Clinical significance of monocyte heterogeneity

Monocytes are primitive hematopoietic cells that primarily arise from the bone marrow, circulate in the peripheral blood and give rise to differentiated macrophages. Over the past two decades, considerable attention to monocyte diversity and macrophage polarization has provided contextual clues into the role of myelomonocytic derivatives in human disease. Until recently, human monocytes were subdivided based on expression of the surface marker CD16. "Classical" monocytes express surface markers denoted as CD14(++)CD16(-) and account for greater than 70% of total monocyte count, while "non-classical" monocytes express the CD16 antigen with low CD14 expression (CD14(+)CD16(++)). However, recognition of an intermediate population identified as CD14(++)CD16(+) supports the new paradigm that monocytes are a true heterogeneous population and careful identification of specific subpopulations is necessary for understanding monocyte function in human disease. Comparative studies of monocytes in mice have yielded more dichotomous results based on expression of the Ly6C antigen. In this review, we will discuss the use of monocyte subpopulations as biomarkers of human disease and summarize correlative studies in mice that may yield significant insight into the contribution of each subset to disease pathogenesis

Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease. Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21(Ras) activity and phosphorylation of multiple downstream kinases, including Erk and Akt. Nf1 heterozygous (Nf1(+/-)) mice develop a robust neointima that mimics human disease. Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells alone are sufficient to reproduce the enhanced neointima observed in Nf1(+/-) mice. Though the molecular mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound mutant and lineage-restricted mice to demonstrate that Nf1(+/-) macrophages produce excessive ROS, which enhance Nf1(+/-) smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1(+/-) mice. Finally, mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing novels therapies and interventions

Health system barriers to strengthening vaccine-preventable disease surveillance and response in the context of decentralization: evidence from Georgia

BACKGROUND: A critical challenge in the health sector in developing countries is to ensure the quality and effectiveness of surveillance and public health response in an environment of decentralization. In Georgia, a country where there has been extensive decentralization of public health responsibilities over the last decade, an intervention was recently piloted to strengthen district-level local vaccine-preventable disease surveillance and response activities through improved capacity to analyze and use routinely collected data. The purpose of the study is 1) to assess the effectiveness of the intervention on motivation and perceived capacity to analyze and use information at the district-level, and 2) to assess the role that individual- and system-level factors play in influencing the effectiveness of the intervention. METHODS: A pre-post quasi-experimental research design is used for the quantitative evaluation. Data come from a baseline and two follow-up surveys of district-level health staff in 12 intervention and 3 control Center of Public Health (CPH) offices. These data were supplemented by record reviews in CPH offices as well as focus group discussions among CPH and health facility staff. RESULTS: The results of the study suggest that a number of expected improvements in perceived data availability and analysis occurred following the implementation of the intervention package, and that these improvements in analysis could be attributable to the intervention package. However, the study results also suggest that there exist several health systems barriers that constrained the effectiveness of the intervention in influencing the availability of data, analysis and response. CONCLUSION: To strengthen surveillance and response systems in Georgia, as well as in other countries, donor, governments, and other stakeholders should consider how health systems factors influence investments to improve the availability of data, analysis, and response. Linking the intervention to broader health sector reforms in management processes and organizational culture will be critical to ensure that efforts designed to promote evidence-based decision-making are successful, especially as they are scaled up to the national level

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Purpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. Methods: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/-), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. Results: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/- retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/- and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/- retinas. Conclusions: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial

Neurofibromin Deficient Myeloid Cells are Critical Mediators of Aneurysm Formation In Vivo

Background Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. Method and Results Utilizing an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/− aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin, reduced aneurysm formation in Nf1+/− mice. Conclusion These data provide genetic and pharmacologic evidence that Nf1+/− myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target

Evaluation of the Performance of Routine Information System Management (PRISM) framework: evidence from Uganda

<p>Abstract</p> <p>Background</p> <p>Sound policy, resource allocation and day-to-day management decisions in the health sector require timely information from routine health information systems (RHIS). In most low- and middle-income countries, the RHIS is viewed as being inadequate in providing quality data and continuous information that can be used to help improve health system performance. In addition, there is limited evidence on the effectiveness of RHIS strengthening interventions in improving data quality and use. The purpose of this study is to evaluate the usefulness of the newly developed Performance of Routine Information System Management (PRISM) framework, which consists of a conceptual framework and associated data collection and analysis tools to assess, design, strengthen and evaluate RHIS. The specific objectives of the study are: a) to assess the reliability and validity of the PRISM instruments and b) to assess the validity of the PRISM conceptual framework.</p> <p>Methods</p> <p>Facility- and worker-level data were collected from 110 health care facilities in twelve districts in Uganda in 2004 and 2007 using records reviews, structured interviews and self-administered questionnaires. The analysis procedures include Cronbach's alpha to assess internal consistency of selected instruments, test-retest analysis to assess the reliability and sensitivity of the instruments, and bivariate and multivariate statistical techniques to assess validity of the PRISM instruments and conceptual framework.</p> <p>Results</p> <p>Cronbach's alpha analysis suggests high reliability (0.7 or greater) for the indices measuring a promotion of a culture of information, RHIS tasks self-efficacy and motivation. The study results also suggest that a promotion of a culture of information influences RHIS tasks self-efficacy, RHIS tasks competence and motivation, and that self-efficacy and the presence of RHIS staff have a direct influence on the use of RHIS information, a key aspect of RHIS performance.</p> <p>Conclusions</p> <p>The study results provide some empirical support for the reliability and validity of the PRISM instruments and the validity of the PRISM conceptual framework, suggesting that the PRISM approach can be effectively used by RHIS policy makers and practitioners to assess the RHIS and evaluate RHIS strengthening interventions. However, additional studies with larger sample sizes are needed to further investigate the value of the PRISM instruments in exploring the linkages between RHIS data quality and use, and health systems performance.</p

Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security