LY 294002 inhibits adenosine receptor activation by a mechanism independent of effects on PI-3 kinase or casein kinase II

Adenosine reduces both evoked and spontaneous calcium-dependent acetylcholine (ACh) release through a mechanism downstream of calcium entry at amphibian motor nerve endings (Silinsky EM. J Physiol 1984; 346: 243-6). LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), an inhibitor of both phosphoinositide-3 kinase (PI-3 kinase) and casein kinase II, has been reported to increase spontaneous ACh release reflected in miniature endplate potential (MEPP) frequencies independently of intraterminal calcium at the frog neuromuscular junction (Rizzoli SO, Betz WJ. J Neurosci 2002; 22: 10680-). It has been suggested that the increase in MEPP frequency caused by LY 294002, is mediated through an action on synaptotagmins, vesicle associated calcium sensors believed to trigger synaptic vesicle exocytosis. We thus examined the effects of adenosine on MEPP frequencies and evoked ACh release reflected as endplate potentials (EPPs) in order to determine if the presumed calcium-independent ACh release is affected by adenosine. We also wanted to determine if PI-3 kinase or casein kinase II is involved in mediating or modulating the inhibitory effects of adenosine. To these ends, we examined the effects of adenosine in the presence of LY 294002, wortmannin (a highly selective the PI-3 kinase inhibitor), or DRB (5,6-dichlorobenzimidazole riboside, an inhibitor of casein kinase II). LY 294002 reduced the sensitivity of both MEPP frequencies and the nerve-evoked calcium dependent EPPs to adenosine. The occlusive effects of LY 294002 on the actions of adenosine on MEPPs and EPPs were overcome by increasing adenosine concentration. Neither wortmannin nor DRB had any effect on the sensitivity of the EPPs to adenosine indicating that neither PI-3 kinase nor casein kinase II inhibition mediates the reduction in motor-nerve terminal sensitivity to adenosine produced by LY 294002. The results indicate a competitive relationship between LY 294002 and adenosine at A1 receptors at the frog neuromuscular junction. This effect is independent of the previously described effects of LY 294002 on the exocytotic process, and is also independent of PI-3 kinase or casein kinase II

The Liberal Playground: Susan Isaacs, Psychoanalysis and Progressive Education in the Interwar Era

The Cambridge Malting House, an experimental school, serves here as a case study for investigating the tensions within 1920s liberal elites between their desire to abandon some Victorian and Edwardian sets of values in favour of more democratic ones, and at the same time their insistence on preserving themselves as an integral part of the English upper class. Susan Isaacs, the manager of the Malting House, provided the parents – some of whom were the most famous scientists and intellectuals of their age – with an opportunity to fulfil their ‘fantasy’ of bringing up children in total freedom. In retrospect, however, she deeply criticized those from their milieu for not fully understanding the real socio-cultural implications of their ideological decision to make independence and freedom the core values in their children’s education. Thus, 1920s progressive education is a paradigmatic case study of the cultural and ideological inner contradictions within liberal thought in the interwar era. The article also shows how psychoanalysis – which attracted many progressive educators – played a crucial role in providing liberals of all sorts with a new language to articulate their political visions, but, at the same time, explored the limits of the liberal discourse as a whole

The effectiveness and cost effectiveness of a hospital avoidance program in a residential aged care facility: a prospective cohort study and modelled decision analysis

Background Residential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable. The EDDIE program is a hospital avoidance initiative designed to enable nursing and care staff to detect, refer and quickly respond to early signals of a deteriorating resident. The program was implemented in a 96-bed residential aged care facility in regional Australia. Methods A prospective pre-post cohort study design was used to collect data on costs of program delivery, hospital admission rates and length of stay for the 12months prior to, and following, the intervention. A Markov decision model was developed to synthesize study data with published literature in order to estimate the costeffectiveness of the program. Quality adjusted life years (QALYs) were adopted as the measure of effectiveness. Results The EDDIE program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. The cost-effectiveness analysis found the program to be both more effective and less costly than usual care, with 0.06 QALYs gained and $249,000 health system costs saved in a modelled cohort of 96 residents. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account. Conclusions This study provides promising evidence for the effectiveness and cost-effectiveness of a nurse led, early intervention program in preventing unnecessary hospital admissions within a residential aged care facility. Further research in multi-site randomised studies is needed to confirm the generalisability of these results

Thermal conductivity of refractory glass fibres

In the present study, the current international standards and corresponding apparatus for measuring the thermal conductivity of refractory glass fibre products have been reviewed. Refractory glass fibres are normally produced in the form of low-density needled mats. A major issue with thermal conductivity measurements of these materials is lack of reproducibility in the test results due to transformation of the test material during the test. Also needled mats are inherently inhomogeneous, and this poses additional problems. To be able to compare the various methods of thermal conductivity measurement, a refractory reference material was designed which is capable of withstanding maximum test temperatures (1673 K) with minimum transformation. The thermal conductivity of this reference material was then measured using various methods according to the different standards surveyed. In order to compare different materials, samples have been acquired from major refractory glass fibre manufacturers and the results have been compared against the newly introduced reference material. Materials manufactured by melt spinning, melt blowing and sol–gel have been studied, and results compared with literature values

Excitatory effect of ATP on rat area postrema neurons

ATP-induced inward currents and increases in the cytosolic Ca2+ concentration ([Ca]in) were investigated in neurons acutely dissociated from rat area postrema using whole-cell patch-clamp recordings and fura-2 microfluorometry, respectively. The ATP-induced current (IATP) and [Ca]in increases were mimicked by 2-methylthio-ATP and ATP-γS, and were inhibited by P2X receptor (P2XR) antagonists. The current–voltage relationship of the IATP exhibited a strong inward rectification, and the amplitude of the IATP was concentration-dependent. The IATP was markedly reduced in the absence of external Na+, and the addition of Ca2+ to Na+-free saline increased the IATP. ATP did not increase [Ca]in in the absence of external Ca2+, and Ca2+ channel antagonists partially inhibited the ATP-induced [Ca]in increase, indicating that ATP increases [Ca]in by Ca2+ influx through both P2XR channels and voltage-dependent Ca2+ channels. There was a negative interaction between P2XR- and nicotinic ACh receptor (nAChR)-channels, which depended on the amplitude and direction of current flow through either channel. Current occlusion was observed at Vhs between −70 and −10 mV when the IATP and ACh-induced current (IACh) were inward, but no occlusion was observed when these currents were outward at a Vh of +40 mV. The IATP was not inhibited by co-application of ACh when the IACh was markedly decreased either by removal of permeant cations, by setting Vh close to the equilibrium potential of IACh, or by the addition of d-tubocurarine or serotonin. These results suggest that the inhibitory interaction is attributable to inward current flow of cations through the activated P2XR- and nAChR-channels

It is time to talk about people: a human-centered healthcare system

Examining vulnerabilities within our current healthcare system we propose borrowing two tools from the fields of engineering and design: a) Reason's system approach [1] and b) User-centered design [2,3]. Both approaches are human-centered in that they consider common patterns of human behavior when analyzing systems to identify problems and generate solutions. This paper examines these two human-centered approaches in the context of healthcare. We argue that maintaining a human-centered orientation in clinical care, research, training, and governance is critical to the evolution of an effective and sustainable healthcare system

Phylogenetic and environmental context of a Tournaisian tetrapod fauna

The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods ($\textit{Perittodus apsconditus}$, $\textit{Koilops herma}$, $\textit{Ossirarus kierani}$, $\textit{Diploradus austiumensis}$ and $\textit{Aytonerpeton microps}$) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere.NERC consortium grants NE/J022713/1 (Cambridge), NE/J020729/1 (Leicester), NE/J021067/1 (BGS), NE/J020621/1 (NMS) and NE/J021091/1 (Southampton