Activation of factor VII-activating protease in human inflammation: a sensor for cell death.

Introduction: Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosomes were suggested to play an important role in inflammation and were demonstrated to correlate with severity and outcome in sepsis patients. We recently showed that plasma can release nucleosomes from late apoptotic cells.

Pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma.

Background: Pulmonary coagulopathy is intrinsic to pneumonia and other forms of acute lung injury. We hypothesized patients with burn injuries and inhalation trauma to have similar alterations in pulmonary coagulation and fibrinolysis.

Methods: We performed a prospective study on changes in pulmonary and systemic thrombin generation and fibrinolytic activity in patients with burn injuries and inhalation trauma requiring mechanical ventilation.

β₂-glycoprotein I: a novel component of innate immunity.

Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis.

Tired of Lyme borreliosis. Lyme borreliosis in the Netherlands.

Lyme borreliosis has become the most common vector-borne illness in North Eastern USA and Europe. It is a zoonotic disease, with well-defined symptoms, caused by B. burgdorferi sensu lato, and transmitted by ticks.

Coagulation biomarkers in critically ill patients.

This article discusses coagulation biomarkers in critically ill patients where coagulation abnormalities occur frequently and may have a major impact on the outcome. An adequate explanation for the cause is important, since many underlying disorders may require specific treatment and supportive therapy directed at the underlying condition. Deficiencies in platelets and coagulation factors in bleeding patients or patients at risk for bleeding can be achieved by transfusion of platelet concentrate or plasma products, respectively.

Kinase activity profiling of gram-negative pneumonia.

Pneumonia is a severe disease with high morbidity and mortality. A major causative pathogen is the Gram-negative bacterium Klebsiella (K.) pneumoniae.

Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule.

Patients without a spleen are susceptible for overwhelming sepsis with Streptococcus pneumoniae. We investigated the relative contribution of the pneumococcal capsule in the reduced host defense after splenectomy. Sham-operated or splenectomized mice were inoculated with serotype 2 or 4 S.

The effect of inflammation on coagulation and vice versa.

Purpose Of Review: In infection, inflammation is frequently accompanied by a disturbance of the normal hemostatic balance provided by procoagulant and anticoagulant mechanisms. This review summarizes recently acquired knowledge on the bimodal interactions between coagulation and inflammation in infection.

Recent Findings: Infection elicits inflammation-induced coagulation via tissue factor.

Impact of endogenous protein C on pulmonary coagulation and injury during lethal H1N1 influenza in mice.

Influenza accounts for 5-10% of community-acquired pneumonia cases, and is a major cause of mortality. Sterile and bacterial lung injury are associated with procoagulant and inflammatory derangements in the lungs and down-regulation of the protein C (PC) pathway has been correlated with disease severity and mortality in severe bacterial pneumonia and sepsis. In addition, during lethal influenza pneumonia, pulmonary and systemic coagulation are activated, which can be attenuated by the administration of recombinant activated (A) PC.

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

Background: Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.

Identification and characterization of Ixodes scapularis antigens that elicit tick immunity using yeast surface display.

Repeated exposure of rabbits and other animals to ticks results in acquired resistance or immunity to subsequent tick bites and is partially elicited by antibodies directed against tick antigens. In this study we demonstrate the utility of a yeast surface display approach to identify tick salivary antigens that react with tick-immune serum. We constructed an Ixodes scapularis nymphal salivary gland yeast surface display library and screened the library with nymph-immune rabbit sera and identified five salivary antigens.

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia.

Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia. CD44 is a transmembrane adhesion molecule, expressed by a wide variety of cell types, that has several functions in innate and adaptive immune responses. In this study, we tested the hypothesis that CD44 is involved in the host response during pneumococcal pneumonia.

Acute stress elicited by bungee jumping suppresses human innate immunity.

Although a relation between diminished human immunity and stress is well recognized both within the general public and the scientific literature, the molecular mechanisms by which stress alters immunity remain poorly understood. We explored a novel model for acute human stress involving volunteers performing a first-time bungee jump from an altitude of 60 m and exploited this model to characterize the effects of acute stress in the peripheral blood compartment. Twenty volunteers were included in the study; half of this group was pretreated for 3 d with the β-receptor blocking agent propranolol.

Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1β or IL-1 receptor type I.

The role of intereukin-1 (IL-1) in mortality caused by endotoxaemia remains controversial. While IL-1 receptor antagonist (IL-1Ra) protects mice from lethal endotoxaemia, mice deficient in IL-1β (IL-1β⁻( /)⁻) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies.

Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit.

Introduction: Absolute lymphocytopenia has been reported as a predictor of bacteremia in medical emergencies. Likewise, the neutrophil-lymphocyte count ratio (NLCR) has been shown a simple promising method to evaluate systemic inflammation in critically ill patients.

Methods: We retrospectively evaluated the ability of conventional infection markers, lymphocyte count and NLCR to predict bacteremia in adult patients admitted to the Emergency Department with suspected community-acquired bacteremia.

Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antimicrobial effects in murine pneumococcal pneumonia.

Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community-acquired pneumonia.

S100A8/A9 is not involved in host defense against murine urinary tract infection.

Background: Inflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders.

Loss of suppression of tumorigenicity 2 (ST2) gene reverses sepsis-induced inhibition of lung host defense in mice.

Rationale: After surviving the initial hyperinflammatory phase, patients with sepsis display features consistent with immunosuppression, which renders the host susceptible to nosocomial infections, in particular bacterial pneumonia. Suppression of tumorigenicity 2 (ST2) is a negative regulator of Toll-like receptor signaling implicated in endotoxin tolerance.

Objectives: The present study sought to determine the role of ST2 in modulating host defense in the lung during sepsis, using a murine model of cecal ligation and puncture (CLP)-induced sepsis followed by a secondary infection with Pseudomonas aeruginosa via the airways.

Therapeutic recombinant murine activated protein C attenuates pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia.

Background: Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy.

Methods: Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 μg), ceftriaxone (500 μg), or rm-APC plus ceftriaxone.

CD44 deficiency is associated with increased bacterial clearance but enhanced lung inflammation during Gram-negative pneumonia.

Klebsiella pneumoniae is a frequently isolated causative pathogen in respiratory tract infections. CD44 is a transmembrane adhesion molecule that has been implicated in several immunological processes. To determine the role of CD44 during Klebsiella pneumonia, we intranasally infected wild-type and CD44 knockout (KO) mice with 10(2) to 10(4) colony-forming units of K.

The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies.

Background: Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear.

Methods: A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined.

Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans.

In diabetes mellitus and sepsis, low erythrocyte glutathione (GSH) concentrations are found. Whether this is caused by lowered GSH production has not been clarified. To obtain insight in the relationship between erythrocyte GSH concentrations and GSH production, GSH kinetics were measured in healthy male volunteers during 4 different clamps (low-dose or medium-dose insulin [100 or 400 pmol/L] and euglycemia or hyperglycemia [5 or 12 mmol/L]) in a control setting (n = 6; all 4 clamps in the same subject) or after systemic administration of lipopolysaccharide (to mimic sepsis) (4 groups of n = 6; each clamp in a different subject).

Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under β-adrenergic blockade.

Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). β-adrenergic blockade enhances BRS during rest, but its effect on BRS during acute psychological stress is unknown. This study tested the hypothesis that BRS is higher during acute psychological stress in healthy subjects under β-adrenergic blockade.