Dopexamine can attenuate the inflammatory response and protect against organ injury in the absence of significant effects on hemodynamics or regional microvascular flow

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Microvesicle Subsets in Sepsis Due to Community Acquired Pneumonia Compared to Faecal Peritonitis.

RATIONALE: Microvesicles (MV) act as a nonsoluble means of intercellular communication, with effector roles in disease pathogenesis and potentially as biomarkers. Previously, we reported that neutrophil MV expressing alpha-2-macroglobulin (A2MG) are protective in experimental sepsis and associate with survival in a small cohort of patients with sepsis due to community acquired pneumonia (CAP). OBJECTIVES: To characterize MV profiles in sepsis due to CAP or fecal peritonitis (FP) and determine their relation to outcome. To investigate the effects of novel sepsis treatments (granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon-υ (IFN-γ)) on MV production and functions in vitro. METHODS: Flow cytometry analysis of MV identified the cell of origin and the proportion of A2MG expression in the plasma of patients with sepsis secondary to CAP (n = 60) or FP (n = 40) and compared with healthy volunteers (HV, n = 10). The association between MV subsets and outcome was examined. The ability of GM-CSF and IFN-γ on A2MG MV production from whole blood was examined together with the assessment of their effect on neutrophil and endothelial functions. RESULTS: Circulating cell-derived and A2MG MV were higher in CAP compared with FP and HV. A2MG MV were higher in survivors of CAP, but not in FP. GM-CSF and IFN-γ enhanced A2MG MV production, with these MV eliciting pathogen clearance in vitro. CONCLUSIONS: Plasma MV profiles vary according to the source of infection. A2MG MV are associated with survival in CAP but not FP. We propose specific MV subsets as novel biomarkers in sepsis and potential effector for some of the actions of experimental therapeutic interventions.National Institute for Health Research, UK

Post-operative immune suppression is mediated via reversible, Interleukin-10 dependent pathways in circulating monocytes following major abdominal surgery.

INTRODUCTION: Post-operative infections occur frequently following major surgery. The magnitude of the post-operative immune response is associated with an increased risk of post-operative infections, although the mechanisms driving post-operative immune-dysfunction and the potential reversibility of this response with immune stimulants are not well understood. This study aims to describe the immediate immune response to major surgery and establish links to both post-operative infection and functional aspects of immune dysregulation. We also investigate the potential of clinically available immune stimulants to reverse features of post-operative immune-dysfunction. METHODS: Patients over 45 years old undergoing elective gastro-intestinal surgery with planned post-operative surgical ICU admission were recruited. The expression of selected genes was determined pre-operatively and at 2, 24 and 48 hours post-operatively using qRT-PCR. Circulating levels of Interleukin-10 protein were determined by ELISA. Peri-operative cell surface monocyte HLA-DR (mHLA-DR) expression was determined using flow cytometry. Gene expression and mHLA-DR levels were determined in healthy monocytes cultured in peri-operative serum with and without neutralising antibodies and immune stimulants. RESULTS: 119 patients were recruited; 44 developed a post-operative infection. Interleukin-10 mRNA and protein increased 4-fold post-operatively (P<0.0001), peaking within 2 hours of the procedure. Higher post-operative Interleukin-10 mRNA (P = 0.007) and protein (P = 0.001) levels were associated with an increased risk of infection. Cell surface mHLA-DR expression fell post-operatively (P<0.0001). Reduced production, rather than intracellular sequestration, accounted for the post-operative decline in cell surface mHLA-DR expression. Interleukin-10 antibody prevented the decrease in mHLA-DR expression observed when post-operative serum was added to healthy monocytes. GM-CSF and IFN-γ prevented the decline in mHLA-DR production through distinct pathways. CONCLUSIONS: Monocyte dysfunction and features of immune suppression occur frequently after major surgery. Greater post-operative Interleukin-10 production is associated with later infection. Interleukin-10 is an important mediator of post-operative reductions in mHLA-DR expression, while clinically available immune stimulants can restore mHLA-DR levels.Royal College of Surgeons of England, The National Institute of Academic Anaesthesia (British Journal of Anaesthesia / Royal College of Anaesthetists Project Grant) European Society of Anaesthesiology

The Effects of Previous Misestimation of Task Duration on Estimating Future Task Duration

It is a common time management problem that people underestimate the duration of tasks, which has been termed the "planning fallacy." To overcome this, it has been suggested that people should be informed about how long they previously worked on the same task. This study, however, tests whether previous misestimation also affects the duration estimation of a novel task, even if the feedback is only self-generated. To test this, two groups of participants performed two unrelated, laboratory-based tasks in succession. Learning was manipulated by permitting only the experimental group to retrospectively estimate the duration of the first task before predicting the duration of the second task. Results showed that the experimental group underestimated the duration of the second task less than the control group, which indicates a general kind of learning from previous misestimation. The findings imply that people could be trained to carefully observe how much they misestimate task duration in order to stimulate learning. The findings are discussed in relation to the anchoring account of task duration misestimation and the memory-bias account of the planning fallacy. © 2014 Springer Science+Business Media New York

Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort

The GenOSept project was supported by the European Critical Care Research network and the European Society of Intensive Care Medicin

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genomewide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit– hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety)