Search

Aims To determine the effect of azithromycin in patients with non-cystic fibrosis bronchiectasis. Methods In a randomized, double-blind trial, we randomly assigned 141 patients with bronchiectasis to receive azithromycin (500 mg three times a week) or placebo for 6 months. Patients were followed for an additional 6 months. Results The annual rate of event-based exacerbations for the 6-month treatment period was 0.59 in the azithromycin group and 1.57 in the placebo group, corresponding to a 62% reduction in the rate of exacerbations with azithromycin (rate ratio, 0.38: P < 0.001). For the 12-month period, the annual rate of exacerbations was 1.58 in the azithromycin group and 2.73 in the placebo group (rate ratio, 0.58: P < 0.001). Azithromycin, as compared with placebo, also increased the time to the first event-based exacerbation in the first 6 months (104 days vs 21 days; hazard ratio, 0.34; P < 0.001) and the time to the first exacerbation in 12 months (239 days vs 85 days; hazard ratio, 0.44: P < 0.001). The CRP level was lower in the azithromycin group at 6 months (P < 0.01). Symptom-based exacerbation frequency, change in FEV1, SGRQ, 6-minute walk distance, and sputum neutrophils were not significantly different between the azithromycin and placebo groups. Gastrointestinal adverse effects were more common in the azithromycin group (P < 0.01). Conclusions Azithromycin decreased the frequency of event-based exacerbations and increased the time to first exacerbation in patients with non-cystic fibrosis bronchiectasis. A treatment effect on exacerbations was present 6 months after completion of treatment.

Background Azithromycin is a macrolide antibiotic with anti-infl ammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fi brosis bronchiectasis. Methods We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defi ned by highresolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratifi ed by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of eventbased exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV1) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. Findings 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 059 per patient in the azithromycin group and 157 per patient in the placebo group in the 6-month treatment period (rate ratio 038, 95% CI 026-054; p<00001). Prebronchodilator FEV1 did not change from baseline in the azithromycin group and decreased by 004 L in the placebo group, but the diff erence was not signifi cant (004 L, 95% CI -003 to 012; p=0251). Additionally, change in SGRQ total score did not diff er between the azithromycin (-517 units) and placebo groups (-192 units; diff erence -325, 95% CI

Coronaviruses have the potential to cause severe transmissible human disease, as demonstrated by the severe acute respiratory syndrome (SARS) outbreak of 2003. We describe here the clinical and virological features of a novel coronavirus infection causing severe respiratory illness in a patient transferred to London, United Kingdom, from the Gulf region of the Middle East.

Background: Mesenchymal stem cells (MSC) have great potential in regenerative medicine, immunotherapy and gene therapy due to their unique properties of self-renewal, high plasticity, immune modulation and ease for genetic modification. However, production of MSC at sufficient clinical scale remains an issue as in vitro generation of MSC inadequately fulfils the demand with respect to patients. Objectives: This study has aimed to establish optimum conditions to generate and characterize MSC from human umbilical cord (UC-MSC). Materials and methods: To optimize MSC population growth, basic fibroblast growth factor (bFGF) was utilized in culture media. Effects of bFGF on expansion kinetics, cell cycle, survival of UC-MSC, cytokine secretion, expression of early stem-cell markers and immunomodulation were investigated. Results: bFGF supplementation profoundly enhanced UC-MSC proliferation by reducing population doubling time without altering immunophenotype and immunomodulatory function of UC-MSC. However, cell cycle studies revealed that bFGF drove the cells into the cell cycle, as a higher proportion of cells resided in S phase and progressed into M phase. Consistent with this, bFGF was shown to promote expression of cyclin D proteins and their relevant kinases to drive UC-MSC to transverse cell cycle check points, thus, committing the cells to DNA synthesis. Furthermore, supplementation with bFGF changed the cytokine profiles of the cells and reduced their apoptotic level. Conclusion: Our study showed that bFGF supplementation of UC-MSC culture enhanced the cells' growth kinetics without compromising their nature.

Contains fulltext : 88453.pdf (publisher's version ) (Open Access), Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients.

This research identifies the information/data required to perform a safety assessment for large-scale systems integration. From these required safety-related information/data, and the utilization of system engineering processes and practices, a safety assessment architecture is developed. As a result, the risk of known hazards is mitigated to as low as reasonably practical (ALARP) and the system health of these large-scale system integrations is improved throughout the system's life cycle. The thesis first identifies the current gap in system safety assessment for large-scale system integrations, especially in the area of Commercial of the Shelf (COTS) and Non-Developmental Item (NDI) systems integration. Next, with reference to the DoD system life cycle process, a COTS/NDI system integration life cycle process model is proposed. In addition, in line with the DoD policy to have a joint weapon system safety review board, a system safety functional hierarchy is then created. Using the functional hierarchy created, more detailed sub-functions and measures of effectiveness for system safety assessment are then analyzed. Finally, a hazard list table is proposed as a tool to be used in relation to the system safety assessment functional hierarchy so as to achieve the objective to identify, mitigate, trace and accept all residual risks associated with the large-scale system integration throughout its life cycle. A case example of the Harpoon Weapon System (HWS) safety assessment on a ship platform is used to further explain the usage and process of generating, maintaining and tracking the hazard list table., The original document contains color images.

Delft Center for Systems and Control, Mechanical, Maritime and Materials Engineering

Although aliphatic amines have been detected in both urban and rural atmospheric aerosols, little is known about the chemistry leading to particle formation or the potential aerosol yields from reactions of gas-phase amines. We present here the first systematic study of aerosol formation from the atmospheric reactions of amines. Based on laboratory chamber experiments and theoretical calculations, we evaluate aerosol formation from reaction of OH, ozone, and nitric acid with trimethylamine, methylamine, triethylamine, diethylamine, ethylamine, and ethanolamine. Entropies of formation for alkylammonium nitrate salts are estimated by molecular dynamics calculations enabling us to estimate equilibrium constants for the reactions of amines with nitric acid. Though subject to significant uncertainty, the calculated dissociation equilibrium constant for diethylammonium nitrate is found to be sufficiently small to allow for its atmospheric formation, even in the presence of ammonia which competes for available nitric acid. Experimental chamber studies indicate that the dissociation equilibrium constant for triethylammonium nitrate is of the same order of magnitude as that for ammonium nitrate. All amines studied form aerosol when photooxidized in the presence of NOx with the majority of the aerosol mass present at the peak of aerosol growth consisting of aminium (R3NH+) nitrate salts, which repartition back to the gas phase as the parent amine is consumed. Only the two tertiary amines studied, trimethylamine and triethylamine, are found to form significant non-salt organic aerosol when oxidized by OH or ozone; calculated organic mass yields for the experiments conducted are similar for ozonolysis (15% and 5% respectively) and photooxidation (23% and 8% respectively). The non-salt organic aerosol formed appears to be more stable than the nitrate salts and does not quickly repartition back to the gas phase.

In atmospheric aerosols, water and volatile inorganic and organic species are distributed between the gas and aerosol phases in accordance with thermodynamic equilibrium. Within an atmospheric particle, liquid and solid phases can exist at equilibrium. Models exist for computation of phase equilibria for inorganic/water mixtures typical of atmospheric aerosols; when organic species are present, the phase equilibrium problem is complicated by organic/water interactions as well as the potentially large number of organic species. We present here an extension of the UHAERO inorganic thermodynamic model (Amundson et al., 2006c) to organic/water systems. Phase diagrams for a number of model organic/water systems characteristic of both primary and secondary organic aerosols are computed. Also calculated are inorganic/organic/water phase diagrams that show the effect of organics on inorganic deliquescence behavior. The effect of the choice of activity coefficient model for organics on the computed phase equilibria is explored.