Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance

During human pregnancy, natural killer (NK) cells accumulate in the maternal decidua, but their specific roles remain to be determined. Decidual NK (dNK) cells are present during trophoblast invasion and uterine spiral artery remodelling. These events are crucial for successful placentation and the provision of an adequate blood supply to the developing fetus. Remodelling of spiral arteries is impaired in the dangerous pregnancy complication pre-eclampsia. We studied dNK cells isolated from pregnancies at 9-14 weeks' gestation, screened by uterine artery Doppler ultrasound to determine resistance indices which relate to the extent of spiral artery remodelling. dNK cells were able to promote the invasive behaviour of fetal trophoblast cells, partly through HGF. Cells isolated from pregnancies with higher resistance indices were less able to do this and secreted fewer pro-invasive factors. dNK cells from pregnancies with normal resistance indices could induce apoptotic changes in vascular smooth muscle and endothelial cells in vitro, events of importance in vessel remodelling, partly through Fas signalling. dNK cells isolated from high resistance index pregnancies failed to induce vascular apoptosis and secreted fewer pro-apoptotic factors. We have modelled the cellular interactions at the maternal-fetal interface and provide the first demonstration of a functional role for dNK cells in influencing vascular cells. A potential mechanism contributing to impaired vessel remodelling in pregnancies with a higher uterine artery resistance is presented. These findings may be informative in determining the cellular interactions contributing to the pathology of pregnancy disorders where remodelling is impaired, such as pre-eclampsia. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Outdoor Recreation Valuation (ORVal) User Guide: Version 2.0

The ORVal Tool is web application developed by the Land, Environment, Economics and Policy (LEEP) Institute at the University of Exeter with support from DEFRA. It can be accessed at: http://leep.exeter.ac.uk/orval.Department for Environment, Food and Rural Affairs (Defra

Outdoor Recreation Valuation (ORVal) User Guide: Version 1.0

The ORVal Tool is web application developed by the Land, Environment, Economics and Policy (LEEP) Institute at the University of Exeter with support from DEFRA. It can be accessed at: http://leep.exeter.ac.uk/orval.Department for Environment, Food and Rural Affairs (Defra

Specifying ODP computational objects in Z

The computational viewpoint contained within the Reference Model of Open Distributed Processing (RM-ODP) shows how collections of objects can be configured within a distributed system to enable interworking. It prescribes certain capabilities that such objects are expected to possess and structuring rules that apply to how these objects can be configured with one another. This paper highlights how the specification language Z can be used to formalise these capabilities and the associated structuring rules, thereby enabling specifications of ODP systems from the computational viewpoint to be achieved

Accretion Disc Theory: From the Standard Model Until Advection

Accretion disc theory was first developed as a theory with the local heat balance, where the whole energy produced by a viscous heating was emitted to the sides of the disc. One of the most important new invention of this theory was a phenomenological treatment of the turbulent viscosity, known as ''alpha'' prescription, when the (r$\phi$) component of the stress tensor was approximated by ($\alpha$ P) with a unknown constant $\alpha$. This prescription played the role in the accretion disc theory as well important as the mixing-length theory of convection for stellar evolution. Sources of turbulence in the accretion disc are discussed, including nonlinear hydrodynamical turbulence, convection and magnetic field role. In parallel to the optically thick geometrically thin accretion disc models, a new branch of the optically thin accretion disc models was discovered, with a larger thickness for the same total luminosity. The choice between these solutions should be done of the base of a stability analysis. The ideas underlying the necessity to include advection into the accretion disc theory are presented and first models with advection are reviewed. The present status of the solution for a low-luminous optically thin accretion disc model with advection is discussed and the limits for an advection dominated accretion flows (ADAF) imposed by the presence of magnetic field are analysed.Comment: Roceeding of the Int. Workshop "Observational Evidence for Black Holes in the Universe". Calcutta, 11-17 January 1998. Kluwer Acad. Pu

The ORVal Recreation Demand Model

Department for Environment, Food and Rural Affairs (Defra

Addressing the Collective Action Problem in Multiple-purchaser PES: An Experimental Investigation of Negotiated Payment Contributions

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Involving multiple-purchasers in a PES scheme has the potential to deliver numerous benefits including cost-sharing, expanded financing and broadened scope. That few such schemes exist is evidence of a classic market failure resulting from incentives to free-ride on the payments of other purchasers. In the context of an experimental investigation, this paper explores the role of negotiation and binding pre-commitments to payments in solving that collective action problem. Our novel experimental setup involves two purchasers seeking a level of payment acceptable to a single provider while also agreeing their own individual contributions to that payment. Contrasting treatments are used to explore complexities of the conditions under which negotiations might take place including asymmetries between the purchasers, treatments with incomplete information and treatments with uncertainty over the levels of benefit. We find that those complexities change the ease with which a negotiated agreement is achieved as well as the relative size of the payoffs enjoyed by the different parties to the negotiations Our findings are generally positive, showing that under many circumstances parties to a multiple-purchaser PES can successfully negotiate a mutually agreeable schedule of payments and contributions.This project was carried out as part of the Defra Payments for Ecosystem Services (PES) Pilot Research Projects: River Fowey Improvement Scheme [NE0131]. It was also supported by a University of East Anglia studentship. Funding support is gratefully acknowledged

Minimum target prices for production of direct acting antivirals and associated diagnostics to combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182