Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.
Molecular biology: principles and applications Analysis of protein synthesis Methods for in situ hybridization Finding disease genes Protein and gene polymorphisms Site directed mutagenesis Tissue specificity Applications of molecular biology to lung disease: bacterial infection Molecular biology and respiratory disease Application to pathology Oncogenes, cancer and growth factors Molecular biology of lung receptors The regulation of collagen and elastin gene expression in normal lung and during pulmonary disease Transepithelial transport of secretory immunoglobulins Heat shock proteins Molecular cellular and genetic studies of atopic disease Interleukins in the pulmonary inflammatory response Gene therapy
We used FIR and submillimeter continuum data from Herschel and the Atacama Pathfinder EXperiment (APEX) to fit pixel-by-pixel modified Planck SEDs to prestellar and protostellar clumps in the Census of High- and Medium-mass Protostars (CHaMP) ($280^{\circ}<\ell<300^{\circ}$, $-4^{\circ}<b<+2^{\circ}$). We present maps of dust temperature ($T_{\text{d}}$) and H$_2$ column density (\ncol) for molecular clumps in the Carina Nebula complex (Regions 9 through 11), and surrounding RCW 64 (Region 26). We compare the column densities of CO and H$_2$ to chart regional variations in their correspondence, and derive maps of the CO abundance. We find the CO abundance varies by an order of magnitude or more across each region, averaging a few$\times$10$^{-5}$ CO per H$_2$, and that the CO abundance distribution across each clump is correlated in both form and magnitude with environmental conditions, especially $T_{\text{d}}$. This demonstrates that no single CO abundance suffices to convert from $N_{\text{CO}}$ to \ncol, even within a single molecular cloud. We also find that $L/M$ traces $T_{\text{d}}$ almost exclusively, and therefore is not an independent star formation tracer, but minima in $T_{\text{d}}$ almost universally coincide with maxima in \ncol, implying that cooling and density enhancement must be simultaneous steps in prestellar clump evolution. Finally, based on generalized histogram N-PDFs of clump-scale (1-5 pc) and cloud-scale ($\gtrsim10$ pc) samples, we could only obtain dual log-normal and power-law fits to $\sim10\%$ of the clumps. The physical parameters derived from these fits approach theoretical expectations, but have largely unknown uncertainties, so we advise treating the results of N-PDF fitting with caution.
1. The effect of two structurally different platelet-activating factor (PAF) receptor antagonists, WEB 2086({3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]-treazolo-[4,3-a][1,4]-diazepine-2-yl]-1-(morpholinyl)-1-propanone}) and BN 52021, on hypoxic pulmonary vasoconstriction (HPV) was studied using an isolated rat lung preparation perfused with blood. 2. In lungs treated with WEB 2086 there was a dose-dependent attenuation of HPV, with complete abolition of HPV at the maximum dose. 3. Low doses of WEB 2086 caused only slight diminution of the pressor response to angiotensin II, although higher doses caused increasing attenuation of the angiotensin pressor response. 4. BN 52021 did not affect HPV. 5. Injection of PAF caused an increase in pulmonary artery pressure of 145%, a response abolished by pre-treatment of the lungs with either WEB 2086 or BN 52021. 6. These results suggest that PAF does not mediate HPV in the rat.
Introduction: Activation of PI3 kinase causes oxidative stress-induced corticosteroid (CS) insensitivity via HDAC2 reduction. We have recently demonstrated that a novel macrolide/fluoroketolide, solithromycin (Soli, CEM-101) restores CS sensitivity via HDAC up-regulation due to PI3K signaling inhibition (ATS2010). However, the mechanism of this effect has not been elucidated. Aims: To investigate the role of a serine/threonine phosphatase PP2A on regulation of the PI3K pathway as the target of Soli. Methods: CS sensitivity was determined by IC 50 of dexamethasone (Dex) on TNFα-induced IL-8 production in U937 monocytic cell. Activities of HDAC2 and PP2A were measured by fluorescence-based activity assay. Phosphorylation levels of Akt as a marker of PI3K activation were determined by Western blotting. Okadaic acid (OA) was used to inhibit PP2A as needed. Results: OA enhanced H 2 O 2 -induced Akt phosphorylation and HDAC2 reduction in U937 cells, and recombinant PP2A reduced Akt phosphorylation levels. Soli restored Dex sensitivity under H 2 O 2 exposure, but pretreatment with OA abrogated Soli-mediated restoration of Dex sensitivity, inhibition of Akt phosphorylation, and HDAC2 activation. In addition, PP2A immunoprecipitates from the membrane fraction and recombinant PP2A were directly activated by Soli. Conclusions: PP2A might be a negative regulator of PI3K signalling. Soli activates PP2A directly, inhibits Akt phosphorylation, then restores HDAC2 activity, resulting in the restoration of CS sensitivity under oxidative stress. Thus, Soli may be a potential treatment for steroid insensitive diseases such as COPD and severe asthma.
"β2-Agonists and Corticosteroids: New Developments and Controversies: Report of a Meeting in November 1990." American Review of Respiratory Disease, 146(6), pp. 1637–1641
