aim of this 220-page review book, as stated by Dr Probert, the book's editor, is to help educate gastroenterology fellows, medical residents, and general practitioners who are developing subspecialty clinics. The book is also intended to help update gastroenterologists in a variety of topics. I believe that Dr Probert and his colleagues have achieved their goals. With respect to general content, including chapters on eosinophilic esophagitis, Barrett's esophagus, bariatric surgery, nonalcoholic fatty liver disease, irritable bowel syndrome, and inflammatory bowel disease is appropriate and necessary given not only the recent advances made in these fields, but also the overall burden of these diseases. For instance, eosinophilic esophagitis is becoming increasingly recognized as an important cause of dysphagia in the young; gastroesophageal reflux disease continues to be highly prevalent; the Western world (especially the United States) is experiencing an epidemic of obesity; irritable bowel syndrome is starting to be rigorously investigated on a scientific level; and anti-tumor necrosis factor agents have not only changed the way we treat inflammatory bowel disease, but may have also changed the natural history of the disease.

Atlas of Pancreatic Cytopathology with Histopathologic Correlation - Uncorrected Proof

Brando Cobanov, Prabodh K. Gupta — 2010-01-25

With the advent and recent advances in endoscopic ultrasound-guided fine needle aspiration of lesions of the gastrointestinal tract, particularly the pancreas, the Atlas of Pancreatic Cytopathology with Histopathologic Correlations is a welcome addition to the literature. Just as the name explicitly states, this hardback book superbly correlates the cytopathology of pancreatic lesions with the histopathology. Being part of The Sol Goldman Pancreatic Cancer Research Center at The Johns Hopkins University, in a very practical atlas, the world-renowned authors have compiled their personal experience with a number of pancreatic lesions sampled by the 2 commonly used imaging techniques—ultrasonography and computer-assisted tomography (CT). Practicing surgical pathologists and cytopathologists, as well as pathology residents and fellows, will find this atlas to be an excellent reference.

Intestinal Disorders, Falk Symposium 164 - Uncorrected Proof

Sonia Friedman — 2010-01-25

The aim of this book is to provide an up-to-date review of the clinical, pathologic, and genetic advances in intestinal disorders. It is a compilation of the proceedings of the Falk Symposium 164 entitled, “Intestinal Disorders,” held in Budapest, Hungary, on May 2–3, 2008. The lectures are mainly written and edited by European authors and give a slightly different perspective than the usual treatment algorithms one encounters in US gastroenterology. For example, there is some data on using mesalamine drugs and probiotics to prevent and treat diverticulitis and on novel agents used to treat irritable bowel syndrome. Because the Falk Symposium occurred about 1.5 years ago, recent data that have been reported is not included. Two examples are new data on prevention and treatment of diverticulitis and emergent management of lower gastrointestinal bleeding (Am J Gastroenterol 2009;104:1221–1230; Gastroenterology 2009;136:115–122; JAMA 2008;300:907–914; Clin Gastroenterol Hepatol 2008;6:1004–1010).

A Knockout for Lynch Syndrome - Uncorrected Proof

Richard Boland — 2010-01-25

See “An MSH2 conditional knockout mouse for studying intestinal cancers,” by Kucherlapati MH, Lee K, Nguyen AA, et al, on page •••.

Tracking Down the Hedgehog's Lair in the Pancreas - Uncorrected Proof

Anirban Maitra — 2010-01-25

See “Pancreatic duct glands are specialized ductal compartments that react to chronic injury and mediate Shh-induced metaplasia,” by Strobel O, Roscow DE, Rakhlin EY, et al, on page •••.

miRNA Delivery: Emerging Therapy for Hepatocellular Carcinoma - Uncorrected Proof

Sara Toffanin, Augusto Villanueva, Josep M. Llovet — 2010-01-25

Kota J, Chivukula RR, O'Donnell KA, et al. (Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio). Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009;137:1005–1017.

The 2-Phase Model of Crohn's Disease: From Immune Defect to Hyperresponse - Uncorrected Proof

Azucena Salas, Julian Panés — 2010-01-25

Smith AM, Rahman FZ, Hayee B, et al. (Department of Medicine, University College London, London, UK). Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 2009;206:1883–1897.

Uncorrected Proof

Anthony W. Segal — 2010-01-25

We thank Drs Salas and Panés for their excellent summary. However, there seems to be a general misunderstanding of the relationship between genes like those for NOD2 and ATG16L1 and the causation of Crohn's disease (CD). The associated abnormalities in these genes are neither necessary nor sufficient to cause the disease.

Colon Capsule Endoscopy: Fantastic Voyage or Ship Adrift in Murky Waters? - Uncorrected Proof

Douglas J. Robertson, Jason A. Dominitz — 2010-01-25

Van Gossum A, Munoz-Navas M, Fernandez-Urien I, et al. (Department of Gastroenterology, Erasme Univeristy Hospital, Université Libre de Bruxelles, Brussels, Belgium). Capsule endoscopy versus colonoscopy for the detection of polyps and cancer. N Engl J Med 2009;361:264–270.

Uncorrected Proof

André Van Gossum, Jacques Devière — 2010-01-25

Robertson and Dominitz adequately pointed out the issues raised in our multicenter trial comparing colon capsule and standard colonoscopy for the detection of polyps and cancer (N Engl J Med 2009;361:264–370). Indeed, colon preparation is currently among the major concerns and is significantly more demanding with capsule colonoscopy. It accounts at least in part for the low sensitivity. As an example, out of the 5 missed cancers at colon capsule, 3 patients had a poor preparation, 1 lesion was located in the rectum in a patient in whom the capsule batteries expired in the sigmoid, and the last patient had 6 other polyps <6 mm. The good news from that is that in real life, all these patients would probably have undergone a subsequent standard colonoscopy.

Bile acid mimetic-activated TGR5 receptor in metabolic-related liver disorder: the good and the bad - Uncorrected Proof

Raoul Poupon — 2010-01-25

Thomas C, Gioiello A, Noriega L, et al. (Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France). TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167–177.

HuR/Methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation and carcinogenesis - Accepted Manuscript

2010-01-25

Abstract: Background & Aims: Hepatic de-differentiation, liver development, and malignant transformation are processes in which the levels of hepatic S-adenosylmethionine (SAMe) are tightly regulated by two genes, MAT1A and MAT2A. MAT1A is expressed in the adult liver, whereas MAT2A expression is primarily extra-hepatic and is strongly associated with liver proliferation. The mechanisms that regulate these expression patterns are not completely understood. In silico analysis of the 3'untranslated region of MAT1A and MAT2A revealed putative binding sites for the RNA-binding proteins AUF1 and HuR, respectively. We investigated the post-transcriptional regulation of MAT1A and MAT2A by AUF1, HuR and methyl-HuR in the aforementioned biological processes.Results: During hepatic de-differentiation, the switch between MAT1A and MAT2A coincided with an increase in HuR and AUF1 expression. SAMe treatment altered this homeostasis by shifting the balance of AUF1 and methyl-HuR/HuR, which was identified for the first time as an inhibitor of MAT2A mRNA stability. We also observed a similar temporal distribution and a functional link between HuR, methyl-HuR, AUF1, and MAT1A and MAT2A during the fetal liver development. Immunofluorescent analysis revealed increased levels of HuR and AUF1, and a decrease in methyl-HuR levels in human livers with hepatocellular carcinoma (HCC).Conclusions: Our data strongly support a role for AUF1 and HuR/methyl-HuR in liver de-differentiation, development and human HCC progression through the post-translational regulation of MAT1A and MAT2A mRNAs.

Clonality Assessment and Clonal Ordering of Individual Neoplastic Crypts Shows Polyclonality of Colorectal Adenomas - Accepted Manuscript

2010-01-25

Abstract: Background & Aims: According to the somatic mutation theory, monoclonal colorectal lesions arise from sequential mutations in the progeny of a single stem cell. However, studies in a mosaic (XO/XY) patient indicated that colorectal adenomas were polyclonal. We assessed adenoma clonality on an individual crypt basis and completed a genetic dependency analysis in carcinomas-in-adenomas to assess mutation order and timing.Methods: Polyp samples were analyzed from: the XO/XY individual; patients with familial adenomatous polyposis (FAP) and attenuated FAP (AFAP); patients with small sporadic adenomas; and patients with sporadic carcinoma-in-adenomas. Clonality was analyzed using X/Y chromosome fluorescence in situ hybridization, analysis of 5q LOH in XO/XY tissue, and sequencing of APC. Individual crypts and different phenotypic areas of carcinoma-in-adenoma lesions were analyzed for mutations in APC, p53, and K-RAS; LOH at 5q, 17p, and 18q LOH; and aneuploidy. Phylogenetic trees were constructed.Results: All FAP-associated adenomas and some sporadic lesions had polyclonal genetic defects. Some independent clones appeared to be maintained in advanced adenomas. No clear obligate order of genetic events was established. Top-down growth of dysplastic tissue into neighboring crypts was a possible mechanism of clonal competition.Conclusions: Human colorectal microadenomas are polyclonal and may arise from a combination of host genetic features, mucosal exposures and active crypt interactions. Analyses of tumor phylogenies show that most lesions undergo intermittent genetic homogenization, but heterotypic mutation patterns indicate that independent clonal evolution can occur throughout adenoma development. Based on observations of clonal ordering the requirement and timing of genetic events during neoplastic progression may be more variable than previously thought.

Aberrant DNA Methylation in Hereditary Non-Polyposis Colorectal Cancer without Mismatch Repair Deficiency - Accepted Manuscript

2010-01-25

Abstract: Background & Aims:: Approximately half of the families that fulfill Amsterdam criteria for Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) do not have evidence of the germline mismatch repair (MMR) gene mutations that define this syndrome and result in microsatellite instability. The carcinogenic pathways and the best diagnostic approaches to detect microsatellite stable (MSS) HNPCC tumors are unclear. We investigated the contribution of epigenetic alterations to development of MSS HNPCC tumors.Methods:: Colorectal cancers were divided in four groups: 1. Microsatellite stable, Amsterdam positive (MSS HNPCC) (N=22); 2. Lynch syndrome cancers (identified mismatch repair mutations) (N=21); 3. Sporadic MSS (N=92); 4. Sporadic MSI (N=46). Methylation status was evaluated for CACNAG1, SOCS1, RUNX3, NEUROG1, MLH1, and LINE-1. KRAS and BRAF mutations status was analyzed.Results:: MSS HNPCC tumors displayed a significantly lower degree of LINE-1 methylation, marker for global methylation, than any other group. Whereas most MSS HNPCC tumors had some degree of CpG island methylation, none presented a high index of methylation. MSS HNPCC tumors had KRAS mutations exclusively in codon 12, but none harbored V600E BRAF mutations.Conclusions:: Tumors from Amsterdam-positive patients without mismatch repair deficiency (MSS HNPCC) have certain molecular features, including global hypomethylation that distinguish them from all other colorectal cancers. These characteristics could have an important impact on tumor behavior or treatment response. Studies are underway to further assess the cause and effects of these features.

Herpes simplex Virus type 1 Infection of the Rat Enteric Nervous System Evokes Small Bowel Neuromuscular Abnormalities - Accepted Manuscript

2010-01-25

Abstract: Background & Aims:: Infectious agents, like neurotropic viruses, are proposed to disrupt the enteric neuromuscular system, leading to dysmotility, although the mechanisms are unknown. Our purpose was to assess whether herpes simplex virus type-1 (HSV-1) establishes an enteric-neuronal infection and induces gut dysmotility.Methods:: Rats were inoculated with HSV-1 intranasally and after 4 weeks intragastrically. After 1–10 weeks, infection was determined by molecular analysis whereas neuromuscular function was evaluated by pharmacological/electrical stimulation of longitudinal ileal segments and by gastrointestinal transit and by [3H]acetylcholine release measurements. Inflammation in neuromuscular layer was assessed by myeloperoxidase and cytokines levels and by anti-CD3+ immunohistochemistry.Results:: Following 1–10 weeks intragastric inoculation, HSV-1 latency-associated mRNA transcripts were detected in the brain and in ileal neurons with no signs of illness or histological gut abnormalities. Using a recombinant HSV-1 carrying the lacZ gene, HSV-1 virions were localized in myenteric ganglia by in situ X-gal staining. IL-2 and IFN-γ levels were significantly increased 1 and 6 weeks post-inoculation. CD3+ cells were found around the myenteric ganglia 6 weeks post-inoculation. Smooth muscle responses to carbachol, CaCl2 and gut transit were significantly increased after 1 and 6 weeks, whereas KCl- and EFS-mediated contractions were significantly modified only 1-2 weeks after HSV-1 administration. The release of [3H]acetylcholine was significantly reduced in ileum segments after 1 and 6 weeks.Conclusions:: Following intragastric inoculation, HSV-1 establishes a latent infection in the rat myenteric ganglia which leads to gut dysmotility.

Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells - Accepted Manuscript

2010-01-25

Abstract: Background & aims:: Previous studies of pancreatic acinar cells characterised the effects of Ca2+ releasing secretagogues and substances inducing acute pancreatitis on mitochondrial Ca2+, transmembrane potential and NAD(P)H, but dynamic measurements of the crucial intracellular ATP levels have not been reported. Here we characterised the effects of these agents on the ATP levels in the cytosol and the mitochondria.Method:: ATP levels were monitored using cytosolic or mitochondrial targeted luciferases.Results:: Inhibition of oxidative phosphorylation produced a substantial decrease in cytosolic ATP comparable to that induced by inhibition of glycolysis. Cholecystokinin (CCK) increased the cytosolic ATP in spite of accelerating ATP consumption. Acetylcholine (ACh), Caerulein and Bombesin had similar effect. A bile acid - taurolithocholic acid 3-sulfate (TLC-S), a fatty acid - palmitoleic acid (POA) and palmitoleic acid ethyl ester (POAEE) reduced cytosolic ATP. The ATP decrease in response to these substances was observed in cells with intact or inhibited oxidative phosphorylation. TLC-S, POA and POAEE reduced mitochondrial ATP, whereas physiological CCK increased mitochondrial ATP. Supramaximal CCK produced a biphasic response composed of a small initial decline followed by a stronger increase.Conclusions:: Both glycolysis and oxidative phosphorylation make substantial contributions to ATP production in acinar cells. Ca2+-releasing secretagogues increased the ATP level in the cytosol and the mitochondria of intact isolated cells. TLC-S, POA and POAEE reduced cytosolic and mitochondrial ATP. When cells rely on non-oxidative ATP production, secretagogues as well as TLC-S, POA and POAEE all diminish cytosolic ATP levels.

Reply - Uncorrected Proof

Damien J. Keating, Nick J. Spencer — 2010-01-25

We would first like to respond directly to some aspects raised in Smith et al. We applied similar resting tension to our preparations (5–10 mN) to that of Heredia et al (8 mN). Additionally, we never measured basal CMMC amplitudes close to 150 mN, as suggested; these authors seem confused with CMMC amplitudes of this magnitude that were evoked by the focal application of 5-HT to the myenteric plexus (Keating and Spencer; Figure 6B). Our CMMC amplitudes (average 30–50 mN; Figure 3C) are of a similar magnitude to those in traces provided by Heredia et al. Any differences in mean CMMC properties between our 2 studies is most likely due to the use of an open sheet conformation, as opposed to the intact tube used by Heredia et al. Furthermore, we find that in the absence of the mucosa, stretch evokes premature CMMCs at the same threshold as when the mucosa is present. Finally, our mucosa-free preparations were always dissected in ice-cold Krebs solution to prevent loading of myenteric neurons with 5-HT. This is most important; it has been illustrated previously that removal of the mucosa results in a lack of 5-HT uptake into myenteric neurons. This eliminates any concerns raised by Smith et al 2009 regarding our recent publication.

Introduction From New Editors for Imaging and Advanced Technology - Uncorrected Proof

Ralf Kiesslich, Pankaj Jay Pasricha — 2010-01-25

The reclusive American poet Emily Dickinson is said to only have allowed doctors to “examine” her as she walked past an open door several feet away. Dickinson, who died of renal failure, was perhaps looking ahead at a future of medical imaging where diagnoses can be made with pinpoint accuracy without the physician even being in the same room. Such a future is here today, and those of us in clinical medicine are particularly fortunate to be in the midst of a far-reaching revolution in diagnostic and therapeutic technology that has transformed the way we take care of our patients. At the same time, the pace of biological discovery is being accelerated dramatically by the introduction of remarkable technological innovations for the analysis and imaging of cellular, subcellular, and molecular structure and function. Indeed, what lies ahead is the very logical fusion of these 2 fronts to provide an integrated approach for spatial, structural, and functional detection and eradication of disease.

Pentoxifylline Does Not Decrease Short-Term Mortality But Does Reduce Complications in Patients With Advanced Cirrhosis - Accepted Manuscript

2010-01-25

Abstract: Background & Aims:: Pentoxifylline, an inhibitor of tumor necrosis factor-alpha, is given to patients with liver diseases, but its effects in patients with advanced cirrhosis are unknown. We performed a randomized, placebo-controlled, double-blind trial of its effects in patients with cirrhosis.Methods:: A total of 335 patients with cirrhosis (Child-Pugh class C) were assigned to groups given either pentoxifylline (400 mg, orally, 3 times daily; n=164) or placebo (n=171) for 6 months. The primary endpoint was mortality at 2 months. The secondary endpoints were mortality at 6 months and the development of liver-related complications.Results:: By 2 months, 28 patients in the pentoxifylline group (16.5%) and 31 in the placebo group (18.2%) had died (P=0.84). At 6 months, 50 patients in the pentoxifylline group (30.0%) and 54 in the placebo group (31.5%) had died (P=0.75). The proportions of patients without complications (bacterial infection, renal insufficiency, hepatic encephalopathy or gastrointestinal hemorrhage) were higher in the pentoxifylline group than in the placebo group at 2 months (78.6% vs. 63.4%, P=0.006) and 6 months (66.8% vs. 49.7%, P=0.002). The probability of survival without complications was higher in the pentoxifylline group than in the placebo group at 2 and 6 months (P=0.04). In multivariate analysis, the factors associated with death were age, the Model for End-Stage Liver Disease score and the presence of early-stage carcinoma. Treatment with pentoxifylline was the only factor associated with liver-related complications.Conclusions:: Although pentoxifylline does not decrease short-term mortality in patients with advanced cirrhosis it does reduce the risk of complications.

Molecular Imaging in Gastrointestinal Endoscopy - Uncorrected Proof

Martin Goetz, Thomas D. Wang — 2010-01-22

Molecular imaging is a rapidly growing new discipline in gastrointestinal endoscopy. It uses the molecular signature of cells for minimally-invasive, targeted imaging of gastrointestinal pathologies. Molecular imaging comprises wide field techniques for the detection of lesions and microscopic techniques for in vivo characterization. Exogenous fluorescent agents serve as molecular beacons and include labeled peptides and antibodies, and probes with tumor-specific activation. Most applications have aimed at improving the detection of gastrointestinal neoplasia with either prototype fluorescence endoscopy or confocal endomicroscopy, and first studies have translated encouraging results from rodent and tissue models to endoscopy in humans. Even with the limitations of the currently used approaches, molecular imaging has the potential to greatly impact on future endoscopy in gastroenterology.

Gastrointestinal Response to Injury at the 2010 Freston Conference - Uncorrected Proof

Dr. Les Lang — 2010-01-22

This year's James W. Freston Single Topic Conference funded by the Takeda Endowment will be Gastrointestinal Response to Injury: 2010 and will be held from September 28 to October 2, 2010, at the Intercontinental Montelucia Resort & Spa in Scottsdale, Arizona.