Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels

The relationship between receptor-induced membrane phosphatidylinositol-4'5'-bisphosphate (PIP2) hydrolysis and M-current inhibition was assessed in single-dissociated rat sympathetic neurons by simultaneous or parallel recording of membrane current and membrane-to-cytosol translocation of the fluorescent PIP2/inositol 1,4,5-trisphosphate (IP3)-binding peptide green fluorescent protein-tagged pleckstrin homology domain of phospholipase C (GFP-PLC delta-PH). The muscarinic receptor agonist oxotremorine-M produced parallel time- and concentration-dependent M-current inhibition and GFP-PLC delta-PH translocation; bradykinin also produced parallel time- dependent inhibition and translocation. Phosphatidylinositol-4-phosphate-5-kinase (PI5-K) overexpression reduced both M-current inhibition and GFP-PLC delta-PH translocation by both oxotremorine-M and bradykinin. These effects were partly reversed by wortmannin, which inhibits phosphatidylinositol-4-kinase (PI4-K). PI5-K overexpression also reduced the inhibitory action of oxotremorine-M on PIP2-gated G-protein-gated inward rectifier (Kir3.1/3.2) channels; bradykinin did not inhibit these channels. Overexpression of neuronal calcium sensor-1 protein (NCS-1), which increases PI4-K activity, did not affect responses to oxotremorine-M but reduced both fluorescence translocation and M-current inhibition by bradykinin. Using an intracellular IP3 membrane fluorescence-displacement assay, initial mean concentrations of membrane [PIP2] were estimated at 261 mu M (95% confidence limit; 192-381 mu M), rising to 693 mu M (417-1153 mu M) in neurons overexpressing PI5-K. Changes in membrane [PIP2] during application of oxotremorine-M were calculated from fluorescence data. The results, taken in conjunction with previous data for KCNQ2/3 (Kv7.2/Kv7.3) channel gating by PIP2 (Zhang et al., 2003), accorded with the hypothesis that the inhibitory action of oxotremorine-M on M current resulted from depletion of PIP2. The effects of bradykinin require additional components of action, which might involve IP3-induced Ca2+ release and consequent M-channel inhibition (as proposed previously) and stimulation of PIP2 synthesis by Ca2+-dependent activation of NCS-1

The ins and outs of participation in a weather information system

In this paper our aim is to show even though access to technology, information or data holds the potential for improved participation, participation is wired into a larger network of actors, artefacts and information practices. We draw on a case study of a weather information system developed and implemented by a non-profit organisation to both describe the configuration of participation, but also critically assess inclusion and exclusion. We present a set of four questions - a basic, practical toolkit - by which we together with the organisation made sense of and evaluated participation in the system

Norovirus infection in primary immune deficiency

Norovirus is acknowledged to be a leading cause of acute gastroenteritis worldwide, and its importance as a cause of chronic infection in immune deficient hosts is increasingly recognised. Current evidence suggests that a coordinated response of innate immune mechanisms, CD8+ cytotoxicity and a humoral response, with CD4+ orchestration, is necessary for norovirus clearance. We explain how primary immune deficiency impairs these host defences and predisposes to chronic infection, associated with protracted diarrhoea, weight loss, and requirement for parenteral nutrition. The mucosal villous atrophy frequently seen in norovirus infection appears to be immune mediated, suggesting that some functional immune response is required in order for chronic norovirus infection to become symptomatic in primary immune deficiency. We provide a comprehensive summary of published cases of norovirus infection in patients with primary immune deficiency. Spontaneous viral clearance has been described; however, the majority of reported cases have had prolonged and severe illness. Treatment strategies are discussed in detail. Approaches that have been tried in patients with primary immune deficiency include exclusion diets, enteral and intravenous immunoglobulins, breast milk, immunosuppressants, ribavirin, and nitazoxanide. To date, only ribavirin has been used with apparent success to achieve clearance of chronic norovirus in primary immune deficiency, and randomised controlled trials are needed to evaluate a number of promising therapies that are discussed

Case Report: Color as a Therapeutic Intervention

Peer reviewedFinal Accepted Versio

Effects on alcohol consumption of announcing and implementing revised UK low-risk drinking guidelines: findings from an interrupted time series analysis

Background: In January 2016, the UK announced and began implementing revised guidelines for low-risk drinking of 14 units (112 g) per week for men and women. This was a reduction from the previous guidelines for men of 3–4 units (24–32 g) per day. There was no large-scale promotion of the revised guidelines beyond the initial media announcement. This paper evaluates the effect of announcing the revised guidelines on alcohol consumption among adults in England. / Methods: Data come from a monthly repeat cross-sectional survey of approximately 1700 adults living in private households in England collected between March 2014 and October 2017. The primary outcomes are change in level and time trend of participants’ Alcohol Use Disorders Identification Test—Consumption (AUDIT-C) scores. / Results: In December 2015, the modelled average AUDIT-C score was 2.719 out of 12 and was decreasing by 0.003 each month. After January 2016, AUDIT-C scores increased immediately but non-significantly to 2.720 (β=0.001, CI −0.079 to 0.099) and the trend changed significantly such that scores subsequently increased by 0.005 each month (β=0.008, CI 0.001 to 0.015), equivalent to 0.5% of the population increasing their AUDIT-C score by 1 point each month. Secondary analyses indicated the change in trend began 7 months before the guideline announcement and that AUDIT-C scores reduced significantly but temporarily for 4 months after the announcement (β=−0.087, CI −0.167 to 0.007). / Conclusions: Announcing new UK drinking guidelines did not lead to a substantial or sustained reduction in drinking or a downturn in the long-term trend in alcohol consumption, but there was evidence of a temporary reduction in consumption

Alcohol devaluation has dissociable effects on distinct components of alcohol behaviour

Rationale: Substance-related behaviour is often viewed as an appetitive behaviour, motivated by the reinforcing effects of the drug. However, there are various indices of substance motivation (e.g. attentional bias, behavioural economic demand, craving) and it is unclear how these are related or whether they play an important role in all types of substance-related behaviour. Objectives: (1) To determine the effect of alcohol devaluation on several indices of alcohol motivation and goal-directed and cue-elicited alcohol behaviour. (2) To investigate which components of motivation mediate any effect of devaluation on behaviour. Methods: Sixty-two social drinkers gave baseline measures of alcohol craving, behavioural economic demand and choice for alcohol vs. soft drink. Participants tasted alcohol which was either unadulterated (control) or adulterated with a bitter solution (devaluation) before craving and demand were measured again. Alcohol choice was assessed in several phases: extinction (evaluating goal-directed behaviour), in the presence of drink cues (Pavlovian-to-instrumental transfer (PIT, cue-elicited behaviour)), and reacquisition. Attentional bias (AB) was measured by tracking eye movements towards the drink cues during novel PIT trials where both cues were presented. Finally, consumption was evaluated in a taste test. Results: Alcohol devaluation reduced alcohol-related demand, AB, alcohol choice in all phases, and consumption. Alcohol cues presented during PIT increased alcohol choice above baseline irrespective of devaluation. AB and demand for alcohol fully mediated the effect of devaluation on alcohol choice during extinction, AB fully mediated the effect on cue-elicited (specific PIT) alcohol choice and alcohol consumption. Conclusions: Alcohol behaviour in social drinkers is largely sensitive to devaluation, i.e. governed by current motivational value of the drug (suggesting goal-directed behaviour). However, a dissociable form of stimulus control can also drive alcohol-seeking independently of drug value (specific PIT). Mediation analyses suggests that AB may play a paradoxical role in both forms of alcohol seeking and consumption

A survey of UK medical schools' arrangements for early patient contact

Background: Many U.K. medical schools have patient contact in the first two years of the undergraduate course. Aim: To compare the purposes and organization of early patient contact in UK medical schools and to relate these arrangements to the schools' curricular objectives. Methods: A telephone survey of lead educators in UK medicals schools. Categories of contact were plotted against phases of the course to discern patterns of organisation. Results: The quantity of contact varies considerably (four to 65 days). There is a pattern, with learning objectives around the social context of health and illness preceding skills based work and integrated clinical knowledge for practice coming later. Schools fall into three categories: close adherence to the preclinical/clinical split, with limited early contact acting as an introduction to social aspects of health; provision of substantial patient contact to maximize the integration of knowledge and skills; and transitional, with limited clinical goals. General practice provides between one third and one half of early patient contact. Conclusions: Arrangements meet the objectives set by each school and reflect differing educational philosophies. Change is toward more early contact. There appears to be no national guidance which supports a minimum quantity of patient contact or specific educational purpose in the early years of U.K. basic medical training