Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration

© Schilter et al. Background and purpose: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Methods: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Results: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. Conclusions and implications: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation

Avaliação do Desempenho de Três Câmaras de Expansão

INTRODUCTION: Several aspects are known to influence the drug distribution within the low respiratory tract, with particular emphasis on those related to the inhalation device. The aim of this work was to assess the performance of three spacers in the drug release, and also the quantity of active agent deposited inside these devices. MATERIALS AND METHODS: In order to evaluate the behaviour of particles in suspension delivered through the Ventilan®HFA inhaler coupled to three different spacers (Volumatic®, AeroChamber MAX® and NebuChamber®) the Multistage Liquid Impinger (MSLI) was used, according to the Portuguese Pharmacopoeia. The mass of salbutamol sulphate deposited on the different impinger compartments and inside the spacer was determined by spectrophotometry, with the purpose of determining the percentage of cumulative mass for each spacer, and then the fine particle fraction. The results were compared statistically using a one-way analysis of variance (one-way ANOVA) with a Bonferroni post-hoc test. RESULTS: About 40 to 50% of salbutamol sulphate was found deposited in the body of the three spacers. This deposition was slightly lower for NebuChamber® (average ± standard deviation of 43.8 % ± 11.6 %), in relation to Volumatic® (p=0.351) or AeroChamber MAX® (p=0.115). The fine particle fraction reached values of 28.2 ± 4.1%, 29.6 ± 2.4% and 30.9 ± 6.7% for Volumatic®, AeroChamber MAX® and NebuChamber®, respectively. CONCLUSION: The spacers showed to have similar efficiencies in the delivery of salbutamol sulphate in the last stages, and there was no relation between the results and the spacers characteristics such as volume, shape and material. Therefore, Volumatic® appears to be perfect for hospital use, since its big volume does not constitute a disadvantage, and its lower cost, when compared to the remaining two spacers, represents an advantage of utmost importance for public hospitals

Evaluation of the performance of three spacer

Introduction: Several aspects are known to influence the drug distribution within the low respiratory tract, with particular emphasis on those related to the inhalation device. The aim of this work was to assess the performance of three spacers in the drug release, and also the quantity of active agent deposited inside these devices. Materials and Methods: In order to evaluate the behaviour of particles in suspension delivered through the Ventilan®HFA inhaler coupled to three different spacers (Volumatic®, AeroChamber MAX® and NebuChamber®) the Multistage Liquid Impinger (MSLI) was used, according to the Portuguese Pharmacopoeia. The mass of salbutamol sulphate deposited on the different impinger compartments and inside the spacer was determined by spectrophotometry, with the purpose of determining the percentage of cumulative mass for each spacer, and then the fine particle fraction. The results were compared statistically using a one-way analysis of variance (one-way ANOVA) with a Bonferroni post-hoc test. Results: About 40 to 50% of salbutamol sulphate was found deposited in the body of the three spacers. This deposition was slightly lower for NebuChamber® (average ± standard deviation of 43.8 % ± 11.6 %), in relation to Volumatic® (p=0.351) or AeroChamber MAX® (p=0.115). The fine particle fraction reached values of 28.2 ± 4.1%, 29.6 ± 2.4% and 30.9 ± 6.7% for Volumatic®, AeroChamber MAX® and NebuChamber®, respectively. Conclusion: The spacers showed to have similar efficiencies in the delivery of salbutamol sulphate in the last stages, and there was no relation between the results and the spacers characteristics such as volume, shape and material. Therefore, Volumatic® appears to be perfect for hospital use, since its big volume does not constitute a disadvantage, and its lower cost, when compared to the remaining two spacers, represents an advantage of utmost importance for public hospitals

Comparative analysis of module-based versus direct methods for reverse-engineering transcriptional regulatory networks

We have compared a recently developed module-based algorithm LeMoNe for reverse-engineering transcriptional regulatory networks to a mutual information based direct algorithm CLR, using benchmark expression data and databases of known transcriptional regulatory interactions for Escherichia coli and Saccharomyces cerevisiae. A global comparison using recall versus precision curves hides the topologically distinct nature of the inferred networks and is not informative about the specific subtasks for which each method is most suited. Analysis of the degree distributions and a regulator specific comparison show that CLR is 'regulator-centric', making true predictions for a higher number of regulators, while LeMoNe is 'target-centric', recovering a higher number of known targets for fewer regulators, with limited overlap in the predicted interactions between both methods. Detailed biological examples in E. coli and S. cerevisiae are used to illustrate these differences and to prove that each method is able to infer parts of the network where the other fails. Biological validation of the inferred networks cautions against over-interpreting recall and precision values computed using incomplete reference networks.Comment: 13 pages, 1 table, 6 figures + 6 pages supplementary information (1 table, 5 figures

Human Angiostrongyliasis Outbreak in Dali, China

Angiostrongyliasis, caused by the rat lungworm Angiostrongylus cantonensis, is a potentially fatal food-borne disease. It is endemic in parts of Southeast Asia, the Pacific Islands, Australia, and the Caribbean. Outbreaks have become increasingly common in China due to the spread of efficient intermediate host snails, most notably Pomacea canaliculata. However, infections are difficult to detect since the disease has a rather long incubation period and few diagnostic clinical symptoms. Reliable diagnostic tests are not widely available. The described angiostrongyliasis epidemic in Dali, China lasted for eight months. Only 11 of a total of 33 suspected patients were clinically confirmed based on a set of diagnostic criteria. Our results demonstrate that the rapid and correct diagnosis of the index patient is crucial to adequately respond to an epidemic, and a set of standardized diagnostic procedures is needed to guide clinicians. Integrated control and management measures including health education, clinical guidelines and a hospital-based surveillance system, should be implemented in areas where snails are a popular food item

A randomized controlled trial to evaluate self-determination theory for exercise adherence and weight control: rationale and intervention description

<p>Abstract</p> <p>Background</p> <p>Research on the motivational model proposed by Self-Determination Theory (SDT) provides theoretically sound insights into reasons why people adopt and maintain exercise and other health behaviors, and allows for a meaningful analysis of the motivational processes involved in behavioral self-regulation. Although obesity is notoriously difficult to reverse and its recidivism is high, adopting and maintaining a physically active lifestyle is arguably the most effective strategy to counteract it in the long-term. The purposes of this study are twofold: i) to describe a 3-year randomized controlled trial (RCT) aimed at testing a novel obesity treatment program based on SDT, and ii) to present the rationale behind SDT's utility in facilitating and explaining health behavior change, especially physical activity/exercise, during obesity treatment.</p> <p>Methods</p> <p>Study design, recruitment, inclusion criteria, measurements, and a detailed description of the intervention (general format, goals for the participants, intervention curriculum, and main SDT strategies) are presented. The intervention consists of a 1-year group behavioral program for overweight and moderately obese women, aged 25 to 50 (and pre-menopausal), recruited from the community at large through media advertisement. Participants in the intervention group meet weekly or bi-weekly with a multidisciplinary intervention team (30 2 h sessions in total), and go through a program covering most topics considered critical for successful weight control. These topics and especially their delivery were adapted to comply with SDT and Motivational Interviewing guidelines. Comparison group receive a general health education curriculum. After the program, all subjects are follow-up for a period of 2 years.</p> <p>Discussion</p> <p>Results from this RCT will contribute to a better understanding of how motivational characteristics, particularly those related to physical activity/exercise behavioral self-regulation, influence treatment success, while exploring the utility of Self-Determination Theory for promoting health behavior change in the context of obesity.</p> <p>Trial Registration</p> <p><b>Clinical Trials Gov. Identifier </b>NCT00513084</p

Cell-intrinsic differences between human airway epithelial cells from children and adults

Summary The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium were similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony-formation ability, sustained in vitro growth and out-competed adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states