The M3 muscarinic receptor Is required for optimal adaptive immunity to Helminth and bacterial infection

Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection

Frame envy in energy policy ideology: a social constructivist framework for wicked energy problems

This article deals with the nexus between energy policymaking and ideology. The article builds and expands upon a theoretical social constructivist analytical strategy, or framework, put forth for the purposes of conducting energy policy analysis. It then addresses criticism that this strategy constitutes “postmodern mush” that has no place in energy analysis before concluding with a review of why social constructivism has a significant role to play in building consensus and enhancing understanding between competing energy policy perspectives. The main contribution made by this paper stems from application of this ontological construct to the analysis of policies targeting wicked energy problems. The study cuts to the core about how energy problems are defined, interpreted, communicated, planned for, and potentially implemented via policy. Put another way, our study offers a timely critique or a call for reconceptualizing the process and practice of energy policy itself

Do Hospitals Respond to Increasing Prices by Supplying Fewer Services?

Medical providers often have a significant influence on treatment decisions which they can use in their own financial interest. Classical models of supplier-induced demand predict that medical providers will supply fewer services if they face increasing prices. We test this prediction based on a reform of hospital financing in Germany. Uniquely, this reform changed the overall level of reimbursement - with increasing prices for some hospitals and decreasing prices for others - without affecting the relative prices for different types of patients. Based on administrative data, we find that hospitals do indeed react to increasing prices by reducing service supply.Anbieter von medizinischen Leistungen treffen häufig Behandlungsentscheidungen für ihre Patienten und haben die Möglichkeit, bei diesen Entscheidungen ihre eigenen finanziellen Interessen zu berücksichtigen. Klassische Modelle der Theorie der 'angebotsinduzierten Nachfrage' prognostizieren, dass medizinische Anbieter auf höhere Preise reagieren, indem sie weniger Leistungen erbringen. Wir testen diese Vorhersage auf Grundlage einer Reform der Krankenhausfinanzierung in Deutschland. Das Besondere an der Finanzierungsreform in Deutschland ist, dass die Reform die Preise für Krankenhäuser verändert hat - mit steigenden Preisen für einige Krankenhäuser und sinkenden Preisen für andere - ohne dabei die relativen Preise für die Behandlung unterschiedlicher Patientengruppen oder unterschiedlicher Krankheiten zu beeinflussen. Unter Nutzung administrativer Daten finden wir, dass Krankenhäuser tatsächlich weniger Leistungen erbringen, wenn die Preise steigen

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion

Central Role of SREBP-2 in the Pathogenesis of Osteoarthritis

Background: Recent studies have implied that osteoarthritis (OA) is a metabolic disease linked to deregulation of genes involved in lipid metabolism and cholesterol efflux. Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors regulating lipid metabolism with so far no association with OA. Our aim was to test the hypothesis that SREBP-2, a gene that plays a key role in cholesterol homeostasis, is crucially involved in OA pathogenesis and to identify possible mechanisms of action. Methodology/Principal Findings: We performed a genetic association analysis using a cohort of 1,410 Greek OA patients and healthy controls and found significant association between single nucleotide polymorphism (SNP) 1784G>C in SREBP-2 gene and OA development. Moreover, the above SNP was functionally active, as normal chondrocytes’ transfection with SREBP-2-G/C plasmid resulted in interleukin-1β and metalloproteinase-13 (MMP-13) upregulation. We also evaluated SREBP-2, its target gene 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR), phospho-phosphoinositide3-kinase (PI3K), phospho-Akt, integrin-alphaV (ITGAV) and transforming growth factor-$\beta$ (TGF-$\beta$) mRNA and protein expression levels in osteoarthritic and normal chondrocytes and found that they were all significantly elevated in OA chondrocytes. To test whether TGF-$\beta$ alone can induce SREBP-2, we treated normal chondrocytes with TGF-$\beta$ and found significant upregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13. We also showed that TGF-$\beta$ activated aggrecan (ACAN) in chondrocytes only through Smad3, which interacts with SREBP-2. Finally, we examined the effect of an integrin inhibitor, cyclo-RGDFV peptide, on osteoarthritic chondrocytes, and found that it resulted in significant upregulation of ACAN and downregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13 expression levels. Conclusions/Significance: We demonstrated, for the first time, the association of SREBP-2 with OA pathogenesis and provided evidence on the molecular mechanism involved. We suggest that TGF-$\beta$ induces SREBP-2 pathway activation through ITGAV and PI3K playing a key role in OA and that integrin blockage may be a potential molecular target for OA treatment

The use of health-related quality of life (HRQOL) in children and adolescents as an outcome criterion to evaluate family oriented support for young carers in Germany: an integrative review of the literature

<p>Abstract</p> <p>Background</p> <p>Young people below the age of 18, whose lives are affected by looking after a relative with a disability or long-term illness, are called young carers. Evidence based family oriented support for young carers and their families in Germany is currently being developed. To allow for scientific evaluation, an outcome criterion needs to be chosen. Until today, there are no assessment instruments available, which focus on young carer's specific demands and needs. As HRQOL seems to be an adequate alternative outcome criterion, an integrative review of the literature was carried out to verify this assumption.</p> <p>Methods</p> <p>The aim of the integrative review was to get information about a) the concept and the common definition of HRQOL in children, b) preferable HRQOL assessment techniques in children, and c) the relevance of HRQOL measures for the population of young carers. An additional aim of the review was to give advice on which instrument fits best to assess young carer's HRQOL in Germany. Searches were conducted in PubMed in order to obtain papers reporting about a) the development or psychometric assessment of instruments measuring HRQOL in children and adolescents up to the age of 18, and b) on the conceptual framework of HRQOL in children.</p> <p>Results</p> <p>HRQOL is a multidimensional construct covering physical, emotional, mental, social, and behavioural components of well-being and functioning as subjective perceived by a person depending on the cultural context and value system one is living in. Young carer's problems and needs are well covered by these common domains of HRQOL. Since no specific HRQOL-measures are available to address young carers, a generic one has to be chosen which a) has been created for use in children, b) allows self- and proxy-report, and c) has good psychometric testing results. Comparing four generic measures with currently best published psychometric testing results, items of the KIDSCREEN cover young carer's specific problems most accurate.</p> <p>Conclusion</p> <p>The KIDSCREEN questionnaires seems adequate to evaluate the intervention as their items cover young carer's needs and problems most accurate.</p

A Proposal for the Attribution of Market Leakage to CDM Projects

Economic models suggest that in many cases, market leakage rates of greenhouse gas abatement reach the two-digit percentage range. Consequently, the Marrakesh Accords require Clean Development Mechanism (CDM) projects to account for leakage. Despite this, most project proponents neglect market leakage for their project, because the influence of an individual project on market prices seems to be negligible. Insufficient leakage accounting is facilitated by a lack of theories and applicable proposals regarding the quantification and attribution of leakage effects. The aim of this paper is to develop a proposal for the attribution of market leakage effects to CDM projects. To this purpose, we identify the transmission mechanisms for CDM project leakage, investigate the current practice of leakage accounting, and analyse alternative attribution methods for leakage effects that are transmitted through price changes. We find that project-specific approaches must fail to take account of such leakage effects. Consequently, we propose to estimate aggregate market leakage effects and attribute them proportionally to individual projects. Our proposal is based on commodity-specific leakage factors which can be applied by project developers to any emission reductions that are associated with a project's leakage-relevant demand or supply changes. The proposal is conservative, equitable, incentive compatible and applicable at manageable costs