Active site-inactivated factor VIIa inhibits nuclear factor kappa B activation in intestinal ischemia and reperfusion.

BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury is a pivotal mechanism in critical illness and in the development of multiple organ dysfunction syndrome, in which the nuclear factor kappa B (NF-κB) activation plays a central role. Intestinal I/R injury initiates the extrinsic tissue factor or factor VIIa-dependent pathway of coagulation, also of importance in multiple organ dysfunction syndrome. Our aim was to analyze NF-κB activation in I/R injury in the rat intestine and in two main "shock" organs, that is, the liver and lungs. Pretreatment with active site-inactivated factor VII (FVIIai), an inhibitor of the extrinsic pathway, was evaluated. MATERIALS AND METHODS: NF-κB activation was analyzed using enzyme-linked immunosorbent assay (ELISA) and electrophoretic mobility shift assay (EMSA) studies of nuclear extracts from the intestine, liver, and lungs in rats subjected to intestinal I/R injury. FVIIai was given 90 min before the induction of intestinal ischemia. RESULTS: I/R induced NF-κB p65 activation in all three organs, especially in the liver. Pretreatment with FVIIai counteracted NF-κB activation in all three tissues studied. A commercially available ELISA for (human) NF-κB p65 and EMSA gave parallel results. CONCLUSIONS: I/R injury in the rat intestine induces a pronounced activation of NF-κB p50 or p65 in the small intestine and in the liver and lungs. The NF-κB activation is especially pronounced in the liver and plays a central role in the regulation of transcription of cytokines, adhesion molecules, and chemokines. ELISA for (human) NF-κB p65 and "gold standard" EMSA gave parallel results. Pretreatment with FVIIai completely counteracted NF-κB activation in the intestine and liver, although not in the lungs.

Dorsal agenesis of the pancreas - a rare cause of abdominal pain and insulin-dependent diabetes.

Dorsal agenesis of the pancreas is a rare congenital disorder. We report a case of a 65-year-old man with mild abdominal pain and insulin-dependent diabetes mellitus. Computed tomography (CT) of the abdomen showed a short pancreas with no pancreatic tissue ventral to the splenic vein. Magnetic resonance cholangiopancreatography (MRCP) visualized the absence of a dorsal duct system and confirmed the suspicion of complete agenesis of the dorsal pancreas. Endoscopic ultrasound (EUS) was also performed to rule out pancreatic malignancy.

The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx, and protease inhibitor levels in rats.

Multiple organ dysfunction syndrome (MODS) is mediated by complex mechanisms in which interactions between activated leukocytes and endothelial cells play a central role. ICAM-1 (intercellular adhesion molecule-1) mediates firm adhesion and transendothelial migration of activated leukocytes from postcapillary venules into the tissue. The present study evaluated the ICAM-1 expression in various organs after 40 min of intestinal ischemia and 1, 3, 6, 12 h of reperfusion (I/R) in the rat, using a dual monoclonal antibody technique (n = 36). Endothelial barrier permeability, using the vascular leakage of radiolabeled human serum albumin was also assessed (n = 12). Neutrophil sequestration in the lungs was quantitated by myeloperoxidase activity and plasma protease inhibitor levels were measured with electroimmunoassay. Significant regional differences were found in ICAM-1 expression between organs, both constitutively and after I/R-injury. The highest constitutive levels were observed in the liver and lungs, followed by the kidneys. The constitutive ICAM-1 expression in the intestines and in the heart was about 1/20 compared with that found in the liver and lungs. The brain and muscle had levels of about 1/150 of that in the liver and lungs. After intestinal I/R, significant increases (17-45%) were found in the lungs, intestines, brain, heart, and muscle. Albumin leakage index (ALI) in all examined organs and myeloperoxidase activity in the lungs increased after I/R-injury. Serum levels of albumin and most protease inhibitors decreased significantly after I/R challenge. Intestinal I/R results in an increase of systemic ICAM-1 expression with marked organ variability. The upregulation of ICAM-1 could represent a crucial step in the adherence- and migration process of activated leukocytes and potentially in the development of tissue injury.

Appendiceal abscesses: primary percutaneous drainage and selective interval appendicectomy.

OBJECTIVE: To present our results of non-surgical primary management of appendiceal abscesses using ultrasonic percutaneous drainage under local anaesthesia, and selective interval appendicectomy. DESIGN: Retrospective study. SETTING: University hospital, Sweden. SUBJECTS: 24 patients with appendiceal abscesses 3-12 cm in size. INTERVENTIONS: Primary ultrasonic percutaneous drainage under local anaesthesia, antibiotic treatment, and selective surgical treatment. MAIN OUTCOME MEASURES: Long-term follow-up. RESULTS: All patients had their abscesses drained successfully without complications. One patient continued to have fever, but eventually responded to conservative treatment and in one the bowel was perforated by the drain but again this was treated conservatively. Four abscesses recurred. Seven patients underwent planned interval appendicectomy. Another three patients were also operated on-one for caecal adenocarcinoma, and two for persisting symptoms and enterocutaneous fistulas. CONCLUSIONS: Appendiceal abscesses can be effectively drained percutaneously using ultrasound-guided drainage under local anaesthesia, without complications. Recurrent appendicitis is common, and malignancy is a substantial risk in elderly patients. Modern laparoscopic appendicectomy and early postoperative discharge makes interval appendicectomy a valid treatment option after primary non-surgical management of appendiceal abscesses.

Effective treatment of gut barrier dysfunction using an antioxidant, a PAF inhibitor, and monoclonal antibodies against the adhesion molecule PECAM-1.

BACKGROUND: Oxygen free radicals (OFRs), platelet activating factor (PAF), cell adhesion molecules, and transmigration of polymorphonuclear leukocytes through the gut barrier are probably all essential in the development of gut barrier dysfunction following intestinal ischemia and reperfusion (I/R). Pretreatment and early treatment of I/R with the OFRs-scavenger (NAC), the PAF inhibitor lexipafant, and monoclonal antibodies against the adhesion molecule PECAM-1 (anti-PECAM-1-Mab) have been reported to be effective in the prevention or recovery of gut barrier dysfunction and result in a decrease in cytokine levels. Less is known about the effect of treatment inserted during the late stage of I/R. The objective of this study was to evaluate the potential therapeutic value of single or combination therapy with NAC, lexipafant, and anti-PECAM-1-MAb administered late during intestinal I/R in the rat. METHODS: NAC, lexipafant, and anti-PECAM-1-MAb were administrated, alone or in combination, after 3 h of reperfusion following 40 min of superior mesenteric arterial ischemia in the rat. Intestinal endothelial and epithelial barrier permeability, myeloperoxidase (MPO) activity, interleukin-1 beta (IL-1 beta), and protease inhibitor levels were evaluated after 12 h of reperfusion. RESULTS: Intestinal endothelial and epithelial permeability significantly increased in rats with I/R and saline treatment. Proteolytic activity in plasma was indicated by low levels of the three measured plasma protease inhibitors. Intestinal mucosal MPO content increased significantly. These changes were, to different degrees, reduced by late inserted treatment with NAC, lexipafant, or anti-PECAM-1-MAb. Alterations in systemic levels of IL-1 beta paralleled the changes found in gut barrier permeability and leukocyte trapping. Systemic antithrombin III levels and increased barrier permeability in remote organs were partly restored, especially by multimodal therapy. CONCLUSION: Treatment with NAC, lexipafant, and/or monoclonal antibodies against PECAM-1, inserted at a later stage of I/R, reduced the severity of I/R-associated intestinal dysfunction and decreased the systemic concentrations of IL-1 beta, local leukocyte recruitment (MPO), and partly restored plasma protease inhibitor levels.