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Talukdar R.,Miles and Shirley Fiterman Center for Digestive Diseases | Talukdar R.,NEMCARE Hospitals | Vege S.S.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Gastroenterology Reports | Year: 2011

Significant literature on the management of acute severe acute pancreatitis has emerged in recent years. The new information ranges from data on newer single or multiparameter severity assessment tools and classification systems to therapeutic modalities. However, a few basic issues - the ideal severity assessment modality, volume of intravenous fluids required in the first 48 to 72 h, and the role of prophylactic antibiotics - are still not clear and are subject to controversy. The International Working Group has devised the Revised Atlanta Classification, which will be published soon. This new classification is eagerly awaited worldwide, and hopefully clarifies many of the problems of the original Atlanta Classification. In this article, we discuss the developments that have arisen in the past 2 to 3 years concerning the classification, prognostication, and early management of severe acute pancreatitis. © Springer Science+Business Media, LLC 2011.

Peyrin-Biroulet L.,Miles and Shirley Fiterman Center for Digestive Diseases | Loftus E.V.,Miles and Shirley Fiterman Center for Digestive Diseases | Colombel J.-F.,Lille University Hospital Center | Sandborn W.J.,Miles and Shirley Fiterman Center for Digestive Diseases
American Journal of Gastroenterology | Year: 2010

Objectives: Natural history studies provide invaluable data on the disease course. First, they help define the end points for clinical trials that are designed to test drugs for the end point of disease modification in chronic disabling diseases. Natural history studies can also help to identify subsets of patients in whom the disease prognosis can be stratified according to clinical features. This comprehensive review summarizes our current knowledge of the natural history of Crohn's disease in adults as reported in population-based studies that include long-term follow-up results. Methods: We conducted a literature search of English and non-English language publications listed in the electronic databases of MEDLINE (source PUBMED, 1935 to December 2008). Results: One-third of the patients had ileitis, colitis, or ileocolitis at the time of diagnosis. Disease location remained broadly stable over time. Up to one-third of the patients had evidence of a stricturing or penetrating intestinal complication at diagnosis, and half of all patients had experienced an intestinal complication within 20 years after diagnosis. Ten percent of the patients had prolonged clinical remission. Steroid dependency occurred in one-third of the patients, and surgery was required in one-third after initiation of steroid therapy. The annual incidence of hospitalizations was 20%. Half of the patients required surgery within 10 years after diagnosis. The risk of postoperative recurrence was 44-55% after 10 years. Conclusions: Crohn's disease is a disabling condition over time. The impact of changing treatment paradigms with increased use of immunosuppressants and biological agents on its natural history is poorly known. © 2010 by the American College of Gastroenterology.

Trikudanathan G.,University of Connecticut | Navaneethan U.,Cleveland Clinic | Vege S.S.,Miles and Shirley Fiterman Center for Digestive Diseases
American Journal of Gastroenterology | Year: 2011

Intra-abdominal infections of pancreatic or peripancreatic necrotic tissue complicate the clinical course of severe acute pancreatitis (SAP) and are associated with significant morbidity. Fungal infection of necrotic pancreatic tissue is increasingly being reported. The incidence of intra-abdominal pancreatic fungal infection (PFI) varies from 5% to 68.5%. Candida albicans is the most frequently isolated fungus in patients with necrotizing pancreatitis. Prolonged use of prophylactic antibiotics, prolonged placement of chronic indwelling devices, and minimally invasive or surgical interventions for pancreatic fluid collections further increase the risk of PFI. Computed tomography- or ultrasound-guided fine-needle aspiration of pancreatic necrosis is a safe, reliable method for establishing pancreatic infection. Amphotericin B appears to be the most effective antifungal treatment. Drainage and debridement of infected necrosis are also critical for eradication of fungi from the poorly perfused pancreatic or peripancreatic tissues where the antifungal agents may not reach to achieve therapeutic levels. Fungal infection adversely affects the outcome of patients with SAP and is associated with increased morbidity, although the mortality rate is not increased specifically because of PFI. Although antifungal prophylaxis has been suggested for patients on broad-spectrum antibiotics, no randomized controlled trials have yet studied its efficacy in preventing PFI. © 2011 by the American College of Gastroenterology.

Garrity-Park M.M.,Mayo Medical School | Loftus E.V.,Miles and Shirley Fiterman Center for Digestive Diseases | Sandborn W.J.,Miles and Shirley Fiterman Center for Digestive Diseases | Bryant S.C.,Mayo Medical School | Smyrk T.C.,Mayo Medical School
American Journal of Gastroenterology | Year: 2010

OBJECTIVES: Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non-neoplastic mucosa of UC-CRC patients and controls to identify potential biomarkers of CRC. METHODS: We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E-cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC-CRC tumors and non-neoplastic sections from both UC-CRC cases and UC controls (n=114 for each) using methylation-specific PCR. Results: Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC-CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC-CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC-CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC-CRC cases (odds ratio12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene. Conclusions: RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia. © 2010 by the American College of Gastroenterology.

Sah R.P.,Miles and Shirley Fiterman Center for Digestive Diseases | Chari S.T.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Immunology Reviews | Year: 2011

IgG4-related Systemic Disease (ISD) is a chronic fibro-inflammatory disorder affecting exocrine and several other organs characterized by the presence of IgG4-positive cellular infiltrates in affected organs and elevated serum IgG4 levels. Autoimmune Pancreatitis (AIP) is the pancreatic manifestation of ISD. Responsiveness to steroid is a characteristic feature ISD and consistently leads to improvement of most lesions including AIP, at least in the short term. However, relapse is common in ISD though there is lack of agreement among different studies on the rates of relapse and factors predicting relapse, with estimates from 25% to upto 50%. Proximal bile duct involvement appears to be predictive of relapse in several studies. Corticosteroids are effective in treating relapses as well and long term maintenance therapy may be necessary in patients who relapse. The role of maintenance of corticosteroid therapy for primary prevention of relapses and utility of immunosuppressive drugs like azathioprine in refractory cases remain to be studied in controlled studies, though there is some experience with successful use of immunosuppressive drugs in refractory cases with frequent relapses. In light of several reports of malignancies, long term follow-up of patients is recommended. Long term survival is currently unknown in ISD due to short-term follow-up and preponderance in older population, and as more follow-up data become available, it will be clear if the consequence of ISD and AIP decreases patient survival. © 2011 Bentham Science Publishers Ltd.

Afif W.,Miles and Shirley Fiterman Center for Digestive Diseases | Loftus Jr. E.V.,Miles and Shirley Fiterman Center for Digestive Diseases | Faubion W.A.,Miles and Shirley Fiterman Center for Digestive Diseases | Kane S.V.,Miles and Shirley Fiterman Center for Digestive Diseases | And 3 more authors.
American Journal of Gastroenterology | Year: 2010

OBJECTIVES: Human anti-chimeric antibodies (HACAs) and subtherapeutic infliximab concentrations are associated with decreased duration of response. We evaluated the clinical utility of measuring HACA and infliximab concentrations.METHODS: The medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured were reviewed to determine whether the result affected clinical management.RESULTS: One hundred fifty-five patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). HACAs were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of 17%. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86% of patients whereas changing to another anti-TNF agent had a response of 33%. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76% of the time and had no evidence of active inflammation by endoscopic/radiographic assessment 62% of the time.CONCLUSIONS: Measurement of HACA and infliximab concentration impacts management and is clinically useful. Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent. © 2010 by the American College of Gastroenterology.

Coelho-Prabhu N.,Miles and Shirley Fiterman Center for Digestive Diseases | Baron T.H.,Miles and Shirley Fiterman Center for Digestive Diseases | Kamath P.S.,Miles and Shirley Fiterman Center for Digestive Diseases
Endoscopy | Year: 2010

Although anorectal varices are a common complication of portal hypertension, there is no consensus on the optimal management of this condition. We present a retrospective case series of ten consecutive patients who underwent endoscopic variceal ligation (EVL) for rectal varices associated with hematochezia, at a single tertiary care center between 1995 and 2008. EVL was performed with a standard esophageal varices multi-shot band ligation device attached to a standard video upper endoscope. Of the ten patients who underwent EVL for rectal varices associated with hematochezia, four of the patients (40 %) experienced a rebleeding event; in three this was controlled with repeat EVL, but one patient died of fatal hemorrhage from the rectal varices. There were no procedural complications. EVL may be an emerging therapeutic option for the management of hematochezia associated with rectal varices in patients with portal hypertension. Prospective studies are needed to determine the safety and efficacy of EVL in these patients. © Georg Thieme Verlag KG Stuttgart, New York.

O'Hara S.P.,Miles and Shirley Fiterman Center for Digestive Diseases | Splinter P.L.,Miles and Shirley Fiterman Center for Digestive Diseases | Gajdos G.B.,Miles and Shirley Fiterman Center for Digestive Diseases | Trussoni C.E.,Miles and Shirley Fiterman Center for Digestive Diseases | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

MicroRNAs, central players of numerous cellular processes, regulate mRNA stability or translational efficiency. Although these molecular events are established, the mechanisms regulating microRNA function and expression remain largely unknown. The microRNA let-7i regulates Toll-like receptor 4 expression. Here, we identify a novel transcriptional mechanism induced by the protozoan parasite Cryptosporidium parvum and Gram(-) bacteria-derived lipopolysaccharide (LPS) mediating let-7i promoter silencing in human biliary epithelial cells (cholangiocytes). Using cultured cholangiocytes, we show that microbial stimulus decreased let-7i expression, and promoter activity. Analysis of the mechanism revealed that microbial infection promotes the formation of a NFκB p50-C/EBPβ silencer complex in the regulatory sequence. Chromatin immunoprecipitation assays (ChIP) demonstrated that the repressor complex binds to the let-7i promoter following microbial stimulus and promotes histone-H3 deacetylation. Our results provide a novel mechanism of transcriptional regulation of cholangiocyte let-7i expression following microbial insult, a process with potential implications for epithelial innate immune responses in general. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Talwalkar J.A.,Advanced Liver Diseases Study Group | Talwalkar J.A.,Miles and Shirley Fiterman Center for Digestive Diseases | Swanson K.L.,Advanced Liver Diseases Study Group | Swanson K.L.,Mayo Medical School | And 6 more authors.
Gastroenterology | Year: 2011

Background & Aims: We documented the frequency of large spontaneous portosystemic shunts in patients with moderate or severe portopulmonary hypertension (POPH) and determined the association between large shunts and response to treatment. Methods: We performed a retrospective case-control study of data from patients with mild (mean pulmonary artery pressure [MPAP], 25-35 mm Hg; n = 18), moderate (MPAP, 35-50 mm Hg; n = 45), and severe POPH (MPAP, >50 mm Hg; n = 16). Data were compared with those from controls (normal echocardiography with estimated right ventricular systolic pressure, <35 mm Hg; n = 122). Spontaneous portosystemic shunts greater than 10 mm in diameter, identified by computed tomography or magnetic resonance, were classified as large. Response to treatment at 6 months was defined by right ventricular systolic pressure or MPAP as significant (<35 mm Hg), partial (35-50 mm Hg), or no response (>50 mm Hg). Results: The frequency of spontaneous shunts did not differ significantly between groups of subjects with severe (n = 14 of 16), moderate (n = 38 of 45), or mild POPH (n = 11 of 18) or normal echocardiograms (controls, n = 86 of 122) (P = .77). Large shunts were associated with severe (14 of 16) and moderate POPH (32 of 45), compared with mild POPH (6 of 18) or controls (30 of 122) (P < .01). In 13 patients with severe POPH, large shunts were associated with lack of response to treatment in 90% (8 of 9) or partial response in 50% (2 of 4). Among 27 patients with moderate POPH, large shunts were associated with no response to treatment in 13 of 19 (68%) and a partial response in 2 of 6 (33%). Conclusions: Large spontaneous portosystemic shunts are associated significantly with moderate and severe POPH, and with lack of response to treatment. © 2011 AGA Institute.

Sah R.P.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases | Chari S.T.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Gastroenterology Reports | Year: 2012

Autoimmune Pancreatitis (AIP) is a recently recognized chronic fibro-inflammatory disease of the pancreas. Although rare, its recognition continues to increase worldwide. Patients often present with painless obstructive jaundice mimicking pancreatic cancer. Two subtypes of AIP are known-type 1 is a multi-organ disease associated with IgG4; type 2 appears to be a pancreas-specific disorder. Dramatic response to steroid treatment is characteristic of both forms. A non-invasive diagnosis of type 1 AIP may be possible using diagnostic criteria (in ~70% cases) while diagnosis of type 2 requires histology. These subtypes differ in natural history- type 1 often relapses while initial reports suggest that type 2 does not. Long term complications include endocrine and exocrine insufficiency and in case of type 1, disease relapses and complications from extra-pancreatic involvement. Neither form affects long term survival. The treatment and follow-up guidelines continue to evolve with our increasing experience in AIP. © Springer Science+Business Media, LLC 2012.

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