Experimental studies of lipid mediator modulation of airway responsiveness

Lipid mediators play an important role in responsiveness of the airways. The roles of prostanoids and leukotrienes in inducing airway inflammation and contraction are reasonably well established. The functions of specialised pro-resolving lipid mediators (SPMs), which are thought to mediate pro-resolving and anti-inflammatory effects, are less well-studied. The current knowledge on SPM functions, specifically in airway inflammation and contractility is limited. Furthermore, mast cells are important innate immune effectors cells found in the lung, known to release a host of pro-inflammatory and contractile cytokines and lipids in allergic airway inflammation and airway hyperreactivity. However, if the presence of mast cells in airways is necessary for antigen-induced airway contractions and induction of airway hyperreactivity remains to be clarified. In addition, though it is known that unselective cyclo-oxygenase (COX)-inhibition results in increased contractions in airways upon mast cell activation by antigen, the exact mechanism behind this is unknown. The aim of this thesis was thus to investigate if selected SPMs have anti-hyperreactive properties, how COX-inhibition results in increased airway constriction and if mast cells are necessary for antigen-induced contraction and airway hyperreactivity. To this end, mouse and guinea pig models of airway hyperreactivity and allergic inflammation were used. Tracheae were dissected free from surrounding tissue and divided in segments of equal size. The isometric contractions of these isolated tracheal preparations were studied in myographs, either immediately after dissection from mice that received intranasal administration of HDM and SPMs beforehand, or after four days of incubation of the segments with cytokines and SPMs. Alongside this, concentrations of released mast cell mediators were determined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). First, it was found that four-day intranasal administration of the SPMs lipoxin A4 (LXA4) and resolvin D1 (RvD1) could reduce house dust mite (HDM)-induced airway hyperreactivity. The reducing effect of LXA4 was replicated when added during four days of incubation of tracheal segments with HDM and TNFα and was also present for lipoxin B4 (LXB4). A potential involvement of the ALX/FPR2 receptor was found, though this should be further backed up by future investigations. Second, IL-13 induced a steroid-resistant airway hyperreactivity in vitro that could be reduced by cysteinyl maresins. This effect could be blocked by three different cysteinyl leukotriene (CysLT) receptor 1 antagonists. However, LTD4 could not reproduce the anti-hyperreactive effect nor did it interfere with cysteinyl maresin signalling. The exact receptor signalling remains to be clarified. Third, prostaglandin D2 (PGD2) was found to be produced by the COX-1 enzyme in mast cells present in tracheal segments from ovalbumin (OVA)-sensitised guinea pigs, when exposed to OVA in vitro. Further release of contractile mediators like histamine and cysteinyl leukotrienes from mast cells was inhibited by PGD2. This was done via the DP1 receptor, therefore PGD2 and the DP1 receptor likely function as an inhibitory, autocrine signalling axis for mast cells. Fourth, the presence of mast cells in lung tissue was necessary for HDM-induced airway contractions and mast cell absence led to reduced airway hyperresponsiveness in mouse models. Repeated HDM-exposure via intranasal instillation led to airway hyperreactivity mediated by carbachol and serotonin (5-HT) in isolated tracheal segments. The data suggest that mast cell activation occurred as an interplay between nerve-endings and mast cells, as mouse mast cells expressed the M3-receptor and activation led to release of 5-HT. To conclude, lipid mediators and mast cells play an essential role in the modulation of airway responsiveness. They do this by either inducing contractions after antigen-exposure (mast cells), reducing cytokine and antigen-induced airway hyperreactivity (SPMs) or inhibiting release of pro-contractile mediators and ultimately airway contractions (PGD2). This makes SPMs and their receptors, as wells as mast cells promising future drugs or drug targets for the treatment of airway hyperreactivity as seen in for example asthma

Bitter Biopharmaceuticals: Biologic Counterfeiting and Supply Chain Concerns

Pharmaceutical counterfeiting is a growing area of public safety and national security concern. Biological medications are a growing portion of counterfeit medicines due to the high cost and opportunities for profit from these innovative drugs. Biologics are a unique target for counterfeiters in international commerce presentingunique hazards over traditional, more stable, pills. This Article explores the international biopharmaceutical supply chain and the regulatory weaknesses that compromise public health

Searching for New Relations among the Eilenberg-Zilber maps

The goal of this project was to write a computer program that would aid in the search for relations among the Eilenberg-Zilber maps, which relate to simplicial objects in algebraic topology. This presentation outlines the process of writing this program, the challenges faced along the way, and the final results of the project

Proving Dirichlet\u27s Theorem on Arithmetic Progressions

First proved by German mathematician Dirichlet in 1837, this important theorem states that for coprime integers a, m, there are an infinite number of primes p such that p = a (mod m). This is one of many extensions of Euclid’s theorem that there are infinitely many prime numbers. In this paper, we will formulate a rather elegant proof of Dirichlet’s theorem using ideas from complex analysis and group theory

Working and Learning with Electronic Performance Support Systems: An Effectiveness Study

In this study the effectiveness of electronic performance support systems (EPSS) is reported. Some of the expected advantages of EPSS, such as an increase in productivity and improved learning are evaluated with insurance agents using laptop computers. Theoretical statements, research design and hypotheses are presented. The conclusion is that EPSS was cheaper than classroom training and had some benefits for learners, but did not produce the expected benefit of an increase in productivity

Treatment of necrotizing fasciitis using negative pressure wound therapy in a puppy

A two-month-old German shepherd dog was presented with anorexia, lethargy and left hind limb lameness associated with swelling of the thigh. Clinical findings combined with cytology led to the presumptive diagnosis of necrotizing fasciitis (NF). Extensive debridement was performed and silver-foam-based negative pressure wound therapy (NPWT) was applied. During the first 48 hours, a negative pressure of -75 mmHg was used. Evaluation of the wound demonstrated no progression of necrosis and a moderate amount of granulation tissue formation. A new dress- ing was placed and a second 48-hour cycle of NPWT was initiated at -125 mmHg. At removal, a healthy wound bed was observed and surgical closure was performed. The prompt implementation of NPWT following surgical debridement led to accelerated wound healing without progression of necrosis in this case of canine NF. Negative pressure wound therapy could become an integral part of the management strategy of canine NF, improving the prognosis of this life-threatening disease

Sexual activity and contraceptive practices among teenagers in the United States, 1988 and 1995

Shipping list no.: 2001-0214-P."April 2001.""[Authors] Joyce C. Abma, Division of Vital Statistics, National Center for Health Statistics, and and Freya L. Sonenstein, Ph.D., Population Studies Center, The Urban Institute." - p. 1Also available via the World Wide Web.Includes bibliographical references (p. 25-27)

Participatory Health Research With Mothers Living in Poverty in the Netherlands: Pathways and Challenges to Strengthen Empowerment

Empowerment von Menschen, die unter prekären Bedingungen leben, ist eine zentrale Prämisse partizipativer Gesundheitsforschung (PGF). Empowerment, die Selbstermächtigung einer Person innerhalb ihrer sozialen Umgebung, hat eine persönliche, eine relationale und eine politische Komponente. Die hier berichtete Studie wurde mit Müttern durchgeführt, die unter prekären Bedingungen in den Niederlanden leben. Wir beschreiben in diesem Beitrag, wie Empowerment im Projekt gefördert werden konnte 1. im Rahmen der Agenda (Eigentumsrechte) und 2. durch die Anerkennung sowohl der Selbstartikulation als auch der geteilten Darstellung der Teilnehmerinnen über ihre eigenen Belange (epistemische Gerechtigkeit). Ein Ergebnis unsere Studie ist, dass insbesondere die Bemühung um relationales und politisches Empowerment sehr herausfordernd sein können: Relationale Spannungen in der Gruppe beeinträchtigten unsere Arbeit, und die Reflexion struktureller Ursachen für die missliche Lage der Mütter benötigte Zeit und relationale Sensitivität. Hier konzentrierten wir uns als Forschende insbesondere auf ethische Fragen und versuchten, mit kreativen Außenstehenden zusammenzuarbeiten, um der Disharmonie in der Gruppe entgegenzuwirken. Relationales und politisches Empowerment ist im Rahmen von PGF ein langfristiges Unterfangen und birgt einige Stolpersteine im Forschungsprozess.Empowerment of people in challenging circumstances is a central premise of participatory health research (PHR). Empowerment, a process of strengthening vis-à-vis one's social environment, has three components: personal, relational, and political. The current PHR study was conducted with mothers living in unfortunate situations in the Netherlands. In this article, we describe how PHR fostered personal empowerment to a certain degree by 1. setting an agenda for the project (ownership), and 2. listening to and acknowledging the articulation of the participants' own story and a collective story about their issues (epistemic justice). One result of the study is that achieving relational and political empowerment can be challenging. Relational tensions in the group distracted us. Conducting critical reflection on more structural causes of the unfortunate situations of the mothers is a process that needs time and calls for relational sensitivity and inclusion. The participatory researcher as facilitator focused on ethics and tried to collaborate with creative outsiders to change the disharmony in the group. Reaching relational and political empowerment is a long-term process in PHR, but not without stumbling blocks on the journey

Job quality, health and at-work productivity

Many countries invest considerable resources into promoting employment and the creation of jobs. At the same time, policies and institutions still pay relatively little attention to the quality of jobs although job quality has been found to be a major driver of employee well being and may be an important factor for work productivity. Eventually, job quality might also influence labour supply choices and lead to higher employment. Providing robust evidence for the relationship between job quality and worker productivity could make a strong case for labour market policies directed at the improvement of job quality.This paper reviews existing evidence on the relationship between the quality of the work environment and individual at-work productivity, defined as reduced productivity while at work,and assesses the effect of health on this relationship. After screening 2319 studies from various fields and disciplines, including economics and medicine, 48studies are reviewed. Strong evidence is found for a negative relationship between job stress or job strain and individual at-work productivity and for a positive relationship between job rewards and productivity. Moderate evidence is found for a negative relationship between work-family conflict and at-work productivity and for a positive relationship between fairness at work and social support from co-workers and productivity. Health influences the relationship between the quality of the work environment and productivity.Specifically, the relationship is stronger for people in good health. Job quality needs a more prominent place in labour market policy. More attention needs to be paid to workers’ perceptions of the quality of their work environment and how policies and practices at both the level of the worker and the work environment may influence this.Furthermore, as health-related factors significantly influence the relationship between job quality and productivity, multidisciplinary approaches are needed to support at-work productivity