Cations Affect the Rate of Gating Charge Recovery in Wild-type and W434F Shaker Channels through a Variety of Mechanisms

In this study we examine the effects of ionic conditions on the gating charge movement in the fast inactivation–removed wild-type Shaker channel and its W434F mutant. Our results show that various ionic conditions influence the rate at which gating charge returns during repolarization following a depolarizing pulse. These effects are realized through different mechanisms, which include the regulation of channel closing by occupying the cavity, the modulation of transitions into inactivated states, and effects on transitions between closed states via a direct interaction with the channel's gating charges. In generating these effects the cations act from the different binding sites within the pore. Ionic conditions, in which conducting wild-type channels close at different rates, do not significantly affect the rate of charge recovery upon repolarization. In these conditions, channel closing is fast enough not to be rate-limiting in the charge recovery process. In the permanently P-inactivated mutant channel, however, channel closing becomes the rate-limiting step, presumably due to weakened ion–ion interactions inside the pore and a slower intrinsic rate of gate closure. Thus, variations in closing rate induced by different ions are reflected as variations in the rate of charge recovery. In 115 mM internal Tris+ and external K+, Cs+, or Rb+, low inward permeation of these ions can be observed through the mutant channel. In these instances, channel closing becomes slower than in Tris+O//Tris+I solutions showing resemblance to the wild-type channel, where higher inward ionic fluxes also retard channel closing. Our data indicate that cations regulate the transition into the inactivated states from the external lock-in site and possibly the deep site. The direct action of barium on charge movement is probably exerted from the deep site, but this effect is not very significant for monovalent cations

Barriers and facilitators for health professionals referring Aboriginal and Torres Strait Islander tobacco smokers to the Quitline

Objective: To examine the barriers and facilitators among health professionals to providing referrals to Quitline for Aboriginal and Torres Strait Islander clients who smoke. Methods: A brief online survey, based on the Theoretical Domains Framework, was completed by 34 health professionals who work with Aboriginal and Torres Strait Islander people in South Australia and the Northern Territory. Results: Respondents who frequently made referrals had higher domain scores than less frequent referrers for ‘Skills and knowledge’ (M=4.44 SD=0.39 vs. M=4.09 SD=0.47, p<0.05) and ‘beliefs about capabilities’ (M=4.33 SD=0.44 vs. M=3.88 SD=0.42, p<0.01). Barriers to providing referrals to Quitline were lack of client access to a phone, cost of a phone call, preference for face-to-face interventions, and low client motivation to quit. Conclusions: Health professionals working with Aboriginal and Torres Strait Islander clients should be supported to build their skills and confidence to provide referrals to Quitline and other brief cessation interventions. Building capacity for face-to-face support locally would be beneficial where phone support is not preferable. Implications for public health: Engaging with health professionals who work with Aboriginal and Torres Strait Islander people to increase referrals to Quitline is strategic as it builds on their existing capacity to provide cessation support.Kimberley Martin, Joanne Dono, Nathan Rigney, Joanne Rayner, Alana Sparrow, Caroline Miller, Andrea Mckivett, Kerin O'Dea, David Roder, Jacqueline Bowde

An evaluation of a nurse led unit: an action research study

This study is an exemplar of working in a participatory way with members of the public and health and social care practitioners as co-researchers. A Nurse Consultant Older People working in a nurse-led bed, intermediate care facility in a community hospital acted as joint project lead with an academic researcher. From the outset, members of the public were part of a team of 16 individuals who agreed an evaluation focus and were involved in all stages of the research process from design through to dissemination. An extensive evaluation reflecting all these stakeholders’ preferences was undertaken. Methods included research and audit including: patient and carer satisfaction questionnaire surveys, individual interviews with patients, carers and staff, staff surveys, graffiti board, suggestion box, first impressions questionnaire, patient tracking and a bed census. A key aim of the study has been capacity building of the research team members which has also been evaluated. In terms of impact, the co-researchers have developed research skills and knowledge, grown in confidence, developed in ways that have impacted elsewhere in their lives, developed posters, presented at conferences and gained a better understanding of the NHS. The evaluation itself has provided useful information on the processes and outcomes of intermediate care on the ward which was used to further improve the service

The effect of transmucosal 0.2mg/kg Midazolam premedication on dental anxiety, anaesthetic induction and psychological morbidity in children undergoing general anaesthesia for tooth extraction

&lt;b&gt;Background:&lt;/b&gt; The project aims were to evaluate the benefit of transmucosal Midazolam 0.2mg/kg pre-medication on anxiety, induction behaviour and psychological morbidity in children undergoing general anaesthesia (GA) extractions. &lt;b&gt;Method:&lt;/b&gt; 179 children aged 5-10 years (mean 6.53 years) participated in this randomised, double blind, placebo controlled trial. Ninety children had Midazolam placed in the buccal pouch. Dental anxiety was recorded pre operatively and 48 hours later using a child reported MCDAS-FIS scale. Behaviour at anaesthetic induction was recorded and psychological morbidity was scored by the parent using the Rutter Scale pre-operatively and again one-week later. Subsequent dental attendance was recorded at one, three and six months after GA. &lt;b&gt;Results:&lt;/b&gt; Whilst levels of mental anxiety did not reduce overall, the most anxious patients demonstrated a reduction in anxiety after receiving midazolam premedicationmay (p=0.01). Neither induction behaviour nor psychological morbidity improved. Irrespective of group, parents reported less hyperactive (p= 0.002) and more prosocial behaviour (p=0.002) after the procedure:;, older children improved most (p=0.048), Post GA Dental attendance was poor and unrelated to after the procedure and unaffected by premedication. &lt;b&gt;Conclusion:&lt;/b&gt; 0.2mg/kg buccal Midazolam provided some evidence for reducing anxiety in the most dentally anxious patients. However, induction behaviour, psychological morbidity and subsequent dental attendance were not found to alter between the premedication groups

MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-¿+TNF-a+IL2+) and multi-(IFN-¿+TNF-a+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-¿ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns

The vertical distribution of ozone instantaneous radiative forcing from satellite and chemistry climate models

We evaluate the instantaneous radiative forcing (IRF) of tropospheric ozone predicted by four state-of-the-art global chemistry climate models (AM2-Chem, CAM-Chem, ECHAM5-MOZ, and GISS-PUCCINI) against ozone distribution observed from the NASA Tropospheric Emission Spectrometer (TES) during August 2006. The IRF is computed through the application of an observationally constrained instantaneous radiative forcing kernels (IRFK) to the difference between TES and model-predicted ozone. The IRFK represent the sensitivity of outgoing longwave radiation to the vertical and spatial distribution of ozone under all-sky condition. Through this technique, we find total tropospheric IRF biases from -0.4 to + 0.7 W/m(2) over large regions within the tropics and midlatitudes, due to ozone differences over the region in the lower and middle troposphere, enhanced by persistent bias in the upper troposphere-lower stratospheric region. The zonal mean biases also range from -30 to + 50 mW/m(2) for the models. However, the ensemble mean total tropospheric IRF bias is less than 0.2 W/m(2) within the entire troposphere