Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase A2.

Extracellular mobilization of Group IIA 14-kD phospholipase A2 (PLA2) in glycogen-induced rabbit inflammatory peritoneal exudates is responsible for the potent bactericidal activity of the inflammatory fluid toward Staphylococcus aureus (1996. J. Clin.

Nutritional modulation of immunity and the inflammatory response.

The metabolic derangements of the injured or stressed patient are governed by multiple factors that partially include the severity of insult, preexisting illnesses, available energy reserves, and appropriateness of intervention. The normal response to injury is further characterized by the release of proinflammatory and antiinflammatory mediators that exert potent effects on cellular and organ function. Although brief periods of starvation and catabolism are tolerable in otherwise healthy individuals, protracted nutritional deprivation can manifest as immunocompromise, irreversible organ injury, and late mortality.

The analysis of exfoliated cervical cells by infrared microscopy.

The screening technique developed by Dr. Papanicolau for cervical cancer has significantly increased opportunities for early detection and treatment of this disease. Recently there has been a great deal of concern related to the accuracy of the Pap smear screening technique for cervical cancer and the need for highly skilled technologists to reliably examine the prepared samples.

Parenteral nutrition facilitates activation of coagulation but not of fibrinolysis during human endotoxemia.

Venous thrombosis and bacterial infections are common complications of parenteral nutrition. To test the hypothesis that infection facilitates activation of coagulation during parenteral nutrition, healthy subjects were intravenously injected with endotoxin (2 ng/kg) after they had received either 1 week of standard parenteral nutrition (n = 7) or normal enteral feeding (n = 8). Compared with enteral feeding, parenteral nutrition was associated with a selectively enhanced activation of the coagulation system (plasma levels of thrombin-antithrombin III complexes) during endotoxemia.

Improved osseointeraction of calcium phosphate-coated external fixation pins. Studies in calves.

We investigated osseointeraction of solution-precipitated calcium phosphate (SPCP)-coated transfixation pins used in external skeletal fixation of a calf stable fracture model. One group (SPCP) received centrally-threaded transfixation pins which had SPCP coating; the other group (control) received identical, but not coated, pins. Radiographs were obtained 1 and 40 days after surgery and examined for evidence of osteolysis.

Evaluation of undergraduate medical education - why and how?

The education of physicians both at the undergraduate and graduate level is no longer a matter for an individual professor or department in a medical faculty. The curriculum has to be developed and carried out according to the needs of the society in which the physician is going to function. Evaluation of the educational programme by external reviewers should therefore be seen as a normal part of the quality control process of all medical faculties.

Epinephrine inhibits endotoxin-induced IL-1 beta production: roles of tumor necrosis factor-alpha and IL-10.

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1 beta production, the following experiments were performed: 1) blood obtained from subjects at 4-21 h after the start of a continuous infusion of epinephrine (30 ng.kg-1.

Catecholamines increase monocyte TNF receptors and inhibit TNF through beta 2-adrenoreceptor activation.

Postinjury deficits in monocyte tumor necrosis factor receptors (moTNFR) activity may alter beneficial functions during an inflammatory response. Several counter-regulatory hormones elicited during inflammation may modulate tumor necrosis factor (TNF) activity, but little is known about their influence on moTNFR. Also, catecholamines inhibit TNF production, but the adrenoreceptor mechanism of this effect has not been fully clarified.

Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia.

Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6-/-) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and interferon-gamma and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05).

Fatal fentanyl intoxication following excessive transdermal application.

The case history and toxicological findings of a fatal fentanyl intoxication due to the application of multiple transdermal patches are presented. An 83 year-old white female with terminal cancer was found dead with three 100 mg/h fentanyl patches on her chest. The autopsy and subsequent histological studies revealed extensive areas of gastric carcinoma, a large atrial tumor, ulceration of esophagus, metastasis of peripancreatic lymph nodes and a recent surgical removal of part of the lower lobe of the left lung.

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.

Objective: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis.

Design: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis.

Setting: Ninety-one academic medical center intensive care units in North America and Europe.

Pretreatment with a 55-kDa tumor necrosis factor receptor-immunoglobulin fusion protein attenuates activation of coagulation, but not of fibrinolysis, during lethal bacteremia in baboons.

Baboons (Papio anubis) receiving a lethal intravenous infusion with live Escherichia coli were pretreated with either a 55-kDa tumor necrosis factor (TNF) receptor-IgG fusion protein (TNFR55:IgG) (n = 4, 4.6 mg/kg) or placebo (n = 4). Neutralization of TNF activity in TNFR55:IgG-treated animals was associated with a complete prevention of mortality and a strong attenuation of coagulation activation as reflected by the plasma concentrations of thrombin-antithrombin III complexes (P < .

Lipopolysaccharide-induced interleukin 8 production by human whole blood is enhanced by epinephrine and inhibited by hydrocortisone.

To determine the effect of epinephrine and hydrocortisone on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production, human whole blood was stimulated with LPS in the presence or absence of these stress hormones. Epinephrine caused a dose-dependent increase in LPS-induced IL-8 production, which was mediated exclusively via beta-adrenergic receptors, as reflected by the facts that beta (but not alpha) receptor blockade reversed the epinephrine effect and beta (but not alpha) receptor stimulation reproduced the epinephrine effect. Further, elevating cellular cyclic AMP (cAMP) concentrations, a known effect of beta-adrenergic stimulation, by addition of dibutyryl cAMP also enhanced LPS-induced IL-8 production.

Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans.

To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 +/- 42 pg/mL; P < .

Epinephrine exerts anticoagulant effects during human endotoxemia.

To determine the effect of a physiologically relevant elevation in the plasma concentrations of epinephrine on the activation of the hemostatic mechanism during endotoxemia, 17 healthy men were studied after intravenous injection of lipopolysaccharide (LPS, 2 ng/kg), while receiving a continuous infusion of epinephrine (30 ng/kg/min) started either 3 h (n = 5) or 24 h (n = 6) before LPS injection, or an infusion of normal saline (n = 6). Activation of the coagulation system (plasma concentrations of thrombin-antithrombin III complexes and prothrombin fragment F1+2) was significantly attenuated in the groups treated with epinephrine when compared with subjects injected with LPS only (P <0.05).

Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia.

IL-10 protects mice from LPS-induced lethality. To determine the effects of IL-10 on LPS-induced inflammatory responses, six Papio anubis baboons were i.v.

Passive immunization against tumor necrosis factor-alpha impairs host defense during pneumococcal pneumonia in mice.

Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. We sought to determine the role of tumor necrosis factor-alpha (TNF) in the pathogenesis of pneumococcal pneumonia. Induction of pneumonia in C57B1/6 mice by intranasal inoculation with 10(6) colony-forming units (cfu) S.

Epinephrine attenuates down-regulation of monocyte tumor necrosis factor receptors during human endotoxemia.

Epinephrine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production by increasing intracellular cAMP concentrations. Because agents that increase cAMP levels can enhance TNF receptor expression in vitro, granulocyte and monocyte TNF receptors were determined by FACS-analysis in 7 normal humans who were receiving a constant 24-h infusion of epinephrine (30 ng/kg/min), and in 15 normal subjects after intravenous injection of LPS (2 ng/kg), while they were receiving a continuous infusion of epinephrine started either 3 h (EPI-3) or 24 h (EPI-24) before LPS injection or an infusion of normal saline (LPS; n = 5 per group). Infusion of epinephrine per se did not influence TNF receptor expression.

Down-regulation of surface receptors for TNF and IL-1 on circulating monocytes and granulocytes during human endotoxemia: effect of neutralization of endotoxin-induced TNF activity by infusion of a recombinant dimeric TNF receptor.

Leukocytes rapidly lose their surface receptors for TNF and IL-1 upon exposure to various stimuli in vitro. We sought to determine by FACS analysis changes in the expression of TNF receptors (TNFR) and type II IL-1R on circulating monocytes and granulocytes during endotoxemia in vivo, and the role of endogenous TNF in these changes. Twelve healthy subjects received an i.

Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13.

Plasma concentrations of soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13 were measured in 42 patients with clinically defined sepsis during a 3-day follow-up and in 7 healthy humans after intravenous injection of endotoxin (2 ng/kg). Levels of soluble IL-1 receptor type II were persistently elevated in patients with sepsis than in healthy controls and higher in nonsurviving patients (n = 22) than in surviving patients (n = 20) at all time points. IL-10 was found in the circulation of 81% of patients with sepsis, while it was not detectable in normal plasma.

Changes in endotoxin-induced cytokine production by whole blood after in vivo exposure of normal humans to endotoxin.

Whole blood of 6 healthy subjects, who were intravenously injected with lipopolysaccharide (LPS, 2 ng/kg), was stimulated ex vivo with LPS (10 ng/mL). Three and 6 h after injection of LPS, whole blood produced less tumor necrosis factor-alpha (TNF), interleukin (IL)-1beta, IL-6, and IL-10 (all P < .05).

Interleukin-10 impairs host defense in murine pneumococcal pneumonia.

The effects of recombinant interleukin (IL)-10 and the role of endogenous IL-10 were determined in C57B1/6 mice with pneumonia induced by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae. Pneumonia induced sustained expression of IL-10 mRNA and protein in lungs, but IL-10 remained undetectable in plasma. Intranasal inoculation of S.

Hypercortisolemia increases plasma interleukin-10 concentrations during human endotoxemia--a clinical research center study.

Hypercortisolemia directly before the administration of endotoxin (LPS) to normal humans completely prevents the release of the proinflammatory cytokine tumor necrosis factor, whereas hypercortisolemia 12 h to 7 days before the injection of LPS is associated with enhanced tumor necrosis factor release. To determine the effect of elevated cortisol levels on the secretion of the antiinflammatory cytokine interleukin-10 (IL-10), 23 healthy men were given iv LPS (lot EC-5; 2 ng/kg) alone or in combination with a continuous iv infusion of hydrocortisone (3 micrograms/kg.min) for 6 h immediately before or 6, 12, or 144 h before LPS injection.

Tumor necrosis factor-alpha induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor.

Tumor necrosis factor-alpha (TNF-alpha) can bind to two distinct transmembrane receptors, the p55 and p75 TNF receptors. We compared the capability of two mutant TNF proteins with exclusive affinity for the p55 or p75 TNF receptor with that of wild type TNF, to activate the hemostatic mechanism in baboons. Both activation of the coagulation system, monitored by the plasma levels of thrombin-antithrombin III complexes, and activation of the fibrinolytic system (plasma levels of tissue-type plasminogen activator, and plasminogen activator inhibitor type I), were of similar magnitude after intravenous injection of wild type TNF or the TNF mutant with affinity only for the p55 receptor.