Effect of direct hemoperfusion using polymyxin B immobilized fiber on inflammatory mediators in patients with severe sepsis and septic shock.

The objective of this study was to investigate retrospectively the effect of direct hemoperfusion using polymyxin B immobilized fiber (PMX-DHP) in a cartridge to remove endotoxin on inflammatory mediators in septic patients. PMX-DHP was performed 59 times in 40 patients with severe sepsis and septic shock due to gram-negative bacterial infection. Mean age and APACHE II score were 63 years and 22, respectively. The first treatments with PMX-DHP were started when patient hemodynamics were unstable even after conventional therapies. The second treatments were performed in 19 patients whose hemodynamics were still unstable after the first PMX-DHP. The changes in inflammatory mediator levels were compared from baseline to post treatment with PMX-DHP. Statistical differences were calculated using the Wilcoxon rank sum test. Plasma endotoxin could be detected in 34 patients, which was significantly decreased in 20 cases measured by a chromogenic kinetic limulus amebocyte lysate assay (p=0.0254) and in 14 cases measured by a new limulus turbidimetric time assay (p=0.0196). Monocyte counts in peripheral blood decreased significantly (p=0.0402). Interleukin-6 decreased significantly (p=0.0020). Blood pyruvate also decreased significantly (p=0.0025). At the same time, mean arterial pressure, pulse pressure, systemic vascular resistance index, and urine output were significantly increased. These results indicated that PMX-DHP could decrease inflammatory mediators and be effective to interrupt the pathogenic sequence leading to septic shock due to gram-negative bacterial infection.

Adenovirus-mediated insulin gene transfer improves nutritional and post-hepatectomized conditions in diabetic rats.

BACKGROUND: Impaired nutritional conditions in patients with diabetes are significant risk factors after major abdominal surgery. We constructed recombinant adenovirus vector carrying the human insulin gene (AxCAIns) for in vivo insulin gene transfer to improve metabolic impairments after a major operation in patients with diabetes. We tested the effects of AxCAIns on nutritional and post-hepatectomized conditions in rats with diabetes treated with streptozotocin (STZ). METHODS: AxCAIns was injected into the spleen in diabetic rats treated with STZ. Blood levels of glucose, total protein, albumin, and C-peptide of human proinsulin were measured and the expression of transferred human insulin gene was analyzed in various organs. Diabetic rats underwent 70% partial hepatectomy with or without AxCAIns injection, and post-hepatectomized conditions were analyzed. RESULTS: STZ-induced hyperglycemia was reduced by AxCAIns injection. Decreased serum levels of total protein and albumin in diabetic rats were significantly restored to normal levels by AxCAIns injection, and human C-peptide was detected in the sera of AxCAIns-treated rats. Human preproinsulin messenger RNA, which represented the expression of transferred insulin gene, was detected in the liver and the spleen, but not in other organs. Serum albumin levels, remnant liver weight, and ratios of postoperative body weight to preoperative body weight were significantly increased by AxCAIns in hepatectomized diabetic rats. CONCLUSIONS: AxCAIns injection to the spleen efficiently transferred the human insulin gene mainly into the hepatocytes and produced enough human proinsulin to improve nutritional impairments and post-hepatectomized conditions in diabetic rats. Insulin gene transfer with intrasplenic injection of AxCAIns may be available to improve metabolic impairment after major abdominal surgery in patients with diabetes.

Specific detection of epstein-barr virus in inflammatory pseudotumor of the spleen in a patient with a high serum level of soluble IL-2 receptor.

A case of inflammatory pseudotumor of the spleen is described in a 63-year-old woman who presented with an intrasplenic tumor and an elevated serum level of soluble interleukin 2 receptor (sIL-2R). Microscopic examination after removal of the spleen revealed that the tumor was composed of mixed cellular infiltrates, mainly lymphocytes and plasma cells, and spindle-cell proliferation. Epstein-Barr virus (EBV) was specifically detected in the tumor by in situ hybridization for EBV RNA. The serum level of sIL-2R level was normalized after splenectomy. EBV infection may play a role in the development of splenic inflammatory pseudotumor and the elevation of sIL-2R level.

Spontaneous rupture of a nonparasitic liver cyst complicated by intracystic hemorrhage.

a case of spontaneous rupture of simple liver cyst complicated by intracystic hemorrhage is described. This rare condition was detected in a 61-year-old man who underwent left trisegmentectomy of liver under a suspected diagnosis of cystadenocarcinoma because of elevated serum levels of carbohydrate antigen (CA) 19-9 and DUPAN 2, and the presence of an intracystic structure. The resected specimen showed a benign liver cyst with intracystic hematoma and high levels of CA19-9 and DUPAN 2 in the cystic fluid. It is suggested that cyst rupture may increase serum levels of tumor markers whose levels are high in the cystic fluid, and that repeated observations of an intracystic structure may be the most reliable method to distinguish intracystic hemorrhage from cystic neoplasm.

Specific mutation in exon 11 of c-kit proto-oncogene in a malignant gastrointestinal stromal tumor of the rectum.

Gastrointestinal stromal tumor (GIST) in the distal third of the rectum was detected in a 57-year-old man who underwent an abdominoperineal resection of the rectum. Because the tumor expressed CD34 and c-kit gene product, but did not express smooth muscle actin or S-100 protein, it was diagnosed as an uncommitted type of GIST. Moreover, a specific mutation in the sequence coding the juxtamembrane domain in exon 11 of the c-kit proto-oncogene was revealed by a polymerase chain reaction-single-strand conformation polymorphism method. One year after resection, the patient developed multiple liver metastases. It is suggested that a specific mutation in exon 11 of the c-kit proto-oncogene may have played an essential role in the development of the liver metastases.

Efficacy of intraportal injection of anti-ICAM-1 monoclonal antibody against liver cell injury following warm ischemia in the rat.

BACKGROUND: Increased expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-function-associated antigen-1 (LFA-1) has been reported to play a major role in reperfusion injury after ischemia. In the present study we tested the effects of anti-rat-ICAM-1 monoclonal antibody (1A29) on partial-liver warm ischemia in rats. METHODS: Histological changes and expression of ICAM-1 and LFA-1 were investigated in rat partial-liver warm ischemia, performed by clamping hepatic hilar vessels distributing to the right lateral lobe for 30, 45, and 60 minutes. In a second study, the effects of intraportal 1A29 injection after 60 minutes of warm ischemia in the rat were examined histologically. In both studies, the liver tissue was removed for analysis 48 hours after clamping. RESULTS: Reperfusion after 60 minutes of warm ischemia induced histological liver injury and strong expression of ICAM-1 and LFA-1, although 30 and 45 minutes of ischemia did not provoke either histological damages or the expression of ICAM-1 and LFA-1. Intraportal injection of 1A29 after 60 minutes of warm ischemia clearly suppressed liver cell injury histologically. CONCLUSION: Intraportal injection of 1A29 prevented the histological inflammation of an ischemic liver and may be useful in liver surgery or liver transplantation, because high concentrations can reach the target organ and nonspecific immunosuppression in other tissues and organs can be decreased.

Effects of insulin-like growth factor-1 on Short bowel syndrome without ileocecal valve in rats.

Insulin-like growth factor-1 (IGF-1) can promote enterocyte proliferation which may be beneficial to postoperative conditions after massive small bowel resection (SBR) including the ileocecal valve (ICV). Wistar rats were subjected to SBR including or preserving ICV and continuously received IGF-1 or saline alone. Nutritional status, enterocyte proliferation, liver damage and hepatic IGF-1 mRNA levels were analyzed. Body weights, serum levels of total protein and transferrin, and enterocyte proliferation were significantly lower after SBR including ICV than preserving it. IGF-1 mRNA levels in the liver were decreased after SBR, especially after SBR including ICV. However, IGF-1 therapy significantly attenuated those decreased levels after SBR including ICV. Furthermore, IGF-1 significantly decreased serum liver transaminase levels which were increased after SBR including ICV. Continuous administration of IGF-1 may be available as a supplemented therapy for short bowel syndrome without ICV.

A monoclonal antibody against ICAM-1 suppresses hepatic ischemia-reperfusion injury in rats.

Since intercellular adhesion molecule-1 (ICAM-1) has been reported to play a major role in reperfusion injury after ischemia, we estimated the effects of an anti-rat ICAM-1 monoclonal antibody (1A29) on hepatic ischemia-reperfusion injury in rats. Partial liver ischemia was achieved by clamping hepatic hilar vessels supplying the cephalad three lobes of the liver for 90 min. An intraportal injection of 1A29 was given 5 min after revascularization (n = 28), and saline was injected in control rats (n = 28). Changes in the proportion of liver necrosis, hepatic tissue blood flow, serum liver enzymes and liver neutrophil sequestration were analyzed at 6, 24, 48 and 72 h after revascularization. The intraportal injection of 1A29 significantly reduced the hepatocellular necrosis, restored the hepatic tissue blood flow at 24, 48 and 72 h of reperfusion (p < 0.05 or p < 0.01), and significantly suppressed the levels of serum liver enzymes at all time points during reperfusion (p < 0.01, respectively). The 1A29 treatment significantly reduced the number of neutrophils at the pericentral area, while those at the periportal area were similar in the two groups. The results suggested that ICAM-1 plays an important role in the development of hepatic ischemia-reperfusion injury, and that 1A29 reduced the injury possibly caused by cytotoxic inflammatory responses, based on neutrophil adherence to pericentral sinusoids.

Prevention of reactive oxygen-induced endothelial cell injury by blocking its process.

Endothelial cell (EC) injury induced by reactive oxygen species (ROS) was investigated and effects of Ca(2+) channel blockers, agents which elevate intracellular cAMP levels ([cAMP](i)), and protein kinase inhibitors on H(2)O(2)-induced EC injury were analyzed using human umbilical vein EC cultures. Exposure to H(2)O(2) increased intracellular Ca(2+) levels and decreased [cAMP](i). Ca(2+) channel blockers, [cAMP](i)-elevating agents, and protein kinase inhibitors significantly inhibited H(2)O(2)-induced EC injury. Data suggest that H(2)O(2)-induced EC injury is mediated by extracellular Ca(2+) influx, intracellular cAMP efflux, and intracellular signaling, each of which is blocked by Ca(2+) channel blockers, [cAMP](i)-elevating agents, or protein kinase inhibitors. It is suggested that ischemia/reperfusion injury induced by ROS may be prevented by Ca(2+) channel blockers, [cAMP](i)-elevating agents, and protein kinase inhibitors.