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Monocytes and macrophages participate in a wide variety of host defense mechanisms. Annexin II, a fibrinolytic receptor, binds plasminogen and tissue plasminogen activator (t-PA) independently at the cell surface, thereby enhancing the catalytic efficiency of plasmin production. We demonstrated previously that annexin II on the surface of both cultured monocytoid cells and monocyte-derived macrophages promotes their ability to remodel extracellular matrix. Here, we demonstrate that human peripheral blood monocytes represent the major circulating annexin II-expressing cell. Annexin II supported t-PA-dependent generation of cell surface plasmin and the matrixpenetrating activity of human monocytes. Compared to polymorphonuclear leukocytes, monocytes supported a 12.9-fold greater rate of plasmin generation in the presence of exogenous t-PA, and this activity was largely attributable to annexin II. Likewise, anti-annexin II IgG directed against the t-PA-binding tail domain inhibited plasminogen-dependent, cytokine-directed monocyte migration through extracellular matrix. On differentiation of monocytes to macrophages, there was a 2.4-fold increase in annexin II-specific mRNA, and a 7.9-fold increase in surface annexin II. Thioglycolate-elicited peritoneal macrophages, furthermore, displayed an additional 3.8-fold increase in annexin II surface expression compared with resident cells. Thus, annexin II-mediated assembly of plasminogen and t-PA on monocyte/macrophages contributes to plasmin generation, matrix remodeling, and directed migration. IntroductionAnnexin II belongs to a family of widely distributed, phospholipidbinding, calcium-regulated, peripheral membrane proteins known as the annexins. 1 Annexin II is richly expressed in the epithelial cells of intestine and lung and is also found on the cell surface of vascular endothelial cells, myelomonocytic leukemia cells, 2 and cells of several monocyte-like lines. 3 Through the expression of independent binding sites for both plasminogen and tissue plasminogen activator (t-PA), annexin II assembles these 2 proteins on the cell surface, thereby accelerating the production of plasmin. 4 Kinetic studies indicate that annexin II enhances the catalytic efficiency (k cat /K m ) of t-PA-dependent plasminogen activation by 60-fold, 5 suggesting that endothelial cell surface generation of plasmin likely contributes to fibrinolytic surveillance, thereby promoting blood vessel patency.Monocytes and macrophages are large, motile, phagocytic cells that have a wide range of biosynthetic and secretory activities depending on their exposure to local stimuli and mediators. 6 They participate routinely in host defense mechanisms, including antigen presentation and clearance of debris, and contribute critically to acute and chronic inflammatory responses, pathogen clearance, and wound healing. 7,8 In many pathologic processes, such as atherosclerosis or disorders of lipid metabolism, furthermore, lipid-laden macrophages accumulate in tissues. 9 The monocyte/macrophage, moreover, ma...

Several barriers challenge development, adoption and scale-up of diagnostics in low and middle income countries. An innovative global health discussion platform allows capturing insights from the global health community on factors driving demand and supply for diagnostics. We conducted a qualitative content analysis of the online discussion ‘Advancing Care Delivery: Driving Demand and Supply of Diagnostics’ organised by the Global Health Delivery Project (GHD) (http://www.ghdonline.org/) at Harvard University. The discussion, driven by 12 expert panellists, explored what must be done to develop delivery systems, business models, new technologies, interoperability standards, and governance mechanisms to ensure that patients receive the right diagnostic at the right time. The GHD Online (GHDonline) platform reaches over 19 000 members from 185 countries. Participants (N=99) in the diagnostics discussion included academics, non-governmental organisations, manufacturers, policymakers, and physicians. Data was coded and overarching categories analysed using qualitative data analysis software. Participants considered technical characteristics of diagnostics as smaller barriers to effective use of diagnostics compared with operational and health system challenges, such as logistics, poor fit with user needs, cost, workforce, infrastructure, access, weak regulation and political commitment. Suggested solutions included: health system strengthening with patient-centred delivery; strengthened innovation processes; improved knowledge base; harmonised guidelines and evaluation; supply chain innovations; and mechanisms for ensuring quality and capacity. Engaging and connecting different actors involved with diagnostic development and use is paramount for improving diagnostics. While the discussion participants were not representative of all actors involved, the platform enabled a discussion between globally acknowledged experts and physicians working in different countries.