[Increased perioperative blood loss during treatment with paroxetine]. / Toegenomen peroperatief bloedverlies bij paroxetinegebruik.

A 63-year-old man who took paroxetine for depression developed massive peroperative haemorrhage during a pancreaticoduodenectomy as a result of paroxetine-induced thrombocytopathy. He lost 4 litres of blood. After administration of 8 units of fresh frozen plasma and 2 times 5 units of thrombocyte concentrate, hemostatic control was obtained and the operation could be continued. Paroxetine is a non-tricyclic serotonin reuptake inhibitor prescribed for the treatment of depression. Since this drug also blocks serotonin reuptake in platelets, a clinically significant platelet dysfunction can occur under certain conditions. Because serotonin promotes platelet aggregation, too low an amount of serotonin in the platelets can result in thrombocytopathy. Before major surgery, it is advised to perform extensive clotting tests if there is any hint of haemorrhagic diathesis in the anamnesis. In case of a prolonged bleeding time, paroxetine treatment should be stopped perioperatively.

CXC chemokine receptor 2 contributes to host defense in murine urinary tract infection.

CXC chemokines have been implicated in the recruitment of neutrophils to sites of infection. To determine the role of CXC chemokines in the host response to urinary tract infection (UTI), female mice were treated with an antibody against the major CXC chemokine receptor in the mouse, CXCR2, before intravesical inoculation with Escherichia coli. Anti-CXCR2 prevented the influx of neutrophils in urine and kidneys. The absence of a neutrophil response only temporarily impaired the clearance of bacteria from the urinary tract, as indicated by 100- and 1000-fold more E. coli colony-forming units in urine and kidneys of anti-CXCR2-treated mice at 24 h, but not at 48 h, after the infection. UTI induced increases in the renal concentrations of the CXCR2 ligands macrophage inflammatory protein-2 and KC, which were not influenced by anti-CXCR2 administration. CXC chemokines play an important role in the development of a local inflammatory response to UTI.

The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy.

BACKGROUND: The benefit of preoperative biliary drainage in jaundiced patients undergoing pancreaticoduodenectomy for a suspected malignancy of the periampullary region is still under debate. This study evaluated preoperative biliary drainage in relation to postoperative outcomes. STUDY DESIGN: At the Academic Medical Center, Amsterdam, the Netherlands, a cohort of 311 patients undergoing pancreaticoduodenectomy from June 1992 up to and including December 1999 was studied. Of this cohort 21 patients with external or surgical biliary drainage were excluded and 232 patients who had received preoperative internal biliary drainage were divided into three groups corresponding with severity of jaundice according to preoperative plasma bilirubin levels: < 40 microM (n = 177), 40 to 100 microM (n = 32), and > 100 microM (n = 23) were designated as groups 1, 2, and 3, respectively. These groups were compared with patients who underwent immediate surgery (n = 58) without preoperative drainage. RESULTS: The median number of stent (re)placements was 2 (range 1 to 6) with a median drainage duration of 41 days (range 2 to 182 days) and a stent dysfunction rate of 33%. Although patients in group 1 were better drained than patients in groups 2 and 3 (median reduction of bilirubin levels 82%, 57%, and 37%, respectively, p < 0.01), there was no difference in overall morbidity among the drained groups (50%, 50%, and 52%, respectively). There was no significant difference in overall morbidity between patients with and without preoperative biliary drainage (50% and 55%, respectively). CONCLUSIONS: Preoperative biliary drainage did not influence the incidence of postoperative complications, and although it can be performed safely in jaundiced patients it should not be used routinely.

IL-10-deficient mice demonstrate multiple organ failure and increased mortality during Escherichia coli peritonitis despite an accelerated bacterial clearance.

To determine the role of endogenous IL-10 in local antibacterial host defense and in the development of a systemic inflammatory response syndrome during abdominal sepsis, IL-10 gene-deficient (IL-10(-/-)) and wild-type (IL-10(+/+)) mice received an i.p. injection with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-10 concentrations in peritoneal fluid and plasma. The recovery of E. coli from the peritoneal fluid, blood, and lungs was diminished in IL-10(-/-) mice, indicating that endogenous IL-10 impaired bacterial clearance. Despite a lower bacterial load, IL-10(-/-) mice had higher concentrations of TNF, macrophage inflammatory protein-2 and keratinocyte in peritoneal fluid and plasma, and demonstrated more severe multiple organ damage as indicated by clinical chemistry and histopathology. Furthermore, IL-10(-/-) mice showed an increased neutrophil recruitment to the peritoneal cavity. To examine the role of elevated TNF levels in the altered host response in IL-10(-/-) mice, the effect of a neutralizing anti-TNF mAb was determined. Anti-TNF did not influence the clearance of E. coli in either IL-10(+/+) or IL-10(-/-) mice. Furthermore, anti-TNF did not affect leukocyte influx in the peritoneal fluid, multiple organ damage, or survival in IL-10(+/+) mice. In IL-10(-/-) mice, anti-TNF partially attenuated neutrophil recruitment and multiple organ damage, and prevented the increased lethality. These data suggest that although endogenous IL-10 facilitates the outgrowth and dissemination of bacteria during E. coli peritonitis, it protects mice from lethality by attenuating the development of a systemic inflammatory response syndrome by a mechanism that involves inhibition of TNF release.

The abnormal lipid spectrum in malignant obstructive jaundice in relation to endotoxin sensitivity and the result of preoperative biliary drainage.

BACKGROUND: Biliary obstruction changes the spectrum of lipoproteins, which are now known to bind and neutralize endotoxin. Postoperative septic complications related to an increased susceptibility to endotoxin occur frequently in patients with obstructive jaundice. The effect of preoperative biliary drainage on changes in the lipoprotein spectrum and its relation to endotoxin sensitivity was studied. METHODS: Abnormalities in the lipoprotein spectrum were assessed in 15 patients with malignant obstructive jaundice before and 3 weeks after endoscopic biliary drainage. Changes in endotoxin responsiveness were assessed by using endotoxin-neutralizing reagents (anti-CD14 monoclonal antibody, polymyxin B, and recombinant bactericidal permeability increasing protein) to block cytokine production in whole blood cell cultures that were stimulated by cholestatic plasma taken before and after drainage. RESULTS: Drainage normalized very-low-density, low-density, and high-density lipoprotein cholesterol fractions from, respectively, 43% to 19%, 50% to 65%, and 6% to 16% (P <.01). Ex vivo stimulation of whole blood with predrainage cholestatic plasma was 20-fold higher (P <.001) than with postdrainage plasma. Blocking the endotoxin response during the stimulation with predrainage cholestatic plasma with anti-CD14 monoclonal antibody, polymyxin B or recombinant bactericidal permeability increasing protein resulted in attenuation of the inflammatory response, reducing tumor necrosis factor-alpha levels at least 5-fold. CONCLUSIONS: Preoperative biliary drainage normalizes the changed lipid profile and the endotoxin-stimulating capacity of cholestatic plasma, and this signifies a change in sensitivity to endotoxin.

Endotoxin-induced mortality in bile duct-ligated rats after administration of reconstituted high-density lipoprotein.

Cholestatic patients have substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide [LPS]). Although reconstituted high-density lipoprotein (rHDL) can bind and neutralize LPS, cholestasis is associated with a near complete absence of HDL. Effects of rHDL infusion on the outcome of LPS-induced inflammatory responses in cholestatic rats were determined. Bile duct-ligated (BDL) and sham rats were treated with rHDL or saline and challenged with LPS. Distribution of cholesterol over the lipoprotein subclasses changed by ligation: levels in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) were increased 2-fold and 5-fold, respectively, and were decreased in HDL 2-fold. rHDL treatment did not affect cholesterol distribution. LPS was mainly found in the HDL fraction, and ligation affected only levels of HDL-bound LPS (50% decrease; P<.05). Although rHDL infusion effectively normalized the lipoprotein-bound LPS distribution, it resulted in increased sensitivity (mortality: 88% in the ligation + rHDL group versus 44% in the ligation + saline group, 25% in the sham + saline group, and 0% in the sham + rHDL group, P <.05). In accordance with these results, plasma tumor necrosis factor (TNF) was significantly highest in the BDL + rHDL group at several hours after LPS challenge as well as the accumulation of LPS in the liver (P<.05). rHDL infusion leads to increased LPS-induced mortality in cholestatic rats. These results sharply contrast with the protective effects of rHDL suppletion in experimental endotoxemia in animals and human volunteers without biliary obstruction and suggest that there may be danger in administration of rHDL to cholestatic patients.

Difference in expression of CD44 splice variants between proximal and distal adenocarcinoma of the large bowel.

To help determine whether adenocarcinomas of the proximal and distal large bowel reflect distinct entities, the expression of two splice variants of the metastasis-associated cell adhesion molecule CD44, carrying exons v5 and v6 respectively, was investigated retrospectively in fresh frozen samples of 23 proximal and 41 distal carcinomas by immunohistochemical staining with specific anti-CD44v5 monoclonal antibody VFF8 and anti-CD44v6 monoclonal antibodies VFF4 and VFF7. Tumours were staged as: Dukes A, 0; Dukes B, 27; Dukes C, 31; and Dukes 'D', six. Compared with distal tumours, proximal lesions expressed significantly more CD44v5 (96 versus 87 per cent, P = 0.02) and CD44v6 (83 versus 61 per cent, P = 0.01). CD44v5 and CD44v6 are considered markers for tumour progression and aggressive behaviour. Their high expression in proximal carcinomas seems to contrast with the general belief that these tumours show less aggressive behaviour than left-sided lesions. Further study of the biological significance of the expression of CD44 splice variants is therefore needed.

Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins.

CD44 variants containing v6 confer metastatic potential to rat carcinoma cell-lines. In man, CD44v6 is increasingly expressed during colorectal tumour progression. In 68 colorectal carcinoma patients, survival analysis showed that CD44v6 expression in the tumours was associated with tumour-related death. In patients who had an apparently radical resection of their primary tumour, CD44v6 expression had prognostic value independent of Dukes' stage. CD44v6 expression may reflect propensity for metastasis after apparently curative surgery, making adjuvant therapy an option in these patients.