Ngozi I. Okoro

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

Expression of prohibitin 1 (PHB), a multifunctional protein in the cell, is decreased during inflammatory bowel disease (IBD). Little is known regarding the regulation and role of PHB during intestinal inflammation. We examined the effect of tumor necrosis factor alpha (TNF-alpha), a cytokine that plays a central role in the pathogenesis of IBD, on PHB expression and the effect of sustained PHB expression on TNF-alpha activation of nuclear factor-kappa B (NF-kappaB) and epithelial barrier dysfunction, two hallmarks of intestinal inflammation. We show that TNF-alpha decreased PHB protein and mRNA abundance in intestinal epithelial cells in vitro and in colon mucosa in vivo. Sustained expression of prohibitin in intestinal epithelial cells in vitro and in vivo (prohibitin transgenic mice, PHB TG) resulted in a marked decrease in TNF-alpha-induced nuclear translocation of the NF-kappaB protein p65, NF-kappaB/DNA binding, and NF-kappaB-mediated transcriptional activation despite robust IkappaB-alpha phosphorylation and degradation and increased cytosolic p65. Cells overexpressing PHB were protected from TNF-alpha-induced increased epithelial permeability. Expression of importin alpha3, a protein involved in p50/p65 nuclear import, was decreased in cells overexpressing PHB and in colon mucosa of PHB TG mice. Restoration of importin alpha3 levels sustained NF-kappaB activation by TNF-alpha during PHB transfection. These results suggest that PHB inhibits NF-kappaB nuclear translocation via a novel mechanism involving alteration of importin alpha3 levels. TNF-alpha decreases PHB expression in intestinal epithelial cells and restoration of PHB expression in these cells can protect against the deleterious effects of TNF-alpha and NF-kappaB on barrier function.

Ursodeoxycholic acid treatment for patients with postcholecystectomy pain and bile microlithiasis

BACKGROUND Microlithiasis has been identified as a cause of idiopathic acute pancreatitis in patients with an intact gallbladder. Microlithiasis has also been identified in the bile of some patients who have undergone cholecystectomy. However, it is unknown whether bile microlithiasis causes postcholecystectomy pain. OBJECTIVE To identify bile microlithiasis in patients with postcholecystectomy pain and to investigate the therapeutic effect of ursodeoxycholic acid (urso) on such patients with microlithiasis in the bile. DESIGN Prospective randomized trial. SETTING Tertiary medical center. PATIENTS Patients with postcholecystectomy pain and bile crystals. INTERVENTIONS Urso treatment. MAIN OUTCOME MEASUREMENTS The severity and frequency of right upper-quadrant abdominal pain were compared with and without urso treatment, and before and after urso treatment. RESULTS A total of 118 patients with postcholecystectomy pain were screened for the study. Twelve patients (10%) were identified with bile crystals. In the first phase, 6 of these patients received urso treatment, whereas the other 6 patients did not receive urso treatment. In the second phase, the latter 6 patients were given the urso treatment. After using urso for a few months, their biliary-type abdominal pain significantly improved or resolved. In the control group, there was no improvement in symptoms. There was a significant difference between the 2 groups (P = .01). LIMITATIONS Single-center, small number of patients. CONCLUSIONS This study provided evidence that supports the hypothesis that bile microlithiasis is indeed a cause for postcholecystectomy pain. Patients with such postcholecystectomy pain may benefit from a microscopic examination of bile for crystals or microlithiasis, and urso treatment if bile crystals are identified.

The Risk of Endoscopic Mucosal Resection in the Setting of Clopidogrel Use

Objective. Guidelines on antiplatelet medication use during endoscopy are based on limited evidence. We investigate the risk of bleeding and ischemic events in patients undergoing endoscopic mucosal resection (EMR) of esophageal lesions in the setting of scheduled cessation and prompt resumption of clopidogrel. Design. Single centre retrospective review. Patients. Patients undergoing EMR of esophageal lesions. Interventions. Use of clopidogrel before EMR and resumption after EMR. Patients cease antiplatelets and anticoagulants 7 days before EMR and resume clopidogrel 2 days after EMR in average risk patients. Main Outcomes. Gastrointestinal bleeding (GIB) and ischemic events (IE) within 30 days of EMR. Results. 798 patients underwent 1716 EMR. 776 EMR were performed on patients on at least 1 antiplatelet/anticoagulant (APAC). 17 EMR were performed following clopidogrel cessation. There were 14 GIB and 2 IE. GIB risk in the setting of recent clopidogrel alone (0%) was comparable to those not on APAC (1.1%) (P = 1.0). IE risk on clopidogrel (6.3%) was higher than those not on APAC (0.1%) (P = 0.03). Limitations. Retrospective study. Conclusions. Temporary cessation of clopidogrel before EMR and prompt resumption is not associated with an increased risk of gastrointestinal bleeding but may be associated with increased ischemic events.