Bone morphogenetic protein (BMP) 9 and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2

Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte-endothelial interactions using an in vitro flow adhesion assay. Herein, we report that while BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergised with Tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with upregulated expression levels of E-selectin, VCAM-1 and ICAM-1 on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the upregulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The upregulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκB-α protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergise with TNFα to induce the upregulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling.This work was supported by a Ph.D. fellowship from the Wellcome Trust Grant 099824/Z/12/Z (to C.-G. M.), British Heart Foundation Programme Grant RG/13/4/30107 (to N. W. M.), and Medical Research Council Experimental Challenge Award MR/KR020919/1 (to N. W. M.). N. W. M. is a founder and director of Morphogen-IX. P. D. U. is a founder of Morphogen-IX

Risk factors for asthma and allergy associated with urban migration: background and methodology of a cross-sectional study in Afro-Ecuadorian school children in Northeastern Ecuador (Esmeraldas-SCAALA Study)

BACKGROUND: Asthma and allergic diseases are becoming increasingly frequent in children in urban centres of Latin America although the prevalence of allergic disease is still low in rural areas. Understanding better why the prevalence of asthma is greater in urban migrant populations and the role of risk factors such as life style and environmental exposures, may be key to understand what is behind this trend. METHODS/DESIGN: The Esmeraldas-SCAALA (Social Changes, Asthma and Allergy in Latin America) study consists of cross-sectional and nested case-control studies of school children in rural and urban areas of Esmeraldas Province in Ecuador. The cross-sectional study will investigate risk factors for atopy and allergic disease in rural and migrant urban Afro-Ecuadorian school children and the nested case-control study will examine environmental, biologic and social risk factors for asthma among asthma cases and non-asthmatic controls from the cross-sectional study. Data will be collected through standardised questionnaires, skin prick testing to relevant aeroallergen extracts, stool examinations for parasites, blood sampling (for measurement of IgE, interleukins and other immunological parameters), anthropometric measurements for assessment of nutritional status, exercise testing for assessment of exercise-induced bronchospasm and dust sampling for measurement of household endotoxin and allergen levels. DISCUSSION: The information will be used to identify the factors associated with an increased risk of asthma and allergies in migrant and urbanizing populations, to improve the understanding of the causes of the increase in asthma prevalence and to identify potentially modifiable factors to inform the design of prevention programmes to reduce the risk of allergy in urban populations in Latin America

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice

Networks relations and local economic development: some causes of differentiated network structures and intensities amoung Turkish industrial firms

The regional-growth literature emphasises the importance of positive network externalities as determinants of the long-run competitiveness of region, highlighting their role in reducing spatial transaction costs and facilitating collective learning and innovation. In this paper we contribute to this literature by presenting new evidence from a firm-based survey within three Turkish industrial centres about the causes of differentiated network activity. Using multivariate analysis, we show that locational rather than sectoral differences explain local-linkage intensities, but this is not the case for global links. Second, there is an important relationship between firm size and local-linkage and global-linkage densities; the density of local networks decreases with increasing firm size, whereas the density of global networks increases with firm size. Third, there is a positive relation between global-network density and firm productivity. We argue that the comparative and quantitative analysis we employ is a useful adjunct to case-study analysis, which could help avoid misconceptions and lead to a more realistic theory

Could valerian have been the first anticonvulsant?

To assess the available evidence for the belief that valerian, highly recommended in the past for treating epilepsy, possessed real anticonvulsant effectiveness.Review of available literature.In 1592, Fabio Colonna, in his botanical classic Phytobasanos, reported that taking powdered valerian root cured his own epilepsy. Subsequent reports of valerian's anticonvulsant effectiveness appeared. By the late 18th and early 19th centuries, it was often regarded as the best available treatment for the disorder. Valerian preparations yield isovaleric acid, a substance analogous to valproic acid and likely to possess anticonvulsant properties, as isovaleramide does. In favorable circumstances, high valerian doses can be calculated to have sometimes provided potentially effective amounts of anticonvulsant substance for epilepsy patients.Valerian probably did possess the potential for an anticonvulsant effect, but the uncertain chemical composition and content of valerian preparations, and their odor and taste, made it unlikely that they could ever prove satisfactory in widespread use