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General Surgery↗
Biomedical subjects
Jeffrey S Upperman
Publications and source records attributed to Jeffrey S Upperman.
Role of nitric oxide and peroxynitrite in gut barrier failure.
Bacterial translocation (BT) may be a normal physiologic process that is important for mucosal antigen sampling in the gut. However, physiologic insults such as endotoxemia, hemorrhagic shock, or necrotizing enterocolitis (NEC) may lead to pathologic BT and thus contribute to the pathogenesis of nosocomial infection. The mechanism may involve accelerated enterocyte apoptosis at the intestinal villus apex resulting, at least transiently, in a "bare area" at the villus tip where bacteria can attach and traverse the epithelium. Evidence suggests that sustained upregulation of the inducible isoform of nitric oxide synthase (NOS-2) co-localizes with enterocyte apoptosis and immunoreactivity to 3-nitrotyrosine, the footprint of peroxynitrite (ONOO-), a potent oxidant formed by the reaction of nitric oxide (NO) with superoxide. We propose that the bare area at the villus apex is caused by apoptosis of enterocytes that have migrated from the base of the crypts to the villus apex and are shed into the intestinal lumen. These bare areas, and thus the degree of BT, may be the result of an imbalance between enterocyte proliferation and apoptosis. We postulate that normal enterocyte apoptosis is mediated by the caspase cascade, whereas enterocyte proliferation and differentiation in the crypt may be regulated by tyrosine kinase-dependent signaling pathways. Both of these cellular pathways may be influenced by overproduction of NO and its metabolite ONOO-. Therefore, sustained NO production and ONOO- formation occurring in inflammatory states may differentially accelerate apoptosis in the villus apex and/or inhibit proliferation at the base of the crypts resulting in expanded extrusion zones at the villus tip and accelerated BT.
Animals↗
NF-kappaB inhibition enhances peroxynitrite-induced enterocyte apoptosis.
BACKGROUND: Sustained overproduction of nitric oxide and peroxynitrite (ONOO(-)) in conditions such as necrotizing enterocolitis and inflammatory bowel disease may promote gut barrier failure by inducing enterocyte apoptosis. NF-kappaB is upregulated in the gut during inflammation and, in addition to its proinflammatory effects, may upregulate protective or antiapoptotic factors such as inhibitor of apoptosis proteins (IAPs). We have previously demonstrated that NF-kappaB inhibition increases cytokine-induced enterocyte apoptosis; however, the effect of NF-kappaB on ONOO(-)-induced enterocyte apoptosis is unknown. MATERIALS AND METHODS: Rat intestinal epithelial cells (IEC-6) were transfected with the adenoviral vector AdIkappaB or AdlacZ. AdIkappaB contains a mutated form of IkappaB which functions as a superrepressor of NF-kappaB. Cells were then treated with 50 microM ONOO(-) or decomposed ONOO(-). Apoptosis was then determined by flow cytometry with annexin V-FITC and propidium iodide staining. Caspase activation and IAP, Bcl-2, Bad, and Bax expression were examined using Western blot analysis, and NF-kappaB activation was determined via electrophoretic mobility shift assay (EMSA). RESULTS: Inhibition of NF-kappaB with AdIkappaB significantly enhanced ONOO(-)-induced apoptosis in IEC-6 cells. ONOO(-) treatment did not activate NF-kappaB in IEC-6 cells as determined by EMSA. There was no difference in IAP, Bcl-2, Bad, and Bax expression between nontransfected, AdlacZ-transfected, and AdIkappaB-transfected cells. Baseline procaspase 3 activation was increased in AdIkappaB-transfected cells. CONCLUSIONS: NF-kappaB inhibition enhances ONOO(-)-induced enterocyte apoptosis, suggesting that NF-kappaB upregulates a protective factor. This protective factor does not appear to be an IAP or Bcl-2 family member and may be expressed constitutively, since ONOO(-) did not activate NF-kappaB over baseline levels of activation.
Adenoviridae↗
Surgical management of open versus laparoscopic adrenalectomy: outcome analysis.
PURPOSE: The authors sought to compare the outcome of children undergoing open versus laparoscopic adrenalectomy for an adrenal tumor. METHODS: Medical records of children that underwent an adrenalectomy from 1990 through 1999 were reviewed. Sixty-four adrenalectomies were performed: 27 pheochromocytomas, 36 neuroblastomas, and 1 virilizing tumor. Sixty adrenalectomies were performed open and 4 laparoscopically. The patient's age, surgical length of stay, operative charge, hospital cost, operating time, blood loss, and outcome were examined. RESULTS: Mean age for an open procedure was 8.9 +/- 0.9 years and 14 +/- 1.1 for laparoscopic (P =.019). Surgical length of stay for open was 5.4 +/-.38 days and 2.7 +/-.62 days for laparoscopic (P =.006). Patient operative charges were $12,941 +/- 676 for laparoscopic and $4,714 +/- 411 for open (P <.001). When total estimated patient cost, including hospital stay, were compared between groups there was no significant difference. Similar mean operating times and blood loss were noted. There were no deaths or complications in children with a pheochromocytoma. The mortality rate in children with neuroblastoma was 28%. CONCLUSIONS: Adrenalectomy for benign tumors can be performed safely. In selected children a laparoscopic procedure can be expected to decrease the surgical length of stay without increasing operating time or complications.
Adolescent↗
Long-term follow-up of patients with necrotizing enterocolitis.
BACKGROUND/PURPOSE: Despite the rise in the incidence of necrotizing enterocolitis (NEC), there is a paucity of data regarding long-term patient outcome. The authors examined functional outcome of infants with NEC (n = 103) treated at our institution between 1991 and 1995. METHODS: The authors reviewed the medical records of infants who were treated both operatively and nonoperatively, n = 103. Variables examined included gestational age, birth weight, Bell stage (I through III), operations performed, and mortality rate. Telephone interviews assessed school enrollment, developmental delay, bowel function, and nutritional status. RESULTS: Children treated operatively had a lower gestational age than those in the nonoperative group. Likewise, birth weight in the operative group was significantly lower. Sixty-three percent of patients had stage III, and the remainder had stage II disease. The telephone response rate was 61%. Mean age at follow-up was 7.5 +/- 2.5 years. All children ate by mouth. Nearly all children were toilet trained. All children were less than the 50th percentile for height and weight, and the majority (83%) were enrolled in school full time. CONCLUSION: Infants with stage II and III NEC who are treated operatively or nonoperatively have a favorable long-term outcome.
Body Height↗