Glucocorticoid receptor expression in human bronchial epithelial cells: effects of smoking and COPD.

Previously, we found that inflammatory mediators modulated the number and binding affinity of glucocorticoid receptors (GR) in human bronchial epithelial cell lines. In this study we investigated whether smoking and chronic obstructive pulmonary disease (COPD), both characterized by airway inflammation with increased levels of inflammatory mediators, affect GR characteristics in cultured human bronchial epithelial cells (HBEC). A statistically significant difference was found between the dissociation constant (Kd) values in HBEC from smoking (Kd = 0.98+/-0.08 nM; n = 6) and nonsmoking controls (Kd = 0.76+/-0.10 nM, P = 0.03; n = 5), but no significant difference was found between the mean number of binding sites. Our results are the first indication that cultured HBEC from smokers possess GR with a lower binding affinity. This may result from the inflammation found in the airways from smokers. Furthermore, these results provide further evidence that the bronchial epithelium may be an actual target for inhaled glucocorticoid therapy

Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a β2-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics

Extending the voltage window in the characterization of electrical transport of large-area molecular junctions

A large bias window is required to discriminate between different transport models in large-area molecular junctions. Under continuous DC bias, the junctions irreversibly break down at fields over 9 MV/cm. We show that, by using pulse measurements, we can reach electrical fields of 35 MV/cm before degradation. The breakdown voltage is shown to depend logarithmically on both duty cycle and pulse width. A tentative interpretation is presented based on electrolysis in the polymeric top electrode. Expanding the bias window using pulse measurements unambiguously shows that the electrical transport exhibits not an exponential but a power-law dependence on bias. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3608154

Expression of lipocortins in human bronchial epithelial cells: effects of IL-1β , TNF-α, LPS and dexamethasone

In this study, we investigated the expression of lipocortin I and II (annexin I and I in the human bronchial epithelium, both in vivo and in vitro. A clear expression of lipocortin I and II protein was found in the epithelium in sections of bronchial tissue. In cultured human bronchial epithelial cells we demonstrated the expression of lipocortin I and II mRNA and protein using Northern blotting, FACScan analysis and ELISA. No induction of lipocortin I or II mRNA or protein was observed after incubation with dexamethasone. Stimulation of bronchial epithelial cells with IL-1β, TNF-α or LPS for 24 h did not affect the lipocortin I or II mRNA or protein expression, although PGE2 and 6-keto-PGF1α production was significantly increased. This IL-1β- and LPS-mediated increase in eicosanoids could be reduced by dexamethasone, but was not accompanied by an increase in lipocortin I or II expression. In human bronchial epithelial cells this particular glucocorticoid action is not mediated through lipocortin I or II induction

Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia

Background: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. Methods: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. Results: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score ≥ 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. Conclusions: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications

DISCO-SCA and Properly Applied GSVD as Swinging Methods to Find Common and Distinctive Processes

BACKGROUND: In systems biology it is common to obtain for the same set of biological entities information from multiple sources. Examples include expression data for the same set of orthologous genes screened in different organisms and data on the same set of culture samples obtained with different high-throughput techniques. A major challenge is to find the important biological processes underlying the data and to disentangle therein processes common to all data sources and processes distinctive for a specific source. Recently, two promising simultaneous data integration methods have been proposed to attain this goal, namely generalized singular value decomposition (GSVD) and simultaneous component analysis with rotation to common and distinctive components (DISCO-SCA). RESULTS: Both theoretical analyses and applications to biologically relevant data show that: (1) straightforward applications of GSVD yield unsatisfactory results, (2) DISCO-SCA performs well, (3) provided proper pre-processing and algorithmic adaptations, GSVD reaches a performance level similar to that of DISCO-SCA, and (4) DISCO-SCA is directly generalizable to more than two data sources. The biological relevance of DISCO-SCA is illustrated with two applications. First, in a setting of comparative genomics, it is shown that DISCO-SCA recovers a common theme of cell cycle progression and a yeast-specific response to pheromones. The biological annotation was obtained by applying Gene Set Enrichment Analysis in an appropriate way. Second, in an application of DISCO-SCA to metabolomics data for Escherichia coli obtained with two different chemical analysis platforms, it is illustrated that the metabolites involved in some of the biological processes underlying the data are detected by one of the two platforms only; therefore, platforms for microbial metabolomics should be tailored to the biological question. CONCLUSIONS: Both DISCO-SCA and properly applied GSVD are promising integrative methods for finding common and distinctive processes in multisource data. Open source code for both methods is provided

Symmetry Breaking and Finite Size Effects in Quantum Many-Body Systems

We consider a quantum many-body system on a lattice with a continuous symmetry which exhibits a spontaneous symmetry breaking in its infinite volume ground states, but in which the order operator does not commute with the Hamiltonian. A typical example is the Heisenberg antiferromagnet with a Neel order. In the corresponding finite system, the symmetry breaking is usually "obscured" by "quantum fluctuation" and one gets a symmetric ground state with a long range order. In such a situation, we prove that there exist ever increasing numbers of low-lying eigenstates whose excitation energies are bounded by a constant times 1/N, where N denotes the number of sites. By forming linear combinations of these low-lying states and the (finite-volume) ground state, and by taking infinite volume limits, we construct infinite volume ground states with explicit symmetry breaking. Our general theorems do not only shed light on the nature ofsymmetry breaking in quantum many-body systems, but provide indispensable information for numerical approaches to these systems. We also discuss applications of our general results to a variety of examples. The present paper is intended to be accessible to the readers without background in mathematical approaches to quantum many-body systems.Comment: LaTeX, 58 pages, no figures. Notes about Bose-Einstein condenstaion are added after the publicatio

Au-Ag template stripped pattern for scanning probe investigations of DNA arrays produced by Dip Pen Nanolithography

We report on DNA arrays produced by Dip Pen Nanolithography (DPN) on a novel Au-Ag micro patterned template stripped surface. DNA arrays have been investigated by atomic force microscopy (AFM) and scanning tunnelling microscopy (STM) showing that the patterned template stripped substrate enables easy retrieval of the DPN-functionalized zone with a standard optical microscope permitting a multi-instrument and multi-technique local detection and analysis. Moreover the smooth surface of the Au squares (abput 5-10 angstrom roughness) allows to be sensitive to the hybridization of the oligonucleotide array with label-free target DNA. Our Au-Ag substrates, combining the retrieving capabilities of the patterned surface with the smoothness of the template stripped technique, are candidates for the investigation of DPN nanostructures and for the development of label free detection methods for DNA nanoarrays based on the use of scanning probes.Comment: Langmuir (accepted

Biomarker-indicated extent of oxidation of plant-derived organic carbon (OC) in relation to geomorphology in an arsenic contaminated Holocene aquifer, Cambodia

The poisoning of rural populations in South and Southeast Asia due to high groundwater arsenic concentrations is one of the world’s largest ongoing natural disasters. It is important to consider environmental processes related to the release of geogenic arsenic, including geomorphological and organic geochemical processes. Arsenic is released from sediments when iron-oxide minerals, onto which arsenic is adsorbed or incorporated, react with organic carbon (OC) and the OC is oxidised. In this study we build a new geomorphological framework for Kandal Province, a highly studied arsenic affected region of Cambodia, and tie this into wider regional environmental change throughout the Holocene. Analyses shows that the concentration of OC in the sediments is strongly inversely correlated to grainsize. Furthermore, the type of OC is also related to grain size with the clay containing mostly (immature) plant derived OC and sand containing mostly thermally mature derived OC. Finally, analyses indicate that within the plant derived OC relative oxidation is strongly grouped by stratigraphy with the older bound OC more oxidised than younger OC

Semiclassical Mechanics of the Wigner 6j-Symbol

The semiclassical mechanics of the Wigner 6j-symbol is examined from the standpoint of WKB theory for multidimensional, integrable systems, to explore the geometrical issues surrounding the Ponzano-Regge formula. The relations among the methods of Roberts and others for deriving the Ponzano-Regge formula are discussed, and a new approach, based on the recoupling of four angular momenta, is presented. A generalization of the Yutsis-type of spin network is developed for this purpose. Special attention is devoted to symplectic reduction, the reduced phase space of the 6j-symbol (the 2-sphere of Kapovich and Millson), and the reduction of Poisson bracket expressions for semiclassical amplitudes. General principles for the semiclassical study of arbitrary spin networks are laid down; some of these were used in our recent derivation of the asymptotic formula for the Wigner 9j-symbol.Comment: 64 pages, 50 figure