摘要:

In injured patients, it has been shown that a polymorphism of the tumor necrosis factor-&bgr; (TNF&bgr;) gene is related to the development of sepsis. We investigated the relation of TNF&bgr; gene polymorphism with the development of severe complications after elective major abdominal operations, and with production of TNF&agr; perioperatively. In the present investigation, theNcoI polymorphism was studied in genomic DNA isolated from the blood of 172 patients. Preoperatively and postoperatively, lipopolysaccharide (LPS)-stimulated production of TNF&agr; in the patients' whole blood was testedin vitro.Genotypes and TNF&agr; production were related to the occurrence of severe complications. Postoperatively, 15% (n = 26) of the patients developed severe complications. The overall mortality was 2% (n = 3). The homozygous TNFB2 genotype was found in 54% of the patients, the homozygous TNFB1 genotype was found in 14% of the patients, and the heterozygous genotype was found in 32% of the patients. In patients with complications, the B2B2 genotype was much more frequent (21/26, 81%) than in those without complications (72/146, 49%;P< 0.003). The development of complications was associated with a lower capacity to produce TNF&agr; 3 and 7 days after the operation. In patients without complications, the TNF&bgr; polymorphism was not related to different levels of TNF&agr; production. These data indicate an association between TNF&bgr; polymorphism and postoperative complications and they suggest the B2/B2 genotype as a high risk factor for the development of sepsis after elective operative trauma.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In polymorphonuclear neutrophils (PMN) CD14, one of the receptors for lipopolysaccharides (LPS) is stored intracellularly as a preformed protein, with only few receptors expressed on the surface. We now report that in patients with severe bacterial infections, CD14 expression is profoundly upregulated, as is CD64 (Fc&ggr;RI), the high-affinity receptor for IgG, whereas CD16 (Fc&ggr;RIII) was partly lost from the surface. To further analyze regulation of these receptors, PMN of healthy donors were exposed to low doses of LPS. By brief exposure (10-120 min) to LPS, CD14 was transferred to the surface in a cytochalasin B-sensitive manner, as were CD16 and CD64. Prolonged culture (up to 48 h) resulted in a further upregulation of CD14, sustained expression of CD64, and profound decline of CD16, yielding a similar pattern of receptor expression as seen in the patients. Subsequent studies revealed that LPS inducedde novosynthesis of CD14: the increase of surface expression could be inhibited by cycloheximide and by interfering with a known LPS-induced signaling event, the translocation of NF&kgr;B. Moreover, an up to 10-fold increase of specific mRNA was seen, as was incorporation into CD14 of35S-methionine. Thede novosynthesis prolonged expression of CD14, whereas the CD16 expression declined, generating a PMN phenotype characteristic for severe infection and indicative of escape from apoptosis of a PMN subpopulation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The prognostic value of basal and corticotropin-stimulated cortisol concentration in patients with sepsis remains a controversial issue. In a retrospective cohort study, 82 consecutive patients with septic shock underwent a short corticotropin test performed more than 24 h after the onset of vasopressor therapy. Forty-one (50%) patients died within 28 days after the onset of septic shock. The mean (SD) basal cortisol level was 22.7 (10.6) &mgr;g/dL. With threshold values of 7 and 9 &mgr;g/dL maximal increases in cortisol level, 28 (34%) and 31 (38%) patients were, respectively, classified as nonresponders to the short corticotropin test. On multivariate analysis, a cortisol level >20 &mgr;g/dL (P= 0.0002), a maximal response to corticotropin <9 &mgr;g/dL (P= 0.044), abnormal lactate values (P= 0.0098), and positive blood cultures (P= 0.004) were independent predictors of 28-day mortality. In conclusion, high basal cortisol and low increase on corticotropin stimulation are predictors of a poor outcome in late septic shock. The underlying mechanisms of these prognostic patterns remain to be elucidated.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Dysbalance in the immune system is perceived as a major factor for adverse outcome after trauma. Transforming growth factor-&bgr;1 (TGF-&bgr;1) is a multifunctional cytokine that regulates proliferation, differentiation of cells, wound healing, and angiogenesis. The influence of TGF-&bgr;1 on trauma patients outcome is still unclear. Injury patterns and clinical outcome parameters of 99 consecutive patients with life-threatening injury and an injury severity score (ISS) > 15 were assessed in a prospective, single-center study at a Level I trauma center. Levels of TGF-&bgr;1 in plasma were measured over a 5-day period by an enzyme-linked immunoabsorbant assay (ELISA). TGF-&bgr;1 plasma levels rise shortly after trauma and gradually drop as the 5th day approaches. Mean and maximal TGF-&bgr;1 plasma levels were significantly higher in patients who developed sepsis and were significantly lower in patients with renal or hepatic failure. Receiver operating characteristics-curve analysis of liver failure shows an area under the curve (AUC) of 0.68 (95%: 0.55–0.81,P= 0.02) and of an AUC of 0.63 (95%: 0.52–0.75,P= 0.03) for renal failure for maximal TGF-&bgr;1 plasma (initial until day 2) levels if lower values represent a more positive test. The data indicate that the increase and decrease of TGF-&bgr;1 plasma levels may contribute to clinical outcome after severe injury. Lower TGF-&bgr;1 levels are associated with liver and renal insufficiency. Higher TGF-&bgr;1 levels 6 h after ICU admission increase the risk of sepsis. TGF-&bgr;1 seems to be an early onset reactant and not a second-line responsive cytokine.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

CD40 is a cell surface protein belonging to the tumor necrosis factor (TNF) receptor family. Ligation of monocyte CD40 by the T cell-derived CD40 ligand can trigger the production of various mediators, the transcription and activation of enzymes, and the upregulation of costimulatory molecules involved in the pathogenesis of sepsis. To test the hypothesis that CD40 is expressed on the surface of monocytes during sepsis, we measured CD40 expression by flow cytometry on freshly sampled monocytes from 40 patients with severe sepsis, including 15 patients with bacteremia, and from eight healthy volunteers. Plasma concentrations of interleukin (IL) 6, IL-10, and IL-13 were also measured. We detected CD40 only on monocytes from patients with sepsis (mean 6.5 ± 0.4 median channel fluorescence). There was an inverse correlation between peak CD40 expression and survival (P= 0.05), particularly in the patients with bacteremia (P= 0.019). In the bacteremic group, there was an inverse correlation between CD40 expression and bilirubin levels (r2= 0.52,P= 0.004) and plasma IL-6 concentrations (r2= 0.30,P= 0.04). Our results showed that upregulation of CD40 expression on peripheral blood monocytes is a protective phenomenon during severe sepsis. Monocyte deactivation reflected by low CD40 expression may represent impairment of immune function associated with severity of illness and poor outcome. Further studies on monocyte phenotype and function may help to assess the immune status of patients with sepsis and perhaps be useful to guide immunomodulatory strategy in the future.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Although laboratory studies indicate that female rodents better tolerate the deleterious consequences of trauma and have higher survival rates than male rodents, it remains unclear whether a similar gender dimorphic pattern is evident in humans. In view of this, the association between gender and mortality in trauma patients admitted to a University Level I Trauma Center was assessed. All adult patients admitted to the University of Alabama at Birmingham Trauma Center with blunt or penetrating injury between July 1996 and March 2001 were selected for analysis. Patients were categorized by mechanism (blunt or penetrating), and odds ratios (ORs) were used to compare the risk of death among males compared with females. The ORs were stratified according to age and were adjusted for demographic, medical, and injury characteristics. Male blunt trauma patients <50 years old had a 2.5 times (95% CI 1.3–4.9) higher risk of death than females; however, for those ≥50 years old, a smaller, nonstatistically significant difference was apparent (OR 1.4, 95% CI 0.8–2.3). Conversely, for penetrating trauma, males <50 years old exhibited an increased yet nonsignificant risk of death (OR 1.8, 95% CI 0.6–5.4), whereas those ≥50 years old had a survival advantage (OR 0.1, 95% CI 0.02–0.5). Laboratory studies have demonstrated that estrogens are salutary and androgens are detrimental for survival following trauma-hemorrhage. The results of this study suggest that the physiologic pattern of premenopausal adult female sex hormones may provide a survival advantage in blunt trauma patients; however, the converse pattern prevails for the penetrating trauma patients.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This study was aimed to determine whether administration of an inhibitor of caspase-3 protects hepatocellular function in rats with hemorrhagic shock and whether caspases are important pharmacological targets in attenuating liver injury induced by hemorrhagic shock and resuscitation. Male adult rats were subjected to hemorrhagic shock by bleeding to a mean arterial blood pressure of 35–40 mmHg for 1 h and were then resuscitation with 60% shed blood and lactated Ringer's solution. A subgroup of animals was injected i.v. with 2 mg/kg caspase inhibitor, Z-DEVD-FMK, prior to blood withdrawal. Fas ligand expression was markedly elevated and caspase-3 activity increased by 3-fold in hemorrhagic untreated rats. The increase in caspase-3 activity was prevented by administration of Z-DEVD-FMK prior to shock and resuscitation. Poly (adenosine diphosphate ribose) polymerase proteolysis was reduced in rats treated with the caspase-3 inhibitor compared with hemorrhagic untreated animals. Plasma aspartate aminotransferase and alanine aminotransferase values showed a significant increase at 6 h of shock in untreated animals (+360% and +515% as compared with sham-operated animals, respectively). Administration of the caspase-3 inhibitor did not prevent the increase in plasma transaminases. The cytosolic concentration of thiobarbituric acid-reactive substances (TBARS) and the oxidized:reduced glutathione ratio increased in the animals with hemorrhagic shock (+94% and +170%, respectively). These parameters were not significantly modified by pretreatment with Z-DEVD-FMK. It appears that caspase inhibition does not attenuate hepatocellular depression and liver injury induced by hemorrhagic shock and resuscitation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Recent findings in human septic shock suggest that glucocorticosteroids can limit and even reverse hemodynamic disturbances and dependence on catecholamines. In a rodent model of hypotensive and hypokinetic septic shock, we investigated the effects of early or late dexamethasone administration on hemodynamics, response to catecholamines, and cardiac &bgr;-adrenergic signalling. As compared with sham-operated rats, the untreated septic rats displayed significant arterial hypotension and reduced aortic blood flow. However,in vivopressor response to epinephrine and phenylephrine was not different among sham and septic animals. Conversely, the chronotropic response to isoproterenol was significantly attenuated in septic animals. Steroid-treated septic animals displayed complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations as compared with untreated septic animals. The number of myocardial &bgr;-adrenergic receptors andin vivoisoproterenol-stimulated myocardial cAMP content were similar in sham and septic animals. Glucocorticosteroids, although not changing these patterns, significantly decreased the receptors affinity when administered late, but not early. In this model of septic shock, hemodynamic abnormalities may not be related to adrenergic receptor desensitization. That steroids can improve them suggests that they could act mainly distal to adrenergic receptors, for instance, on myocardial and vascular smooth fiber contraction properties through mechanisms probably including inducible nitric oxide synthase inhibition.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Previous studies have demonstrated sepsis-specific changes in the transcription of key hepatic genes. However, the role of hepatic transcription factors in sepsis-associated organ dysfunction has not been well established. We hypothesize that the binding activities of C/EBP&agr; and &bgr;, HNF-1&agr;, and HNF-3 transiently decrease during mild sepsis but persistently decrease after fulminant sepsis, and that the decrease in this binding activity correlates in time and severity with previously described decreases in the transcription of key hepatic genes. Male C57/BL6 mice had nonlethal sepsis induced by cecal ligation and single puncture (CLP) and fulminant sepsis via cecal ligation and double puncture (2CLP). Sham-operated and unoperated animals served as controls. Transcription factor binding activity was assessed with electrophoretic mobility shift assays. C/EBP-&agr; and HNF-1&agr; binding activity decreased transiently after CLP and persistently after 2CLP. Binding activity of both C/EBP-&bgr; and HNF-3 were unchanged. The decrease in C/EBP-&agr; and HNF-1&agr; binding activities correlated in time and magnitude with the decreased hepatic gene transcription previously observed in sepsis. Furthermore, the loss of activity after 2CLP correlated in time with outcome. Sepsis decreases DNA binding activities of C/EBP&agr; and HNF-1&agr;, two key hepatocyte transcription factors, in a time course consistent with down-regulation of their target hepatic genes. Therefore, alterations in transcription factor binding are likely important in the transcriptional modulation that is characteristic of hepatic dysfunction in sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Clinical and laboratory evidence shows that enteral feeding significantly reduces pneumonia and intra-abdominal abscess formation after celiotomy for severe trauma. Supplementation of total parenteral nutrition (TPN) with glutamine (GLN) supports impaired immunity induced by TPN in several animal and human studies. This work investigates the peritoneal cellular response and polymorphonuclear neutrophil (PMN) bactericidal function after mouse chemical peritonitis after TPN with and without GLN. Thirty-three mice received chow, TPN, or 2% GLN-supplemented TPN (GLN-TPN) for 5 days. All mice then received 2 mL of a 1% glycogen solution intraperitoneally to induce cell exudation, and peritoneal exudative cells (PECs) were recovered 4 h later. Total and differential PEC numbers, as well as PMN phagocytosis, reactive oxygen intermediate production (ROI), CD11b (integrin &agr;M chain) expression, and CD16/32 (Fc&ggr; II/III receptor) expression were measured. PMN, macrophage, and lymphocyte cell numbers were significantly lower with TPN than with chow or GLN-TPN groups, with no differences between chow and GLN-TPN. TPN significantly lowered peritoneal PMN phagocytosis compared with chow (P< 0.05) and approached significance with GLN-TPN (P= 0.06). There were no significant differences in ROI production or CD11b and CD16/32 expression on peritoneal PMN. GLN supplementation improved the reduction in cell exudation and PMN phagocytosis induced by TPN after chemical peritonitis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID