Inflammation and Immune-Related Candidate Gene Associations with Acute Lung Injury Susceptibility and Severity: A Validation Study

Introduction: Common variants in genes related to inflammation, innate immunity, epithelial cell function, and angiogenesis have been reported to be associated with risks for Acute Lung Injury (ALI) and related outcomes. We tested whether previously-reported associations can be validated in an independent cohort at risk for ALI. Methods: We identified 37 genetic variants in 27 genes previously associated with ALI and related outcomes. We prepared allelic discrimination assays for 12 SNPs from 11 genes with MAF>0.05 and genotyped these SNPs in Caucasian subjects from a cohort of critically ill patients meeting criteria for the systemic inflammatory response syndrome (SIRS) followed for development of ALI, duration of mechanical ventilation, and in-hospital death. We tested for associations using additive and recessive genetic models. Results: Among Caucasian subjects with SIRS (n = 750), we identified a nominal association between rs2069832 in IL6 and ALI susceptibility (OR$_{adj}$ 1.61; 95% confidence interval [CI], 1.04–2.48, P = 0.03). In a sensitivity analysis limiting ALI cases to those who qualified for the Acute Respiratory Distress Syndrome (ARDS), rs61330082 in NAMPT was nominally associated with risk for ARDS. In terms of ALI outcomes, SNPs in MBL2 (rs1800450) and IL8 (rs4073) were nominally associated with fewer ventilator-free days (VFDs), and SNPs in NFE2L2 (rs6721961) and NAMPT (rs61330082) were nominally associated with 28-day mortality. The directions of effect for these nominal associations were in the same direction as previously reported but none of the associations survived correction for multiple hypothesis testing. Conclusion: Although our primary analyses failed to statistically validate prior associations, our results provide some support for associations between SNPs in IL6 and NAMPT and risk for development of lung injury and for SNPs in IL8, MBL2, NFE2L2 and NAMPT with severity in ALI outcomes. These associations provide further evidence that genetic factors in genes related to immunity and inflammation contribute to ALI pathogenesis

Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction

INTRODUCTION: Multiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury. METHODS: We administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 μg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS). RESULTS: Myeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-α. CONCLUSION: Non-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury

Discovery of Orbital Ordering in Bi2Sr2CaCu2O8+x

The primordial ingredient of cuprate superconductivity is the CuO2 unit cell. Here, theoretical attention usually concentrates on the intra-atom Coulombic interactions dominating the 3d^9 and 3d^10 configurations of each copper ion. However, if Coulombic interactions also occur between electrons of the 2p^6 orbitals of each planar oxygen atom, spontaneous orbital ordering may split their energy levels. This long predicted intra-unit cell symmetry breaking should then generate an orbital ordered phase, for which the charge-transfer energy E separating the 2p^6 and 3d^10orbitals is distinct for the two oxygen atoms. Here we introduce sublattice resolved E(r) imaging techniques to CuO2 studies and discover intra-unit-cell rotational symmetry breaking of E(r), with energy-level splitting between the two oxygen atoms on the 50 meV scale. Spatially, this state is arranged in disordered Ising domains of orthogonally oriented orbital order that appear bounded by dopant ions, and within whose domain walls low energy electronic quadrupolar two-level systems occur. Overall, these data reveal a Q=0 orbitally ordered state that splits the energy levels of the oxygen orbitals by ~50 meV, in underdoped CuO2

Ultrafast relaxation of symmetry-breaking photo-induced atomic forces

We present a first-principles method for the calculation of the temperature-dependent relaxation of symmetry-breaking atomic driving forces in photoexcited systems. We calculate the phonon-assisted decay of the photoexcited force on the low-symmetry Eg mode following absorption of an ultrafast pulse in Bi, Sb, and As. The force decay lifetimes for Bi and Sb are of the order of 10 fs and in agreement with recent experiments, demonstrating that electron-phonon scattering is the primary mechanism relaxing the symmetry-breaking forces. Calculations for a range of absorbed photon energies suggest that larger amplitude, symmetry-breaking atomic motion may be induced by choosing a pump photon energy which maximizes the product of the initial Eg force and its lifetime. The high-symmetry A1g force undergoes a partial decay to a nonzero constant on similar timescales, which has not yet been measured in experiments. The average imaginary part of the electron self-energy over the photoexcited carrier distribution provides a crude indication of the decay rate of symmetry-breaking forces

Measurements of nonequilibrium interatomic forces using time-domain x-ray scattering

We demonstrate an experimental approach to determining the excited-state interatomic forces using femtosecond x-ray pulses from an x-ray free-electron laser. We determine experimentally the excited-state interatomic forces that connect photoexcited carriers to the nonequilibrium lattice dynamics in the prototypical Peierls-distorted material, bismuth. The forces are obtained by a constrained least-squares fit of a pairwise interatomic force model to the excited-state phonon dispersion relation as measured by the time- and momentum-resolved x-ray diffuse scattering. We find that photoexcited carriers weaken predominantly the nearest-neighbor forces, which drives the measured softening of the transverse acoustic modes throughout the Brillouin zone as well as the zone-center A1g optical mode. This demonstrates a bond-selective approach to measuring electron-phonon coupling relevant to a broad range of photoinduced phase transitions and transient light-driven states in quantum materials

Direct measurement of anharmonic decay channels of a coherent phonon

We report channel-resolved measurements of the anharmonic coupling of the coherent A1g phonon in photoexcited bismuth to pairs of high wave vector acoustic phonons. The decay of a coherent phonon can be understood as a parametric resonance process whereby the atomic displacement periodically modulates the frequency of a broad continuum of modes. This coupling drives temporal oscillations in the phonon mean-square displacements at the A1g frequency that are observed across the Brillouin zone by femtosecond x-ray diffuse scattering. We extract anharmonic coupling constants between the A1g and several representative decay channels that are within an order of magnitude of density functional perturbation theory calculations

Intervention for depression among palliative care patients and their families: A study protocol for evaluation of a training program for professional care staff

Background: Clinical depression is highly prevalent yet under-detected and under-treated in palliative care settings and is associated with a number of adverse medical and psychological outcomes for patients and their family members. This article presents a study protocol to evaluate a training intervention for non-physician palliative care staff to improve the recognition of depression and provide support for depressed patients and their family members. Details of the hypotheses and expected outcomes, study design, training program development and evaluation measures are described.Methods and Design: A randomised controlled trial will be implemented across two palliative care services to evaluate the &ldquo;Training program for professional carers to recognise and manage depression in palliative care settings&rdquo;. Pre-, post- and three-month follow-up data will be collected to assess: the impact of the training on the knowledge, attitudes, self-efficacy and perceived barriers of palliative care staff when working with depression; referral rates for depression; and changes to staff practices. Quantitative and qualitative methods, in the form of self-report questionnaires and interviews with staff and family members, will be used to evaluate the effectiveness of the intervention.Discussion: This study will determine the effectiveness of an intervention that aims to respond to the urgent need for innovative programs to target depression in the palliative care setting. The expected outcome of this study is the validation of an evidence-based training program to improve staff recognition and appropriate referrals for depression, as well as improve psychosocial support for depressed patients and their family members.<br /

Differential Constitutive and Cytokine-Modulated Expression of Human Toll-like Receptors in Primary Neutrophils, Monocytes, and Macrophages

Human Toll-like receptors (TLRs) comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs) and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the human innate immune system. Proinflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interferon-&#947; (IFN-&#947;), have been shown to up-regulate microbicidal activity in these effector cells of innate immunity. Currently, the cellular and molecular mechanisms responsible for these effects are not completely understood. We hypothesized that these cytokines may up-regulate TLR expression as a mechanism to facilitate microbial recognition and augment the innate immune response. Using quantitative realtime rt-PCR technology, we examined constitutive expression of TLR2, TLR4, TLR5, and TLR9 mRNA and the effects of G-CSF, GM-CSF, M-CSF, and IFN-&#947; on TLR mRNA expression in purified populations of normal human neutrophils, monocytes, and monocyte-derived macrophages. Relative constitutive expression of TLR2, TLR4, and TLR9 was similar in neutrophils and monocytes. Constitutive expression of TLR5 was less in neutrophils compared to monocytes. Constitutive expression of TLR4 was greater and that of TLR9 lower in monocyte-derived macrophages compared to monocytes. Of the cytokines examined, IFN-&#947; and GM-CSF caused the greatest effects on TLR expression. IFN- &#947; up-regulated TLR2 and TLR4 in neutrophils and monocytes. GM-CSF up-regulated expression of TLR2 and TLR4 in neutrophils and TLR2 in monocytes. TLR5 was down-regulated by inflammatory cytokines in monocytes. These results suggest a potential role for IFN- &#947; and/or GM-CSF as therapeutic immunomodulators of the host defense to infection.</p