Publications by authors named "Michael J Walter"

43 Publications

The HXD95: a modified Bassett-type hydrothermal diamond-anvil cell for in situ XRD experiments up to 5 GPa and 1300 K.

J Synchrotron Radiat 2020 Mar 29;27(Pt 2):529-537. Epub 2020 Jan 29.

Diamond Light Source Ltd, Harwell Science and Innovation Campus, Diamond House, Didcot OX11 0DE, UK.

A new diamond-anvil cell apparatus for in situ synchrotron X-ray diffraction measurements of liquids and glasses, at pressures from ambient to 5 GPa and temperatures from ambient to 1300 K, is reported. This portable setup enables in situ monitoring of the melting of complex compounds and the determination of the structure and properties of melts under moderately high pressure and high temperature conditions relevant to industrial processes and magmatic processes in the Earth's crust and shallow mantle. The device was constructed according to a modified Bassett-type hydrothermal diamond-anvil cell design with a large angular opening (θ = 95°). This paper reports the successful application of this device to record in situ synchrotron X-ray diffraction of liquid Ga and synthetic PbSiO glass to 1100 K and 3 GPa.
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http://dx.doi.org/10.1107/S1600577519016801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064104PMC
March 2020

Laser-heating system for high-pressure X-ray diffraction at the Extreme Conditions beamline I15 at Diamond Light Source.

J Synchrotron Radiat 2018 Nov 24;25(Pt 6):1860-1868. Epub 2018 Oct 24.

Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.

In this article, the specification and application of the new double-sided YAG laser-heating system built on beamline I15 at Diamond Light Source are presented. This system, combined with diamond anvil cell and X-ray diffraction techniques, allows in situ and ex situ characterization of material properties at extremes of pressure and temperature. In order to demonstrate the reliability and stability of this experimental setup over a wide range of pressure and temperature, a case study was performed and the phase diagram of lead was investigated up to 80 GPa and 3300 K. The obtained results agree with previously published experimental and theoretical data, underlining the quality and reliability of the installed setup.
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http://dx.doi.org/10.1107/S1600577518013383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225745PMC
November 2018

Magnesium isotope evidence that accretional vapour loss shapes planetary compositions.

Nature 2017 09;549(7673):511-515

School of Earth Sciences, University of Bristol, Wills Memorial Building, Queens Road, Bristol BS8 1RJ, UK.

It has long been recognized that Earth and other differentiated planetary bodies are chemically fractionated compared to primitive, chondritic meteorites and, by inference, the primordial disk from which they formed. However, it is not known whether the notable volatile depletions of planetary bodies are a consequence of accretion or inherited from prior nebular fractionation. The isotopic compositions of the main constituents of planetary bodies can contribute to this debate. Here we develop an analytical approach that corrects a major cause of measurement inaccuracy inherent in conventional methods, and show that all differentiated bodies have isotopically heavier magnesium compositions than chondritic meteorites. We argue that possible magnesium isotope fractionation during condensation of the solar nebula, core formation and silicate differentiation cannot explain these observations. However, isotopic fractionation between liquid and vapour, followed by vapour escape during accretionary growth of planetesimals, generates appropriate residual compositions. Our modelling implies that the isotopic compositions of magnesium, silicon and iron, and the relative abundances of the major elements of Earth and other planetary bodies, are a natural consequence of substantial (about 40 per cent by mass) vapour loss from growing planetesimals by this mechanism.
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http://dx.doi.org/10.1038/nature23899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624506PMC
September 2017

Slab melting as a barrier to deep carbon subduction.

Nature 2016 Jan;529(7584):76-9

School of Earth Sciences, University of Bristol, Bristol BS8 1RJ, UK.

Interactions between crustal and mantle reservoirs dominate the surface inventory of volatile elements over geological time, moderating atmospheric composition and maintaining a life-supporting planet. While volcanoes expel volatile components into surface reservoirs, subduction of oceanic crust is responsible for replenishment of mantle reservoirs. Many natural, 'superdeep' diamonds originating in the deep upper mantle and transition zone host mineral inclusions, indicating an affinity to subducted oceanic crust. Here we show that the majority of slab geotherms will intersect a deep depression along the melting curve of carbonated oceanic crust at depths of approximately 300 to 700 kilometres, creating a barrier to direct carbonate recycling into the deep mantle. Low-degree partial melts are alkaline carbonatites that are highly reactive with reduced ambient mantle, producing diamond. Many inclusions in superdeep diamonds are best explained by carbonate melt-peridotite reaction. A deep carbon barrier may dominate the recycling of carbon in the mantle and contribute to chemical and isotopic heterogeneity of the mantle reservoir.
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http://dx.doi.org/10.1038/nature16174DOI Listing
January 2016

Predictors of response to tiotropium versus salmeterol in asthmatic adults.

J Allergy Clin Immunol 2013 Nov 29;132(5):1068-1074.e1. Epub 2013 Sep 29.

Wake Forest School of Medicine, Winston-Salem, NC. Electronic address:

Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.

Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response.

Methods: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs).

Results: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not.

Conclusion: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.
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http://dx.doi.org/10.1016/j.jaci.2013.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826080PMC
November 2013

Earth science: Plumbing nickel from the core.

Authors:
Michael J Walter

Nature 2013 Jan 9;493(7432):309-10. Epub 2013 Jan 9.

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http://dx.doi.org/10.1038/nature11852DOI Listing
January 2013

Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial.

JAMA 2012 Sep;308(10):987-97

Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.

Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.

Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.

Design, Setting, And Participants: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.

Interventions: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.

Main Outcome Measure: The primary outcome was time to treatment failure.

Results: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).

Conclusion: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.

Trial Registration: clinicaltrials.gov Identifier: NCT00495157.
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http://dx.doi.org/10.1001/2012.jama.10893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697088PMC
September 2012

Sensory functions of motile cilia and implication for bronchiectasis.

Front Biosci (Schol Ed) 2012 Jan 1;4:1088-98. Epub 2012 Jan 1.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Cilia are specialized organelles that extend from the cell surface into the local environment. Cilia of the airway epithelia are motile to provide mucociliary clearance. On other cells, solitary cilia are specialized to detect chemical or mechanosensory signals. Sensory proteins in motile cilia have recently been identified that detect fluid flow, bitter taste and sex hormones. The relationship of these sensory functions in motile cilia to disease is now being revealed. An example are the polycystin-1 and polycystin-2 proteins that function as a flow sensor in kidney cilia and are mutated in autosomal dominant polycystic kidney disease (ADPKD). These polycystins are also expressed in motile cilia, potentially operating as sensors in the lung. Computed tomography studies from patients with ADPKD reveal evidence of bronchiectasis, suggesting polycystins are important in lung function. The motile cilia expression of this protein complex, as well as sensory channel TRPV4, bitter taste and sex hormones receptors, indicate that the cilia is wired to interpret environmental cues. Defective signaling of sensory proteins may result in a ciliopathy that includes lung disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841983PMC
http://dx.doi.org/10.2741/s320DOI Listing
January 2012

Tiotropium bromide step-up therapy for adults with uncontrolled asthma.

N Engl J Med 2010 Oct 19;363(18):1715-26. Epub 2010 Sep 19.

Wake Forest University Health Sciences, Center for Genomics and Personalized Medicine Research, Medical Center Blvd., Winston-Salem, NC 27157, USA.

Background: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed.

Methods: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison).

Results: The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003).

Conclusions: When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).
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http://dx.doi.org/10.1056/NEJMoa1008770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011177PMC
October 2010

A trial of clarithromycin for the treatment of suboptimally controlled asthma.

J Allergy Clin Immunol 2010 Oct;126(4):747-53

National Jewish Health, Denver, CO 80206, USA.

Background: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma.

Objective: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids.

Methods: Adults with an Asthma Control Questionnaire score ≥1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae.

Results: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 ± 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 ± 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 ± 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 ± 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC(20) by 1.2 ± 0.5 doubling doses (P = .02) in the study population.

Conclusion: Adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes.
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http://dx.doi.org/10.1016/j.jaci.2010.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950827PMC
October 2010

Detection of respiratory viruses and the associated chemokine responses in serious acute respiratory illness.

Thorax 2010 Jul;65(7):639-44

Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Background: A specific diagnosis of a lower respiratory viral infection is often difficult despite frequent clinical suspicion. This low diagnostic yield may be improved by use of sensitive detection methods and biomarkers.

Methods: The prevalence, clinical predictors and inflammatory mediator profile of respiratory viral infection in serious acute respiratory illness were investigated. Sequential bronchoalveolar lavage (BAL) fluids from all patients hospitalised with acute respiratory illness over 12 months (n=283) were tested for the presence of 17 respiratory viruses by multiplex PCR assay and for newly discovered respiratory viruses (bocavirus, WU and KI polyomaviruses) by single-target PCR. BAL samples also underwent conventional testing (direct immunoflorescence and viral culture) for respiratory virus at the clinician's discretion. 27 inflammatory mediators were measured in a subset of the patients (n=64) using a multiplex immunoassay.

Results: 39 respiratory viruses were detected in 37 (13.1% of total) patients by molecular testing, including rhinovirus (n=13), influenza virus (n=8), respiratory syncytial virus (n=6), human metapneumovirus (n=3), coronavirus NL63 (n=2), parainfluenza virus (n=2), adenovirus (n=1) and newly discovered viruses (n=4). Molecular methods were 3.8-fold more sensitive than conventional methods. Clinical characteristics alone were insufficient to separate patients with and without respiratory virus. The presence of respiratory virus was associated with increased levels of interferon gamma-inducible protein 10 (IP-10) (p<0.001) and eotaxin-1 (p=0.017) in BAL.

Conclusions: Respiratory viruses can be found in patients with serious acute respiratory illness by use of PCR assays more frequently than previously appreciated. IP-10 may be a useful biomarker for respiratory viral infection.
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http://dx.doi.org/10.1136/thx.2009.132480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018337PMC
July 2010

Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis.

Respir Res 2010 Jun 30;11:90. Epub 2010 Jun 30.

Division of Allergy, Immunology & Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St, Louis, MO; USA.

Background: Viral bronchiolitis is the leading cause of hospitalization in young infants. It is associated with the development of childhood asthma and contributes to morbidity and mortality in the elderly. Currently no therapies effectively attenuate inflammation during the acute viral infection, or prevent the risk of post-viral asthma. We hypothesized that early treatment of a paramyxoviral bronchiolitis with azithromycin would attenuate acute and chronic airway inflammation.

Methods: Mice were inoculated with parainfluenza type 1, Sendai Virus (SeV), and treated daily with PBS or azithromycin for 7 days post-inoculation. On day 8 and 21 we assessed airway inflammation in lung tissue, and quantified immune cells and inflammatory mediators in bronchoalveolar lavage (BAL).

Results: Compared to treatment with PBS, azithromycin significantly attenuated post-viral weight loss. During the peak of acute inflammation (day 8), azithromycin decreased total leukocyte accumulation in the lung tissue and BAL, with the largest fold-reduction in BAL neutrophils. This decreased inflammation was independent of changes in viral load. Azithromycin significantly attenuated the concentration of BAL inflammatory mediators and enhanced resolution of chronic airway inflammation evident by decreased BAL inflammatory mediators on day 21.

Conclusions: In this mouse model of paramyxoviral bronchiolitis, azithromycin attenuated acute and chronic airway inflammation. These findings demonstrate anti-inflammatory effects of azithromycin that are not related to anti-viral activity. Our findings support the rationale for future prospective randomized clinical trials that will evaluate the effects of macrolides on acute viral bronchiolitis and their long-term consequences.
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http://dx.doi.org/10.1186/1465-9921-11-90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906448PMC
June 2010

Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rbeta1 isoform that enhances DC migration.

J Exp Med 2010 Mar 8;207(3):591-605. Epub 2010 Mar 8.

Trudeau Institute, Inc., Saranac Lake, NY 12983, USA.

RNA splicing is an increasingly recognized regulator of immunity. Here, we demonstrate that after Mycobacterium tuberculosis infection (mRNA) il12rb1 is spliced by dendritic cells (DCs) to form an alternative (mRNA) il12rb1Deltatm that encodes the protein IL-12Rbeta1DeltaTM. Compared with IL-12Rbeta1, IL-12Rbeta1DeltaTM contains an altered C-terminal sequence and lacks a transmembrane domain. Expression of IL-12Rbeta1DeltaTM occurs in CD11c(+) cells in the lungs during M. tuberculosis infection. Selective reconstitution of il12rb1(-/-) DCs with (mRNA) il12rb1 and/or (mRNA) il12rb1Deltatm demonstrates that IL-12Rbeta1DeltaTM augments IL-12Rbeta1-dependent DC migration and activation of M. tuberculosis-specific T cells. It cannot mediate these activities independently of IL12Rbeta1. We hypothesize that M. tuberculosis-exposed DCs express IL-12Rbeta1DeltaTM to enhance IL-12Rbeta1-dependent migration and promote M. tuberculosis-specific T cell activation. IL-12Rbeta1DeltaTM thus represents a novel positive-regulator of IL12Rbeta1-dependent DC function and of the immune response to M. tuberculosis.
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http://dx.doi.org/10.1084/jem.20091085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839154PMC
March 2010

Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome.

J Heart Lung Transplant 2010 May 4;29(5):531-7. Epub 2010 Feb 4.

Department of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Background: Previous studies have suggested that azithromycin improves lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, these studies did not include a non-treated BOS control cohort or perform survival analysis. This study was undertaken to estimate the effect of azithromycin treatment on survival in lung transplant recipients with BOS.

Methods: We conducted a retrospective cohort study of consecutive lung transplant recipients who developed BOS between 1999 and 2007. An association between azithromycin treatment and death was assessed using univariate and multivariate time-dependent Cox regression analysis.

Results: Of the 178 recipients who developed BOS in our study, 78 did so after 2003 and were treated with azithromycin. The azithromycin-treated and untreated cohorts had similar baseline characteristics. Univariate analysis demonstrated that azithromycin treatment was associated with a survival advantage and this beneficial treatment effect was more pronounced when treatment was initiated during BOS Stage 1. Multivariate analysis demonstrated azithromycin treatment during BOS Stage 1 (adjusted hazard ratio = 0.23, p = 0.01) and absolute forced expiratory volume in 1 second (FEV(1)) at the time of BOS Stage 1 (adjusted hazard ratio = 0.52, p = 0.003) were both associated with a decreased risk of death.

Conclusions: In lung transplant recipients with BOS Stage 1, azithromycin treatment initiated before BOS Stage 2 was independently associated with a significant reduction in the risk of death. This finding supports the need for a randomized, controlled trial to confirm the impact of azithromycin on survival in lung transplant recipients.
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http://dx.doi.org/10.1016/j.healun.2009.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854291PMC
May 2010

Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.

Lancet 2009 Nov;374(9703):1754-64

Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid.

Methods: In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.

Findings: After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.

Interpretation: In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(09)61492-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914569PMC
November 2009

Entry of Burkholderia organisms into respiratory epithelium: CFTR, microfilament and microtubule dependence.

J Cyst Fibros 2010 Jan 14;9(1):36-43. Epub 2009 Nov 14.

Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Background: The pathogenesis of infection with Burkholderia cepacia complex (Bcc) organisms may be linked to its capacity to invade respiratory epithelium.

Methods: An antibiotic exclusion assay was used to study B. dolosa AU4459 and B. cenocepacia J2315 invasion into wild-type (WT) and CFTR-deficient respiratory epithelial cells. Inhibitors were used to evaluate Bcc invasion dependency on host microtubule (mt) and microfilament (mf) systems.

Results: B. dolosa entered WT-CFTR cells with 5-fold greater efficiency than CFTR deficient cells (25% vs 5%, respectively). Invasion dropped to <0.5% after either mf or mt inhibition. B. cenocepacia entered WT (0.05%) and CFTR-deficient cells (0.07%) with similarly low efficiencies, which significantly decreased with either mf or mt inhibition (0.008% and 0.002%, respectively).

Conclusion: B. dolosa and B. cenocepacia enter respiratory epithelial cells in a mf and mt dependent fashion. Mutated CFTR leads to less internalization of B. dolosa, but not B. cenocepacia.
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http://dx.doi.org/10.1016/j.jcf.2009.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818354PMC
January 2010

Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis.

Immunity 2009 Nov 22;31(5):799-810. Epub 2009 Oct 22.

Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.

The importance of T helper type 1 (Th1) cell immunity in host resistance to the intracellular bacterium Francisella tularensis is well established. However, the relative roles of interleukin (IL)-12-Th1 and IL-23-Th17 cell responses in immunity to F. tularensis have not been studied. The IL-23-Th17 cell pathway is critical for protective immunity against extracellular bacterial infections. In contrast, the IL-23-Th17 cell pathway is dispensable for protection against intracellular pathogens such as Mycobacteria. Here we show that the IL-23-Th17 pathway regulates the IL-12-Th1 cell pathway and was required for protective immunity against F.tularensis live vaccine strain. We show that IL-17A, but not IL-17F or IL-22, induced IL-12 production in dendritic cells and mediated Th1 responses. Furthermore, we show that IL-17A also induced IL-12 and interferon-gamma production in macrophages and mediated bacterial killing. Together, these findings illustrate a biological function for IL-17A in regulating IL-12-Th1 cell immunity and host responses to an intracellular pathogen.
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http://dx.doi.org/10.1016/j.immuni.2009.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789998PMC
November 2009

Impact of hydrogel nanoparticle size and functionalization on in vivo behavior for lung imaging and therapeutics.

Mol Pharm 2009 Nov-Dec;6(6):1891-902

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Polymer chemistry offers the possibility of synthesizing multifunctional nanoparticles which incorporate moieties that enhance diagnostic and therapeutic targeting of cargo delivery to the lung. However, since rules for predicting particle behavior following modification are not well-defined, it is essential that probes for tracking fate in vivo are also included. Accordingly, we designed polyacrylamide-based hydrogel particles of differing sizes, functionalized with a nona-arginine cell-penetrating peptide (Arg(9)), and labeled with imaging components to assess lung retention and cellular uptake after intratracheal administration. Radiolabeled microparticles (1-5 microm diameter) and nanoparticles (20-40 nm diameter) without and with Arg(9) showed diffuse airspace distribution by positron emission tomography imaging. Biodistribution studies revealed that particle clearance and extrapulmonary distribution was, in part, size dependent. Microparticles were rapidly cleared by mucociliary routes but, unexpectedly, also through the circulation. In contrast, nanoparticles had prolonged lung retention enhanced by Arg(9) and were significantly restricted to the lung. For all particle types, uptake was predominant in alveolar macrophages and, to a lesser extent, lung epithelial cells. In general, particles did not induce local inflammatory responses, with the exception of microparticles bearing Arg(9). Whereas microparticles may be advantageous for short-term applications, nanosized particles constitute an efficient high-retention and non-inflammatory vehicle for the delivery of diagnostic imaging agents and therapeutics to lung airspaces and alveolar macrophages that can be enhanced by Arg(9). Importantly, our results show that minor particle modifications may significantly impact in vivo behavior within the complex environments of the lung, underscoring the need for animal modeling.
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http://dx.doi.org/10.1021/mp900215pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804872PMC
February 2010

Interleukin 12 stimulates IFN-gamma-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance.

Cancer Res 2009 Nov 20;69(22):8700-9. Epub 2009 Oct 20.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor-dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN-gamma mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-gamma-independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN-gamma signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12-IFN-gamma axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783758PMC
November 2009

Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses.

Crit Care Med 2010 Jan;38(1):223-41

Departments of Surgery, Washington University School of Medicine, St. Louis, MO, USA.

Objective: Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, then treatment involves only nonspecific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar after disparate infections with similar mortalities.

Design: Prospective, randomized controlled study.

Setting: Animal laboratory in a university medical center.

Interventions: Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple time points.

Measurements And Main Results: The host response was dependent on the causative organism as well as kinetics of mortality, but the pro-inflammatory and anti-inflammatory responses were independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of five distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary macrophage inflammatory peptide-2 and interleukin-10 with progression of infection, whereas elevated plasma tumor necrosis factor sr2 and macrophage chemotactic peptide-1 were indicative of fulminant disease with >90% mortality within 48 hrs.

Conclusions: Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a potential therapeutic approach in the treatment of sepsis.
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http://dx.doi.org/10.1097/CCM.0b013e3181b4a76bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796712PMC
January 2010

[18F]fluorodeoxyglucose positron emission tomography for lung antiinflammatory response evaluation.

Am J Respir Crit Care Med 2009 Sep 2;180(6):533-9. Epub 2009 Jul 2.

Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Campus Box 8223, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA.

Rationale: Few noninvasive biomarkers for pulmonary inflammation are currently available that can assess the lung-specific response to antiinflammatory treatments. Positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) is a promising new method that can be used to quantify pulmonary neutrophilic inflammation.

Objectives: To evaluate the ability of FDG-PET to measure the pulmonary antiinflammatory effects of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and recombinant human activated protein C (rhAPC) in a human model of experimentally-induced lung inflammation.

Methods: Eighteen healthy volunteers were randomized to receive placebo, lovastatin, or rhAPC before intrabronchial segmental endotoxin challenge. FDG-PET imaging was performed before and after endotoxin instillation. The rate of [(18)F]FDG uptake was calculated as the influx constant K(i) by Patlak graphical analysis. Bronchoalveolar lavage (BAL) was performed to determine leukocyte concentrations for correlation with the PET imaging results.

Measurements And Main Results: There was a statistically significant decrease in K(i) in the lovastatin-treated group that was not seen in the placebo-treated group, suggesting attenuation of inflammation by lovastatin treatment despite a small decrease in BAL total leukocyte and neutrophil counts that was not statistically significant. No significant decrease in K(i) was observed in the rhAPC-treated group, correlating with a lack of change in BAL parameters and indicating no significant antiinflammatory effect with rhAPC.

Conclusions: FDG-PET imaging is a sensitive method for quantifying the lung-specific response to antiinflammatory therapies and may serve as an attractive platform for assessing the efficacy of novel antiinflammatory therapies at early phases in the drug development process. Clinical trial registered with www.clinicaltrials.gov (NCT00741013).
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http://dx.doi.org/10.1164/rccm.200904-0501OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742744PMC
September 2009

In vitro and murine efficacy and toxicity studies of nebulized SCC1, a methylated caffeine-silver(I) complex, for treatment of pulmonary infections.

Antimicrob Agents Chemother 2009 Aug 18;53(8):3285-93. Epub 2009 May 18.

Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1002, USA.

The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.
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http://dx.doi.org/10.1128/AAC.00314-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715611PMC
August 2009

Azithromycin attenuates airway inflammation in a noninfectious mouse model of allergic asthma.

Chest 2009 Aug 8;136(2):498-506. Epub 2009 May 8.

Department of Pediatrics, and the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO. Electronic address:

Background: Definitive conclusions regarding the antiinflammatory effects of macrolide antibiotics for treatment of asthma are difficult to formulate since their beneficial effects may be related to their antimicrobial action. We hypothesized that azithromycin possesses distinct antiinflammatory properties and tested this assumption in a noninfectious mouse model of allergic asthma.

Methods: To induce allergic airway inflammation, 7-week-old BALB/cJ mice underwent intraperitoneal ovalbumin sensitization on days 0 and 7 followed by an intranasal challenge on day 14. Mice were treated with azithromycin or phosphate-buffered saline (PBS) solution on days 13 through 16. On day 17, airway inflammation was assessed by quantifying leukocytes in the airway, expression of multiple inflammatory mediators in the BAL fluid, and mucous cell metaplasia. In a separate set of experiments, azithromycin or PBS solution treatment were initiated after the ovalbumin challenge. Each experiment was repeated 3 times (a total of 9 to 11 mice in each group).

Results: Compared to treatment with PBS solution, azithromycin attenuated the ovalbumin-dependent airway inflammation. We observed a decrease in total leukocytes in the lung tissue and BAL fluid. In addition, azithromycin attenuated the expression of cytokines (eg, interleukin [IL]-13 and IL-5) and chemokines (eg, CCL2, CCL3, and CCL4) in the BAL fluid and abrogated the extent of mucous cell metaplasia. Similar antiinflammatory effects were observed when azithromycin treatment was initiated after the ovalbumin challenge.

Conclusion: In this noninfectious mouse model of allergic asthma, azithromycin attenuated allergic airway inflammation. These findings demonstrate an antiinflammatory effect of azithromycin and suggest azithromycin may have beneficial effects in treating noninfectious airway inflammatory diseases, including asthma.
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http://dx.doi.org/10.1378/chest.08-3056DOI Listing
August 2009

IL-12 p80-dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection.

Immunology 2009 Apr 6;126(4):500-13. Epub 2008 Sep 6.

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

A protective immune response to a respiratory viral infection requires a series of coordinated cellular and molecular responses. We have previously demonstrated that increased expression of airway epithelial cell interleukin (IL)-12 p80, a macrophage chemoattractant, is associated with human respiratory viral infection and mediates post-viral mortality in the mouse. To better understand the role of IL-12 p80-dependent macrophage chemotaxis in mediating viral immunity, we generated a transgenic mouse strain utilizing a promoter to drive IL-12 p40 gene expression in the airway epithelium. This transgenic strain secreted biologically active IL-12 p80 in a lung-specific manner, and demonstrated a selective increase in the number of resident, unactivated airway macrophages at baseline. Following infection with a sublethal dose of mouse parainfluenza virus type 1 (Sendai virus), the transgenic mice demonstrated an earlier peak and decline in the number of airway inflammatory cells. The transgenic mice were resistant to a lethal dose of virus and this viral resistance was dependent on the increased number of airway macrophages at baseline as partial depletion prior to infection abrogated this phenotype. The survival advantage in the transgenic mice was independent of viral load but was associated with a more rapid decline in the number of airway inflammatory cells and concentrations of multiple chemokines including the CC chemokine ligand 2 (CCL2)/JE, CCL3/macrophage inflammatory protein (MIP)-1alpha, CCL4/MIP-1beta, and CCL5/RANTES. Collectively, these results suggest that IL-12 p80-driven increases in the number of resident airway macrophages prime the host for a protective immune response that can confer increased survival following a lethal respiratory viral infection.
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http://dx.doi.org/10.1111/j.1365-2567.2008.02923.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673362PMC
April 2009

Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells.

J Immunol 2008 Mar;180(5):2752-6

Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080,USA.

The cytokine IL-27 is important for restricting inflammation in response to a wide variety of immune challenges. In this study, we demonstrate that IL-27 induces expression of the anti-inflammatory cytokine IL-10 by CD4+ and CD8+ T cells. IL-27 relied upon the Th1 transcription factor STAT1 to induce IL-10+IFN-gamma+FoxP3- Th1 cells, which were recently shown to be key negative regulators during certain infections. Il27ra-/- mice generated fewer IL-10+ T cells during both Listeria monocytogenes infection and experimental autoimmune encephalomyelitis. The data presented here indicate a novel mechanism for the induction of IL-10 expression by T cells and provide a mechanistic basis for the suppressive effects of IL-27.
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http://dx.doi.org/10.4049/jimmunol.180.5.2752DOI Listing
March 2008

Role of PKCdelta in IFN-gamma-inducible CIITA gene expression.

Mol Immunol 2007 Apr 7;44(11):2841-9. Epub 2007 Mar 7.

Department of Microbiology and Immunology, The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCdelta plays an important role in regulating IFN-gamma-inducible CIITA gene expression in macrophages. Inhibition of PKCdelta by either a PKCdelta inhibitor or a dominant negative (DN) mutant form of PKCdelta led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCdelta inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-gamma induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCdelta did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCdelta is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-gamma in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-gamma inducible CIITA promoter, the effect of PKCdelta on CIITA expression is mediated primarily by serine phosphorylation of Stat 1.
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http://dx.doi.org/10.1016/j.molimm.2007.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1924468PMC
April 2007

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome.

Am J Respir Crit Care Med 2007 Mar 7;175(5):507-13. Epub 2006 Dec 7.

Division of Pulmonary and Critical Care, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8052, St. Louis, MO 63110, USA.

Rationale: Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality.

Objective: We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome.

Methods: We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models.

Main Results: Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis.

Conclusions: Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.
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http://dx.doi.org/10.1164/rccm.200608-1079OCDOI Listing
March 2007

Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells.

J Virol 2006 Aug;80(15):7469-80

Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Recent human infections caused by the highly pathogenic avian influenza virus H5N1 strains emphasize an urgent need for assessment of factors that allow viral transmission, replication, and intra-airway spread. Important determinants for virus infection are epithelial cell receptors identified as glycans terminated by an alpha2,3-linked sialic acid (SA) that preferentially bind avian strains and glycans terminated by an alpha2,6-linked SA that bind human strains. The mouse is often used as a model for study of influenza viruses, including recent avian strains; however, the selectivity for infection of specific respiratory cell populations is not well described, and any relationship between receptors in the mouse and human lungs is incompletely understood. Here, using in vitro human and mouse airway epithelial cell models and in vivo mouse infection, we found that the alpha2,3-linked SA receptor was expressed in ciliated airway and type II alveolar epithelial cells and was targeted for cell-specific infection in both species. The alpha2,6-linked SA receptor was not expressed in the mouse, a factor that may contribute to the inability of some human strains to efficiently infect the mouse lung. In human airway epithelial cells, alpha2,6-linked SA was expressed and functional in both ciliated and goblet cells, providing expanded cellular tropism. Differences in receptor and cell-specific expression in these species suggest that differentiated human airway epithelial cell cultures may be superior for evaluation of some human strains, while the mouse can provide a model for studying avian strains that preferentially bind only the alpha2,3-linked SA receptor.
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http://dx.doi.org/10.1128/JVI.02677-05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563738PMC
August 2006

Phase 1 safety and immunogenicity trial of malaria vaccine RTS,S/AS02A in adults in a hyperendemic region of western Kenya.

Am J Trop Med Hyg 2006 Jul;75(1):166-70

U.S. Army Medical Research Unit, Nairobi, Kenya.

We conducted a phase 1 trial of candidate malaria vaccine RTS,S/AS02A in western Kenya to determine its safety and immunogenicity in healthy adults in an area hyperendemic for malaria. Twenty adults were enrolled and received RTS,S/AS02A (50 microg of RTS,S in 0.5 mL of AS02A) by intramuscular injection on a 0-, 28-, and 178-day schedule. All 60 scheduled immunizations were given, and 18 of 20 volunteers completed the last study visit on day 210. The vaccine was safe and well-tolerated. There were no vaccine-related severe adverse events. The most common solicited adverse events associated with immunization were injection site pain and headache. The geometric mean concentration of antibodies to circumsporozoite protein was 1.9 microg/mL at baseline and it increased 2-4 weeks after each dose to 16, 17.8, and 36.6 microg/mL, respectively. These safety and immunogenicity data from adults in hyperendemic Kenya are comparable to data reported earlier from two trials in west African adults in hypo-endemic and meso-endemic areas of The Gambia. We conclude that in this small study, RTS,S/AS02A is safe and similarly immunogenic in malaria-exposed African adults of different ethnicity in different transmission settings.
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July 2006

Accretion of the Earth and segregation of its core.

Nature 2006 Jun;441(7095):825-33

Macquarie University, Department of Earth and Planetary Sciences, North Ryde, New South Wales 2109, Australia.

The Earth took 30-40 million years to accrete from smaller 'planetesimals'. Many of these planetesimals had metallic iron cores and during growth of the Earth this metal re-equilibrated with the Earth's silicate mantle, extracting siderophile ('iron-loving') elements into the Earth's iron-rich core. The current composition of the mantle indicates that much of the re-equilibration took place in a deep (> 400 km) molten silicate layer, or 'magma ocean', and that conditions became more oxidizing with time as the Earth grew. The high-pressure nature of the core-forming process led to the Earth's core being richer in low-atomic-number elements, notably silicon and possibly oxygen, than the cores of the smaller planetesimal building blocks.
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http://dx.doi.org/10.1038/nature04763DOI Listing
June 2006