175 research outputs found
A Critical Role for Induced IgM in the Protection against West Nile Virus Infection
In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578–2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM−/−) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM−/− mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM−/− mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection
Investigating Financial Incentives for Maternal Health: An Introduction
Projection of current trends in maternal and neonatal mortality
reduction shows that many countries will fall short of the UN
Millennium Development Goal 4 and 5. Underutilization of maternal
health services contributes to this poor progress toward reducing
maternal and neonatal morbidity and mortality. Moreover, the quality of
services continues to lag in many countries, with a negative effect on
the health of women and their babies, including deterring women from
seeking care. To enhance the use and provision of quality maternal
care, countries and donors are increasingly using financial incentives.
This paper introduces the JHPN Supplement, in which each paper reviews
the evidence of the effectiveness of a specific financial incentive
instrument with the aim of improving the use and quality of maternal
healthcare and impact. The US Agency for International Development and
the US National Institutes of Health convened a US Government Evidence
Summit on Enhancing Provision and Use of Maternal Health Services
through Financial Incentives on 24-25 April 2012 in Washington, DC. The
Summit brought together leading global experts in finance, maternal
health, and health systems from governments, academia, development
organizations, and foundations to assess the evidence on whether
financial incentives significantly and substantially increase
provision, use and quality of maternal health services, and the
contextual factors that impact the effectiveness of these incentives.
Evidence review teams evaluated the multidisciplinary evidence of
various financial mechanisms, including supply-side incentives (e.g.
performance-based financing, user fees, and various insurance
mechanisms) and demand-side incentives (e.g. conditional cash
transfers, vouchers, user fee exemptions, and subsidies for
care-seeking). At the Summit, the teams presented a synthesis of
evidence and initial recommendations on practice, policy, and research
for discussion. The Summit enabled structured feedback on
recommendations which the teams included in their final papers
appearing in this Supplement. Papers in this Supplement review the
evidence for a specific financial incentive mechanism (e.g. pay for
performance, conditional cash transfer) to improve the use and quality
of maternal healthcare and makes recommendations for programmes and
future research. While data on programmes using financial incentives
for improved use and indications of the quality of maternal health
services support specific conclusions and recommendations, including
those for future research, data linking the use of financial incentives
with improved health outcomes are minimal
Evidence Acquisition and Evaluation for Evidence Summit on Enhancing Provision and Use of Maternal Health Services through Financial Incentives
Recognizing the need for evidence to inform US Government and
governments of the low- and middleincome countries on efficient,
effective maternal health policies, strategies, and programmes, the US
Government convened the Evidence Summit on Enhancing Provision and Use
of Maternal Health Services through Financial Incentives in April 2012
in Washington, DC, USA. This paper summarizes the background and
methods for the acquisition and evaluation of the evidence used for
achieving the goals of the Summit. The goal of the Summit was to obtain
multidisciplinary expert review of literature to inform both US
Government and governments of the low- and middle-income countries on
evidence-informed practice, policies, and strategies for financial
incentives. Several steps were undertaken to define the tasks for the
Summit and identify the appropriate evidence for review. The process
began by identifying focal questions intended to inform governments of
the low-and middle-income countries and the US Government about the
efficacy of supply- and demand-side financial incentives for enhanced
provision and use of quality maternal health services. Experts were
selected representing the research and programme communities, academia,
relevant non-governmental organizations, and government agencies and
were assembled into Evidence Review Teams. This was followed by a
systematic process to gather relevant peer-reviewed literature that
would inform the focal questions. Members of the Evidence Review Teams
were invited to add relevant papers not identified in the initial
literature review to complete the bibliography. The Evidence Review
Teams were asked to comply with a specific evaluation framework for
recommendations on practice and policy based on both expert opinion and
the quality of the data. Details of the search processes and methods
used for screening and quality reviews are described
Universal Non-Oblique Corrections in Higgsless Models and Beyond
Recently Barbieri, et al. have introduced a formalism to express the
deviations of electroweak interactions from their standard model forms in
"universal" theories, i.e. theories in which the corrections due to new physics
can be expressed solely by modifications to the two-point correlation function
of electroweak gauge currents of fermions. The parameters introduced by these
authors are defined by the properties of the correlation functions at zero
momentum, and differ from the quantities calculated by examining the on-shell
properties of the electroweak gauge bosons. In this letter we discuss the
relationship between the zero-momentum and on-shell parameters. In addition, we
present the results of a calculation of these zero-momentum parameters in an
arbitrary Higgsless model in which the low-energy rho parameter is one and
which can be deconstructed to a linear chain of SU(2) groups adjacent to a
chain of U(1) groups. Our results demonstrate the importance of the universal
"non-oblique" corrections which are present and elucidate the relationships
among various calculations of electroweak quantities in these models. Our
expressions for these zero-momentum parameters depend only on the spectrum of
heavy vector-boson masses; therefore, the minimum size of the deviations
present in these models is related to the upper bound on the heavy vector-boson
masses derived from unitarity. We find that these models are disfavored by
precision electroweak data, independent of any assumptions about the background
metric or the behavior of the bulk coupling.Comment: 13 pages, 2 eps figure
Partnerships for Enhanced Engagement in Research (PEER) health: a new programme to facilitate LMIC research capacity
AbstractBackgroundThe Partnership for Enhanced Engagement in Research (PEER) Health programme, funded by the United States Agency for International Development (USAID), is a new research partnership programme that directly supports researchers from developing countries as Principal Investigators in partnership with collaborators at the US National Institutes of Health (NIH). The goals of this programme are threefold: (1) to advance critical evidence to address crucial health challenges facing LMICs; (2) to support collaboration and build on existing relationships between local public health and research institutions, global health practitioners, host country government, NIH researchers, and USAID Missions and Embassy staff; and (3) to build capacity by supporting researchers in LMICs thereby enabling local solutions to context specific challenges.MethodsMore than 180 preproposals from 25 LMICs were submitted to the first PEER Health research solicitation focused on Child Survival. After consultation with USAID Missions to ensure relevance to host country health priorities, about 80 applicants were invited to submit a full proposal. The National Institute of Child Health and Human Development organised a special emphasis panel for the scientific review of PEER Health full proposals to address both scientific merit and research capacity building aspects of the grant proposals, whilst maintaining key elements of the standard NIH peer review model. 40 experienced NIH reviewers, representing a wide variety of scientific disciplines and global public health experience, did the peer review of grants using a novel IT system developed for the PEER Health initiative. The National Academies of Sciences hosted an interagency protocol review to ensure scientific validity and compliance with international human subject guidelines.FindingsSixteen diverse grant partnerships were awarded in ten USAID Child Survival priority countries in Africa and Asia. Research funded under this programme is varied and includes studies from diverse topical areas, including malaria, neonatal sepsis, breast-feeding, tuberculosis, prevention of mother-to-child transmission, among others. Studies include investigation of both facility and community level interventions. NIH partners are largely US based and half are support by the National Institute of Allergy and Infectious Disease (NIAID).InterpretationBroad interest in this novel programme and applications from 25 countries show a crucial need for more directed funding for research strengthening and partnerships with LMIC Principal Investigators.FundingUSAID, in-kind support from NIH
Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus.
OBJECTIVE: To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE).
METHODS: Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting.
RESULTS: ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells.
CONCLUSION: Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response
Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.
Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABAA receptor β2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders
The effect of intranasal insulin on appetite and mood in women with and without obesity: an experimental medicine study
Background/Objectives Intranasal (IN) administration of insulin decreases appetite in humans, but the underlying mechanisms are unclear, and it is unknown whether IN insulin affects the food intake of women with obesity. Subjects/Methods In a double-blind, placebo-controlled, crossover design, participants (35 lean women and 17 women with obesity) were randomized to receive 160 IU/1.6 mL of IN insulin or placebo in a counterbalanced order in the post prandial state. The effects of IN insulin on cookie intake, appetite, mood, food reward, cognition and neural activity were assessed. Results IN insulin in the post prandial state reduced cookie intake, appetite and food reward relative to placebo and these effects were more pronounced for women with obesity compared with lean women. IN insulin also improved mood in women with obesity. In both BMI groups, IN insulin increased neural activity in the insula when viewing food pictures. IN insulin did not affect cognitive function. Conclusions These results suggest that IN insulin decreases palatable food intake when satiated by reducing food reward and that women with obesity may be more sensitive to this effect than lean women. Further investigation of the therapeutic potential of IN insulin for weight management in women with obesity is warranted
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