Hypoxemia After Endobronchial Valve Deployment for Persistent Air Leak.

Endobronchial valves (EBVs) are a novel, minimally invasive bronchoscopic management technique for persistent air leaks that fail conservative therapy. Currently, 2 EBVs are available in the United States: the Spiration Valve System (Olympus, Redmond, WA) and the Zephyr Valve (Pulmonx, Redwood, CA). These valves are Food and Drug Administration-approved to reduce hyperinflation in emphysematous patients via bronchoscopic lung-volume reduction. However, more recently, the Spiration Valve has been granted a compassionate use exemption through the Food and Drug Administration for persistent postsurgical air leaks. Despite their popularity, these devices are not free from side effects. As an anesthesiologist, it is vital to be aware of the pathophysiology of this patient population so that safe and effective anesthetics may be provided during valve placement. Here, the use of EBVs is discussed in a patient who presented with a persistent air leak after a transthoracic needle aspiration that failed treatment due to persistent hypoxemia, warranting EBV removal.

The TNF-Alpha Inducing Protein is Associated With Gastric Inflammation and Hyperplasia in a Murine Model of Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach leading to the development of chronic gastritis, peptic ulcers and gastric adenocarcinoma. A combination of host, environment and bacterial virulence factors contribute to disease development. The H. pylori TNFα inducing protein (Tipɑ) is a virulence factor shown to induce multiple pro-inflammatory cytokines in addition to TNFα in vitro. The goal of the present study was to elucidate the role of Tipα in promoting inflammation in vivo and to identify the molecular pathways associated with Tipα associated virulence. Mice were infected with wild-type Sydney strain (SS1) or a tipα mutant (Δtipα) for 1 month and 4 months. We also completed a second 4 months infection including a 1:1 SS1 to Δtipα co-infected group in addition to SS1 and Δtipα infected groups. The expression of TNFα, and KC were significantly higher in the SS1 infected group compared to both uninfected control (naïve) and Δtipα groups. Mice infected with Tipα expressing SS1 induced more severe histological gastritis and developed hyperplasia compared to Δtipα infected mice. Microarray analysis of gastric epithelial cells co-cultured with recombinant Tipα (rTipα) demonstrates up-regulation of the NFκB pathway. This data suggest Tipα plays an important role in H. pylori induced inflammation.

VapA of Rhodococcus equi binds phosphatidic acid.

Rhodococcus equi is a multihost, facultative intracellular bacterial pathogen that primarily causes pneumonia in foals less than six months in age and immunocompromised people. Previous studies determined that the major virulence determinant of R. equi is the surface bound virulence associated protein A (VapA). The presence of VapA inhibits the maturation of R. equi-containing phagosomes and promotes intracellular bacterial survival, as determined by the inability of vapA deletion mutants to replicate in host macrophages. While the mechanism of action of VapA remains elusive, we show that soluble recombinant VapA32-189 both rescues the intramacrophage replication defect of a wild type R. equi strain lacking the vapA gene and enhances the persistence of nonpathogenic Escherichia coli in macrophages. During macrophage infection, VapA was observed at both the bacterial surface and at the membrane of the host-derived R. equi containing vacuole, thus providing an opportunity for VapA to interact with host constituents and promote alterations in phagolysosomal function. In support of the observed host membrane binding activity of VapA, we also found that rVapA32-189 interacted specifically with liposomes containing phosphatidic acid in vitro. Collectively, these data demonstrate a lipid binding property of VapA, which may be required for its function during intracellular infection.

Microfabricated gas chromatograph for rapid, trace-level determinations of gas-phase explosive marker compounds.

A prototype microfabricated gas chromatograph (µGC) adapted specifically for the rapid determination of selected gas-phase marker compounds of the explosive 2,4,6-trinitrotoluene (TNT) at sub-parts-per-billion (

Neutral 5-substituted 4-indazolylaminoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.

We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.

Neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.

Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.

A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion.

The development and progression of cancer is controlled by gene expression, often regulated through chromatin packaging. Heterochromatin protein 1(Hsalpha) (HP1(Hsalpha)), one of three human HP1 family members, participates in heterochromatin formation and gene regulation. HP1(Hsalpha) possesses an amino-terminal chromodomain, which binds methylated lysine 9 of histone H3 (meK9 H3), and a carboxyl-terminal chromoshadow domain (CSD) that is required for dimerization and interaction with partner proteins. HP1(Hsalpha) is down-regulated in invasive metastatic breast cancer cells compared with poorly invasive nonmetastatic breast cancer cells. Expression of EGFP-HP1(Hsalpha) in highly invasive MDA-MB-231 cells causes a reduction in in vitro invasion, without affecting cell growth. Conversely, knock-down of HP1(Hsalpha) levels in the poorly invasive breast cancer cell line MCF-7 increased invasion, without affecting cell growth. To determine whether functions of the CSD were required for the regulation of invasion, mutant forms of HP1(Hsalpha) were expressed in MDA-MB-231 cells. A W174A mutation that disrupts interactions between HP1(Hsalpha) and PXVXL-containing partner proteins reduced invasion similar to that of the wild type protein. In contrast, an I165E mutation that disrupts dimerization of HP1(Hsalpha) did not decrease invasion. No gross changes in localization and abundance of HP1(Hsbeta), HP1(Hsgamma), and meK9 H3 were observed upon expression of wild type and mutant forms of HP1(Hsalpha) in MDA-MB-231 cells. Taken together, these data demonstrate that modulation of HP1(Hsalpha) alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization, but not interactions with PXVXL-containing proteins.