Adenosine induces histamine release from human bronchoalveolar lavage mast cells

Previous studies have shown that in vitro adenosine enhances histamine release from activated human lung mast cells obtained by enzymic dispersion of lung parenchyma. However, adenosine alone has no effect on histamine release from these cells. Given the evidence for direct activation of mast cells after endobronchial challenge with adenosine and previous studies indicating that mast cells obtained at bronchoalveolar lavage are a better model for asthma studies than those obtained by enzymic dispersion of lung tissue, the histamine-releasing effect of adenosine was examined on lavage mast cells. Bronchoalveolar lavage fluid was obtained from patients attending hospital for routine bronchoscopy (n = 54). Lavage cells were challenged with adenosine or adenosine receptor agonists (20 min, 37 degrees C) and histamine release determined using an automated fluorometric assay. Endogenous adenosine levels were also measured in lavage fluid (n = 9) via an HPLC method. Adenosine alone caused histamine release from ravage mast cells in 37 of 54 patients with a maximal histamine release of 20.56 +/- 2.52% (range 5.2-61 %). The adenosine receptor agonists (R)-N-6-(2-phenylisopropyl)adenosine, 5'-N-ethylcarboxamido-adenosine and CGS21680 also induced histamine release from lavage mast cells. Preincubation of lavage mast cells with the adenosine receptor antagonist xanthine amine congener caused significant inhibition of the response to adenosine (P = 0.007). There was an inverse correlation between endogenous adenosine levels in the lavage fluid and the maximal response to in vitro adenosine challenge of the lavage cells. The findings of the present study indicate a means by which adenosine challenge of the airways can induce bronchoconstriction and support a role for adenosine in the pathophysiology of asthma. The results also suggest that cells obtained from bronchoalveolar ravage fluid may provide the ideal model for the testing of novel, adenosine receptor, targeted therapies for asthma.

A Paradoxical Effect of Systemic IL-23 in EAE – Limitation of Autoimmune Inflammatory Demyelination

The heterodimeric cytokine IL-23 plays a non-redundant function in the development of cell-mediated, organspecific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). To further characterize the mechanisms of action of IL-23 in autoimmune inflammation, we administered IL-23 systemically at different time points during both relapsing and chronic EAE. Surprisingly, we found suppression of disease in all treatment protocols. We observed a reduction in the number of activated macrophages and microglia in the CNS, while T cell infiltration was not significantly affected. Disease suppression correlated with reduced expansion of myelin-reactive T cells, loss of T-bet expression, loss of lymphoid structures, and increased production of IL-6 and IL-4. Here we describe an unexpected function of exogenous IL-23 in limiting the scope and extent of organ-specific autoimmunity.

Turning solid aluminium transparent by intense soft X-ray photoionization

Saturable absorption is a phenomenon readily seen in the optical and infrared wavelengths. It has never been observed in core-electron transitions owing to the short lifetime of the excited states involved and the high intensities of the soft X-rays needed. We report saturable absorption of an L-shell transition in aluminium using record intensities over 10(16)W cm(-2) at a photon energy of 92 eV. From a consideration of the relevant timescales, we infer that immediately after the X-rays have passed, the sample is in an exotic state where all of the aluminium atoms have an L-shell hole, and the valence band has approximately a 9 eV temperature, whereas the atoms are still on their crystallographic positions. Subsequently, Auger decay heats the material to the warm dense matter regime, at around 25 eV temperatures. The method is an ideal candidate to study homogeneous warm dense matter, highly relevant to planetary science, astrophysics and inertial confinement fusion.

Cluster randomised controlled trial of an infection control education and training intervention programme focusing on meticillin-resistant Staphylococcus aureus in nursing homes for older people

The aim of this cluster randomised controlled trial was to test the impact of an infection control education and training programme on meticillin-resistant Staphylococcus aureus (MRSA) prevalence in nursing homes. Nursing homes were randomised to intervention (infection control education and training programme; N¼16) or control (usual practice continued; N¼16). Staff in intervention homes were educated and trained (0, 3 and 6 months) in the principles and implementation of good infection control practice with infection control audits conducted in all sites (0, 3, 6 and 12 months) to assess compliance with good practice. Audit scores were fed back to nursing home managers in intervention homes, together with a written report indicating where practice could be improved. Nasal swabs were taken from all consenting residents and staff at 0, 3, 6 and 12 months. The primary outcome was MRSA prevalence in residents and staff, and the secondary outcome was a change in infection control audit scores. In all, 793 residents and 338 staff were recruited at baseline. MRSA prevalence did not change during the study in residents or staff. The relative risk of a resident being colonised with MRSA in an intervention home compared with a control home at 12 months was 0.99 (95% con?dence interval: 0.69, 1.42) after adjustment for clustering. Mean infection control audit scores were signi?cantly higher in the intervention homes (82%) compared with the control homes (64%) at 12 months (P<0.0001). Consideration should be given to other approaches which may help to reduce MRSA in this setting.

The Effect of Antinotches on Domain Wall Mobility in Single Crystal Ferroelectric Nanowires

Changes in domain wall mobility, caused by the presence of antinotches in single crystal BaTiO3 nanowires, have been investigated. While antinotches appeared to cause a slight broadening in the distribution of switching events, observed as a function of applied electric field (inferred from capacitance-voltage measurements), the effect was often subtle. Greater clarity of information was obtained from Rayleigh analysis of the capacitance variation with ac field amplitude. Here the magnitude of the domain wall mobility parameter (R) associated with irreversible wall movements was found to be reduced by the presence of antinotches - an effect which became more noticeable on heating toward the Curie temperature. The reduction in this domain wall mobility was contrasted with the noticeable enhancement found previously in ferroelectric wires with notches. Finite element modeling of the electric field, developed in the nanowires during switching, revealed regions of increased and decreased local field at the center of the notch and antinotch structures, respectively; the absolute magnitude of field enhancement in the notch centers was considerably greater than the field reduction in the center of the antinotches and this was commensurate with the manner in, and degree to, which domain wall mobility appeared to be affected. We therefore conclude that the main mechanism by which morphology alters the irreversible component of the domain wall mobility in ferroelectric wire structures is via the manner in which morphological variations alter the spatial distribution of the electric field.

Development and Single-Laboratory Validation of a Pseudofunctional Biosensor Immunoassay for the Detection of the Okadaic Acid Group of Toxins

A rapid analytical optical biosensor-based immunoassay was developed and validated for the detection of okadaic acid (OA) and its structurally related toxins from shellfish matrix. The assay utilizes a monoclonal antibody which binds to the OA group of toxins in order of their toxicities, resulting in a pseudofunctional assay. Single-laboratory validation of the assay for quantitative detection of OA determined that it has an action limit of 120 mu g/kg, a limit of detection of 31 mu g/kg, and a working range of 31-174 mu g/kg. The midpoint on the standard matrix calibration curve is 80 mu g/kg, half the current regulatory limit. Inter- and intra-assay studies of negative mussel samples spiked with various OA concentrations produced average coefficient of variation (CV) and standard deviation (SD) values of 7.9 and 10.1, respectively. The assay was also validated to confirm the ability to accurately codetect and quantify dinophysistoxin-1 (DTX-1), DTX-2, and DTX-3 from shellfish matrix. Alkaline hydrolysis was not required for the detection of DTX-3 from matrix. Excellent correlations with the data generated by the biosensor method and liquid chromatography/tandem mass spectrometry (LC/MS/MS) were obtained using a certified reference material (R-2 = 0.99), laboratory reference material, and naturally contaminated mussel samples (R-2 = 0.97). This new procedure could be used as a rapid screening procedure replacing animal-based tests for DSP toxins.

Remote chiral induction in the organocatalytic hydrosilylation of aromatic ketones and ketimines

Lewis basic, metal-free pyridyloxazolines catalyze the redn. of prochiral arom. ketones and ketimines with Cl3SiH in good enantioselectivity (? 94% ee). Arene-arene interactions between the substrate and the catalyst are likely to play a role in the enantiodifferentiation process.

The role of human demographic history in determining the distribution and frequency of transferase-deficient galactosaemia mutations

Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype diversity, in conjunction with measures of genetic diversity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa. Heredity (2010) 104, 148-154; doi:10.1038/hdy.2009.84; published online 29 July 2009