Signaling from blood vessels to CNS axons through nitric oxide

Brain function is usually perceived as being performed by neurons with the support of glial cells, the network of blood vessels situated nearby serving simply to provide nutrient and to dispose of metabolic waste. Revising this view, we find from experiments on a rodent central white matter tract (the optic nerve) in vitro that microvascular endothelial cells signal persistently to axons using nitric oxide (NO) derived from the endothelial NO synthase (eNOS). The endogenous NO acts to stimulate guanylyl cyclase-coupled NO receptors in the axons, leading to a raised cGMP level which then causes membrane depolarization, apparently by directly engaging hyperpolarization-activated cyclic nucleotide-gated ion channels. The tonic depolarization and associated endogenous NO-dependent cGMP generation was absent in optic nerves from mice lacking eNOS, although such nerves responded to exogenous NO, with raised cGMP generation in the axons and associated depolarization. In addition to the tonic activity, exposure of optic nerves to bradykinin, a classical stimulator of eNOS in endothelial cells, elicited reversible NO- and cGMP-dependent depolarization through activation of bradykinin B-2 receptors, to which eNOS is physically complexed. No contribution of other NO synthase isoforms to either the action of bradykinin or the continuous ambient NO level could be detected. The results suggest that microvascular endothelial cells participate in signal processing in the brain and can do so by generating both tonic and phasic NO signals

All things being equal: Does it matter for equity how you organise and pay for health care? A review of the International Evidence

Over the last 25 years, the health care systems of most high-income countries have experienced extensive—usually market-based—organizational and financial reforms. The impact of these system changes on health equity has been hotly debated. Examining evidence from systematic reviews of the effects of health care system organizational and financial reforms will add empirical information to this debate, identify any evidence gaps, and help policy development. Systematic review methodology was used to locate and evaluate published systematic reviews of quantitative intervention studies (experimental and observational) of the effects on equity in health care access and/or health status of health care system organizational and financial reforms (system financing, funding allocations, direct purchasing arrangements, organization of service provision, and health and social care system integration) in high-income countries. Nine systematic reviews were identified. Private insurance and out-of-pocket payments as well as the marketization and privatization of services have either negative or inconclusive equity effects. The evidence base on the health equity effects of managed care programs or integrated partnerships between health and social services is inconclusive. There were no relevant studies located that related to resource allocation reforms. The systematic review-level evidence base suggests that financial and organizational health care system reforms have had either inconclusive or negative impacts on health equity both in terms of access relative to need and in terms of health outcomes

After Atos Healthcare: is the Employment and Support Allowance fit for purpose and does the Work Capability Assessment have a future?

In June 2014 the BBC reported that it had seen a number of UK Department for Work and Pensions documents relating to the Employment and Support Allowance (ESA). These documents, which included six memos written by civil servants and government advisers, tell us very little that we did not know already; namely that the ESA is in crisis, and that waiting lists for assessment and appeals are unacceptable. However, what is significant is that these concerns are being raised within the Department for Work and Pensions itself. The underlying drift is that the question of whether the current model of ESA and Work Capability Assessment is sustainable is now firmly on the UK government’s radar

Management of Fluid Status in Haemodialysis Patients: The Roles of Technology and Dietary Advice, Technical Problems in Patients on Hemodialysis

The kidneys play a vital role in maintaining normal tissue hydration and serum sodium level. In haemodialysis patients, with impaired or absent kidney function, fluid status is managed by removing excess fluid using ultrafiltration and by restricting dietary sodium intake. Ideally, haemodialysis patients should remain close to normal hydration throughout the interdialytic period, with minimal periods of excessive dehydration or fluid overload and with no fluid–related co-morbidity. Optimal fluid management is achieved by adjusting the post-dialysis ‘target’ weight and, where necessary, limiting the fluid gained between dialysis sessions. While clinical history and examination remain the basis for prescribing the target weight, technology can provide useful objective information especially where the clinical indications are ambiguous. A simple non-invasive test can now be carried out when a patient attends for dialysis enabling staff to pick up changes in body composition so that their target weight can be adjusted to maintain optimal fluid status. In most patients, interdialytic fluid gain (IDFG) is directly related to sodium intake. Acceptable fluid gains can usually be achieved by limiting salt intake to the recommended daily allowance for the general population and avoiding unnecessary sodium loading during dialysis. Low pre-dialysis serum sodium levels can help identify patients with other causes of high IDFG, such as high blood sugar or social drinking, who need additional counselling. For the patients, lowering sodium intake may also improve blood pressure control and reduce requirements for antihypertensive medication. Staff education, and preferably participation, is vital when implementing salt restriction in a haemodialysis unit

Desperately seeking reductions in health inequalities: perspectives of UK researchers on past, present and future directions in health inequalities research

Following government commitments to reducing health inequalities from 1997 onwards, the UK has been recognised as a global leader in health inequalities research and policy. Yet health inequalities have continued to widen by most measures, prompting calls for new research agendas and advocacy to facilitate greater public support for the upstream policies that evidence suggests are required. However, there is currently no agreement as to what new research might involve or precisely what public health egalitarians ought to be advocating. This article presents an analysis of discussions among 52 researchers to consider the feasibility that research-informed advocacy around particular solutions to health inequalities may emerge in the UK. The data indicate there is a consensus that more should be been done to learn from post-1997 efforts to reduce health inequalities, and an obvious desire to provide clearer policy guidance in future. However, discussions as to where researchers should now focus their efforts and with whom researchers ought to be engaging reveal three distinct ways of approaching health inequalities, each of which has its own epistemological foundations. Such differences imply that a consensus on reducing health inequalities is unlikely to materialise. Instead, progress seems most likely if all three approaches are simultaneously enabled

Investigating GNSS multipath effects induced by co-located Radar Corner Reflectors

Abstract Radar Corner Reflectors (CR) are increasingly used as reference targets for land surface deformation measurements with the Interferometric Synthetic Aperture Radar (InSAR) technique. When co-located with ground-based Global Navigation Satellite Systems (GNSS) infrastructure, InSAR observations at CR can be used to integrate relative measurements of surface deformation into absolute reference frames defined by GNSS. However, CR are also a potential source of GNSS multipath effects and may therefore have a detrimental effect on the GNSS observations. In this study, we compare daily GNSS coordinate time series and 30-second signal-to-noise ratio (SNR) observations for periods before and after CR deployment at a GNSS site. We find that neither the site coordinates nor the SNR values are significantly affected by the CR deployment, with average changes being within 0.1 mm for site coordinates and within 1 % for SNR values. Furthermore, we generate empirical site models by spatially stacking GNSS observation residuals to visualise and compare the spatial pattern in the surroundings of GNSS sites. The resulting stacking maps indicate oscillating patterns at elevation angles above 60 degrees which can be attributed to the CR deployed at the analysed sites. The effect depends on the GNSS antenna used at a site with the magnitude of multipath patterns being around three times smaller for a high-quality choke ring antenna compared to a ground plane antenna without choke rings. In general, the CR-induced multipath is small compared to multipath effects at other GNSS sites located in a different environment (e. g. mounted on a building)

Response of airway epithelial cells to double-stranded RNA in an allergic environment.

BACKGROUND: Respiratory viral infections are the most common trigger of acute exacerbations in patients with allergic asthma. The anti-viral response of airway epithelial cells (AEC) may be impaired in asthmatics, while cytokines produced by AEC may drive the inflammatory response. We investigated whether AEC cultured in the presence of Th2 cytokines associated with an allergic environment exhibited altered responses to double-stranded RNA, a virus-like stimulus. METHODS: We undertook preliminary studies using the MLE-12 cell line derived from mouse distal respiratory epithelial cells, then confirmed and extended our findings using low-passage human AEC. Cells were cultured in the absence or presence of the Th2 cytokines IL-4 and IL-13 for 48 hours, then stimulated with poly I:C for 4 hours. Expression of relevant anti-viral response and cytokine genes was assessed by quantitative real-time PCR. Secretion of cytokine proteins was assessed by immunoassay. RESULTS: Following stimulation with poly I:C, MLE-12 cells pre-treated with Th2 cytokines exhibited significantly higher levels of expression of mRNA for the cytokine genes Cxcl10 and Cxcl11, as well as a trend towards increased expression of Cxcl9 and Il6. Expression of anti-viral response genes was mostly unchanged, although Stat1, Ifit1 and Ifitm3 were significantly increased in Th2 cytokine pre-treated cells. Human AEC pre-treated with IL-4 and IL-13, then stimulated with poly I:C, similarly exhibited significantly higher expression of IL8, CXCL9, CXCL10, CXCL11 and CCL5 genes. In parallel, there was significantly increased secretion of CXCL8 and CCL5, as well as a trend towards increased secretion of CXCL10 and IL-6. Again, expression of anti-viral response genes was not decreased. Rather, there was significantly enhanced expression of mRNA for type III interferons, RNA helicases and other interferon-stimulated genes. CONCLUSION: The Th2 cytokine environment appears to promote increased production of pro-inflammatory chemokines by AEC in response to double-stranded RNA, which could help explain the exaggerated inflammatory response to respiratory viral infection in allergic asthmatics. However, any impairment of anti-viral host defences in asthmatics appears unlikely to be a consequence of Th2 cytokine-induced downregulation of the expression of viral response genes by AEC

Plausibility functions and exact frequentist inference

In the frequentist program, inferential methods with exact control on error rates are a primary focus. The standard approach, however, is to rely on asymptotic approximations, which may not be suitable. This paper presents a general framework for the construction of exact frequentist procedures based on plausibility functions. It is shown that the plausibility function-based tests and confidence regions have the desired frequentist properties in finite samples---no large-sample justification needed. An extension of the proposed method is also given for problems involving nuisance parameters. Examples demonstrate that the plausibility function-based method is both exact and efficient in a wide variety of problems.Comment: 21 pages, 5 figures, 3 table

Bayes linear kinematics in the analysis of failure rates and failure time distributions

Collections of related Poisson or binomial counts arise, for example, from a number of different failures in similar machines or neighbouring time periods. A conventional Bayesian analysis requires a rather indirect prior specification and intensive numerical methods for posterior evaluations. An alternative approach using Bayes linear kinematics in which simple conjugate specifications for individual counts are linked through a Bayes linear belief structure is presented. Intensive numerical methods are not required. The use of transformations of the binomial and Poisson parameters is proposed. The approach is illustrated in two examples, one involving a Poisson count of failures, the other involving a binomial count in an analysis of failure times