Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The role of anti-malarial drugs in eliminating malaria

Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and transmissibility coincides with peak asexual parasite densities. Mature Plasmodium falciparum gametocytes are more drug resistant and affected only by artemisinins and 8-aminoquinolines. The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection. Radical treatment with primaquine plays a key role in the eradication of vivax and ovale malaria. More evidence is needed on the safety of primaquine when administered without screening for G6PD deficiency to inform individual and mass treatment approaches in the context of malaria elimination programmes

Mechanisms of toxic smoke inhalation and burn injury: Role of neutral endopeptidase and vascular leakage in mice

The effects of neutral endopeptidase (NEP) in acute inflammation in the lung were studied using a newly developed murine model of smoke and burn (SB) injury. C57BL/6 mice were pretreated with an i.v. dose of a specific NEP antagonist CGS-24592 (10 mg/Kg) 1 h prior to SB injury (n = 5–8/group). Mice were anesthetized with i.p. ketamine/xylazine, intubated, and exposed to cooled cotton smoke (2 × 30 s). After s.c. injection of 1 ml 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphene (2 mg/kg) was given i.p. and resuscitated by saline. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were analyzed for their levels of EB dye and myeloperoxidase (MPO). In mice pretreated with CGS-24592 followed by SB injury the EB levels were significantly higher (61%, p = 0.043) than those with SB injury alone. There was a significant increase (144%, p = 0.035) in EB dye in animals with SB injury alone as compared to shams. In mice pretreated with CGS-24592 prior to SB injury wet/dry weight ratios were significantly (27%, p = 0.042) higher compared to animals with SB injury alone. CGS-24592 pretreatment also caused a significant increase in MPO (29%, p = 0.026) as compared to mice with SB injury alone. In conclusion the current study indicates that specific NEP inhibitor CGS 24592 exacerbates the SB-induced lung injury and inflammation in mice

Phenotypic and Functional Characterization of Human Memory T Cell Responses to Burkholderia pseudomallei

The Gram-negative bacterium, Burkholderia pseudomallei, is a public health problem in southeast Asia and northern Australia and a Centers for Disease Control and Prevention listed Category B potential bioterrorism agent. It is the causative agent of melioidosis, and clinical manifestations vary from acute sepsis to chronic localized and latent infection, which can reactivate decades later. B. pseudomallei is the major cause of community-acquired pneumonia and septicemia in northeast Thailand. In spite of the medical importance of B. pseudomallei, little is known about the mechanisms of pathogenicity and the immunological pathways of host defense. There is no available vaccine, and the mortality rate in acute cases can exceed 40% with 10–15% of survivors relapsing or being reinfected despite prolonged and complete treatments. In this article, we describe cell-mediated immune responses to B. pseudomallei in humans living in northeast Thailand and demonstrate clear evidence of T cell priming in healthy seropositive individuals and patients who recovered from melioidosis. This is the most detailed study yet performed on the cell types that produce interferon-gamma to B. pseudomallei in humans and the antigens that they recognize and the first to study large sample numbers in the primary endemic focus of melioidosis in the world

Reduced Risk of Malaria Parasitemia Following Household Screening and Treatment: A Cross-Sectional and Longitudinal Cohort Study

BACKGROUND: In regions of declining malaria transmission, new strategies for control are needed to reduce transmission and achieve elimination. Artemisinin-combination therapy (ACT) is active against immature gametocytes and can reduce the risk of transmission. We sought to determine whether household screening and treatment of infected individuals provides protection against infection for household members. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted in two areas in Southern Province, Zambia in 2007 and 2008/2009. To determine the impact of proactive case detection, households were randomly selected either to join a longitudinal cohort, in which participants were repeatedly screened throughout the year and those infected treated with artemether-lumefantrine, or a cross-sectional survey, in which participants were visited only once. Cross-sectional surveys were conducted throughout the year. The prevalence of RDT positivity was compared between the longitudinal and cross-sectional households at baseline and during follow-up using multilevel logistic regression. In the 2007 study area, 174 and 156 participants enrolled in the cross-sectional and longitudinal groups, respectively. In the 2008/2009 study area, 917 and 234 participants enrolled in the cross-sectional and longitudinal groups, respectively. In both study areas, participants and households in the longitudinal and cross-sectional groups were similar on demographic characteristics and prevalence of RDT positivity at baseline (2007: OR = 0.97; 95% CI:0.46, 2.03 | 2008/2009: OR = 1.28; 95% CI:0.44, 3.79). After baseline, the prevalence of RDT positivity was significantly lower in longitudinal compared to cross-sectional households in both study areas (2007: OR = 0.44; 95% CI:0.20, 0.96 | 2008/2009: OR = 0.16; 95% CI:0.05, 0.55). CONCLUSIONS/SIGNIFICANCE: Proactive case detection, consisting of screening household members with an RDT and treating those positive with ACT, can reduce transmission and provide indirect protection to household members. A targeted test and treat strategy could contribute to the elimination of malaria in regions of low transmission

Integrated climate-chemical indicators of diffuse pollution from land to water

Management of agricultural diffuse pollution to water remains a challenge and is influenced by the complex interactions of rainfall-runoff pathways, soil and nutrient management, agricultural landscape heterogeneity and biogeochemical cycling in receiving water bodies. Amplified cycles of weather can also influence nutrient loss to water although they are less considered in policy reviews. Here, we present the development of climate-chemical indicators of diffuse pollution in highly monitored catchments in Western Europe. Specifically, we investigated the influences and relationships between weather processes amplified by the North Atlantic Oscillation during a sharp upward trend (20102016) and the patterns of diffuse nitrate and phosphorus pollution in rivers. On an annual scale, we found correlations between local catchment-scale nutrient concentrations in rivers and the influence of larger, oceanic-scale climate patterns defined by the intensity of the North Atlantic Oscillation. These influences were catchment-specific showing positive, negative or no correlation according to a typology. Upward trends in these decadal oscillations may override positive benefits of local management in some years or indicate greater benefits in other years. Developing integrated climate-chemical indicators into catchment monitoring indicators will provide a new and important contribution to water quality management objectives

Feasible mitigation actions in developing countries

Energy use is not only crucial for economic development, but is also the main driver of greenhouse-gas emissions. Developing countries can reduce emissions and thrive only if economic growth is disentangled from energy-related emissions. Although possible in theory, the required energy-system transformation would impose considerable costs on developing nations. Developed countries could bear those costs fully, but policy design should avoid a possible 'climate rent curse', that is, a negative impact of financial inflows on recipients' economies. Mitigation measures could meet further resistance because of adverse distributional impacts as well as political economy reasons. Hence, drastically re-orienting development paths towards low-carbon growth in developing countries is not very realistic. Efforts should rather focus on 'feasible mitigation actions' such as fossil-fuel subsidy reform, decentralized modern energy and fuel switching in the power sector

Methods for evaluating delivery systems for scaling-up malaria control intervention

BACKGROUND: Despite increased resources over the past few years the coverage of malaria control interventions is still inadequate to reach national and international targets and achieve the full potential of the interventions to improve population health. One of the reasons for this inadequate coverage of efficacious interventions is the limited understanding of the optimum delivery systems of the interventions in different contexts. Although there have been debates about how to deliver interventions, the methods for evaluating the effectiveness of different delivery systems have rarely been discussed. Delivery of interventions is relatively complex and a thorough evaluation would need to look holistically at multiple steps in the delivery process and at multiple factors influencing the process. A better understanding of the strength of the evidence on delivery system effectiveness is needed in order to optimise delivery of efficacious interventions. METHODS: A literature review was conducted of methods used to evaluate delivery systems for insecticide treated nets, intermittent preventive treatment in pregnant women, and treatment for malaria in children. RESULTS: The methodology of delivery system evaluations varied. There were inconsistencies between objectives and methods of the evaluations including inappropriate outcome measures and unnecessary controls. There were few examples where the delivery processes were adequately described, or measured. We propose a cross sectional observational study design with attribution of the outcomes to a specific delivery system as an appropriate method for evaluating delivery systems at scale. CONCLUSIONS: The proposed evaluation framework is adaptable to natural experiments at scale, and can be applied using data from routine surveys such as the Demographic and Health Surveys, modified by the addition of one to two questions for each intervention. This framework has the potential to enable wider application of rigorous evaluations and thereby improve the evidence base on which decisions about delivery systems for malaria control and other public health interventions are taken

Osteopontin Impairs Host Defense during Established Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

Melioidosis is a severe tropical disease caused by infection with the bacterium Burkholderia (B.) pseudomallei. In northeast Thailand infection with this bacterium is the major cause of community-acquired septicemia with a mortality rate up to 40%. Extending the knowledge on the mechanisms of host defense against B. pseudomallei infection would be helpful to improve treatment of this severe illness. Osteopontin (OPN) is a cytokine that is involved in several immune responses that occur during bacterial infection. In this study, we investigated levels of OPN in patients with melioidosis, and studied the function of OPN during experimental melioidosis in mice. We found that OPN concentrations were elevated in patients with severe melioidosis, and that high OPN concentrations are associated with poor outcome in patients with melioidosis. In experimental melioidosis in mice plasma and lung OPN levels were also increased. Moreover, mice with melioidosis that were deficient for OPN demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, and decreased neutrophil infiltration into the lungs during established melioidosis. Moreover, these mice displayed a delayed mortality as compared to control mice. In conclusion, sustained production of OPN impairs host defense during melioidosis