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 90min 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

Femoral hernia: clinical significance of radiologic diagnosis

A retrospective study of 18 patients with femoral hernia assessed by herniography is presented. Although a palpable lump was present in 11 patients (61%), the diagnosis of a femoral hernia was not made before herniography. Surgical exploration was performed in 12 patients and a femoral hernia was found and repaired with beneficial outcome in 9 of them. In conclusion: herniography is of value for the diagnosis of a femoral hernia in patients with obscure groin pain

Ipsilateral multiple groin hernias

BACKGROUND. Recurrence rates after surgical repair of groin hernia vary between 3% and 20%. One possible reason for recurrent hernias are ipsilateral multiple hernias, which might have been overlooked at the primary operation. METHODS. In the present series 1010 patients with unclear groin pain underwent herniography. RESULTS. A total of 314 patients had hernias, and seventy-one (23%) of these had multiple hernias. Ipsilateral multiple hernias were found in 18 (6%) patients. Ipsilateral multiple hernias were present in 9 (6%) of 144 patients with an indirect hernia, in 17 (12%) of 144 patients with a direct hernia, in 5 (21%) of 24 patients with a femoral hernia, and in 3 (23%) of 13 patients with an obturator hernia. The hernias were of indirect, direct, femoral, and obturator types. CONCLUSIONS. The frequency of ipsilateral multiple hernias is much higher than the frequency reported during herniorrhaphy. Such overlooked ipsilateral multiple groin hernias may account for some of the so-called recurrences after herniorrhaphy. Therefore a careful exploration of the groin is mandatory. Preoperative herniography may also prove to be useful in patients with recurrent groin symptoms after herniorrhaphy

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

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 involvement of multiple protease-antiprotease systems and gut origin sepsis in zymosan-associated endothelial barrier injury and multiple organ dysfunction in rats

Multiple organ dysfunction syndrome is a dominant cause of mortality in the intensive care unit. Experimentally, a condition similar to the multiple organ dysfunction syndrome can be induced by the intraperitoneal injection of sterile zymosan. In the present study we investigate potential alterations in multiple organ functions, endothelial permeability, and antiproteinases after intraperitoneal injection of zymosan at various doses. Zymosan-induced generalized inflammation lead to endothelial barrier injury in multiple organs/tissues, a decrease in systemic arterial pressure, impaired organ function and gut defence function, and consumption of protease inhibitors, particularly the consumption of alpha (2) antiplasmin. Endothelial barrier injury appears to present a dose- and organ-dependent pattern in multiple organs/tissues, and the increase in endothelial barrier permeability occurred prior to organ dysfunction. Zymosan induced the development of multiple organ dysfunction syndrome, probably initiating multiple protease-antiprotease systems, particularly the fibrinolytic system, leading to endothelial barrier injury, tissue edema, parenchymal cell damage, and eventual organ dysfunction, potentially augmented by a secondary bacterial infection

Effects of inhibition of PAF, ICAM-1, and PECAM-1 on gut barrier failure caused by intestinal ischemia and reperfusion.

BACKGROUND: The role of cell adhesion molecules and transmigration of PMNs through the endothelial barrier is probably essential in intestinal ischemia and reperfusion (I/R)-induced gut barrier dysfunction. Although cytokines are released in I/R, it is unclear whether cytokines directly increase permeability or if this phenomenon requires both expression of cell adhesion molecules and PMN adhesion-activation. Endothelial barrier dysfunction plays an important role in the pathogenesis of multiple organ dysfunction syndrome, inducing gut barrier failure, but the mechanisms are not fully understood. The purpose of this study was to evaluate the potential therapeutic value of inhibition of platelet activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) in gut barrier dysfunction induced by intestinal I/R. METHODS: A PAF antagonist (lexipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM-1-MAb) an

Multimodal management - of value in fulminant acute pancreatitis?

Abstract in UndeterminedBackground: The multiple organ dysfunction syndrome (MODS) is the major cause of morbidity and mortality associated with acute pancreatitis. Presently, therapy is merely organ supportive as no effective therapy against underlying causative pathophysiologicla mechanisms exists. Aims: To evaluate the effect of treatmetn with a platelet-activating factor inhibitor (PAFI), a monoclonal antibody against platelet endothelial cell adhesion molecule (PECAM-1-MAb) and an oxygen free radical scavenger (N-acetylcystein; NAC), alone or in combination, on systemic organ dysfunction in experimental acute pancreatitis. Methods: Severe acute pancreatitis induced in rats by the intraductal administration of tauro-deoxycholate. Treatment was given after 1 or 3 h, and evaluations were performed 6 h after induction. Organ dysfunction was evaluated by means of endothelial integrity impairment expressed as endothelial barrier leakage index. Results: Severe acute pancreatitis caused a significant impairment in endothelial integrity in all organs studied and decreased levels of protease inhibitors compared to controls. The endothelial barrier impairment was significantly ameliorated by all treatment modalities, either given early or later. Combinations of NAC and the PECAM-1-MAb or the PECAM-1-MAb and the PAFI were the only schedules to restore endothelial barrier integrity to normal levels in most of the organs studied. Conclusion: Combination therapy with NAC and PECAM-1-MAb and/or PAFI may offer effective, causative-directed supplements to organ-supportive therapy of MODS in severe acute pancreatitis

Pancreatitis-associated pulmonary injury - effects of Lexipafant, a PAF-antagonist

Objective. Pulmonary injury is an important determinant of outcome in severe acute pancreatitis. The aim of this experimental study was to investigate the potential effect of lexipafant, a platelet-activating factor (PAF) antagonist, on pancreatitis-associated pulmonary injury in experimental acute pancreatitis. Material and methods. Acute pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats that were given the PAF antagonist lexipafant either before (pretreatment) or after (treatment) induction of pancreatitis. Pulmonary endothelial barrier permeability, oedema, protease inhibitor levels, pulmonary ultrastructure and membrane system integrity and levels of interleukin-1 and -6 were evaluated. Results. Pulmonary injury was characterized by increased pulmonary endothelial barrier permeability, alveolar oedema and hypoxaemia, which were noted 12 h after the induction of pancreatitis. Pretreatment with lexipafant counteracted the increase in endothelial permeability and partially prevented derangements of protease inhibitor levels. Treatment with lexipafant reduced the severity of pulmonary endothelial barrier dysfunction and diminished the pancreatitis-induced increase in cytokines. Conclusions. PAF seems to play a major role in experimental pancreatitis-associated pulmonary injury and protease inhibitor imbalance. Treatment with a PAF inhibitor may ameliorate pancreatitis-associated pulmonary injury