Functional P2X7 receptors in the auditory nerve of hearing rodents localize exclusively to peripheral glia

P2X7 receptors (P2X7Rs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2X7R-expressing cells in the nervous system remains contentious. Here we examined P2X7R functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomical expression pattern. In whole-cell recordings from rat spiral ganglion cultures, the purinergic agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) activated desensitizing currents in spiral ganglion neurons (SGNs), but non-desensitizing currents in glia that were blocked by P2X7R-specific antagonists. In imaging experiments, BzATP gated sustained Ca2+ entry into glial cells. BzATP-gated uptake of the fluorescent dye YO-PRO-1 was reduced and slowed by P2X7R-specific antagonists. In rats, P2X7Rs were immuno-localized predominantly within satellite glial cells (SGCs) and Schwann cells (SCs). P2X7R expression was not detected in the portion of the auditory nerve within the central nervous system. Mouse models allowed further exploration of the distribution of cochlear P2X7Rs. In GENSAT reporter mice, EGFP expression driven via the P2rx7 promoter was evident in SGCs and SCs but was undetectable in SGNs. A second transgenic model showed a comparable cellular distribution of EGFP-tagged P2X7Rs. In wild-type mice the discrete glial expression was confirmed using a P2X7-specific nanobody construct. Our study shows that P2X7Rs are expressed by peripheral glial cells, rather than by afferent neurons. Description of functional signatures and cellular distributions of these enigmatic proteins in the peripheral nervous system will help our understanding of ATP-dependent effects contributing to hearing loss and other sensory neuropathies.Significance statementP2X7 receptors have been the subject of much scrutiny in recent years. They have been promoted as therapeutic targets in a number of diseases of the nervous system, yet the specific cellular location of these receptors remains the subject of intense debate. In the auditory nerve, connecting the inner ear to the brainstem, we show these multi-modal ATP-gated channels localize exclusively to peripheral glial cells rather than the sensory neurons, and are not evident in central glia. Physiological responses in the peripheral glia display classical hallmarks of P2X7 receptor activation, including the formation of ion-permeable and also macromolecule-permeable pores. These qualities suggest these proteins could contribute to glial-mediated inflammatory processes in the auditory periphery under pathological disease states

Direct electronic measurement of the spin Hall effect

The generation, manipulation and detection of spin-polarized electrons in nanostructures define the main challenges of spin-based electronics[1]. Amongst the different approaches for spin generation and manipulation, spin-orbit coupling, which couples the spin of an electron to its momentum, is attracting considerable interest. In a spin-orbit-coupled system, a nonzero spin-current is predicted in a direction perpendicular to the applied electric field, giving rise to a "spin Hall effect"[2-4]. Consistent with this effect, electrically-induced spin polarization was recently detected by optical techniques at the edges of a semiconductor channel[5] and in two-dimensional electron gases in semiconductor heterostructures[6,7]. Here we report electrical measurements of the spin-Hall effect in a diffusive metallic conductor, using a ferromagnetic electrode in combination with a tunnel barrier to inject a spin-polarized current. In our devices, we observe an induced voltage that results exclusively from the conversion of the injected spin current into charge imbalance through the spin Hall effect. Such a voltage is proportional to the component of the injected spins that is perpendicular to the plane defined by the spin current direction and the voltage probes. These experiments reveal opportunities for efficient spin detection without the need for magnetic materials, which could lead to useful spintronics devices that integrate information processing and data storage.Comment: 5 pages, 4 figures. Accepted for publication in Nature (pending format approval

Topical and Systemic Cannabidiol Improves Trinitrobenzene Sulfonic Acid Colitis in Mice

Background/Aims: Compounds of Cannabis sativa are known to exert anti-inflammatory properties, some of them without inducing psychotropic side effects. Cannabidiol (CBD) is such a side effect-free phytocannabinoid that improves chemically induced colitis in rodents when given intraperitoneally. Here, we tested the possibility whether rectal and oral application of CBD would also ameliorate colonic inflammation, as these routes of application may represent a more appropriate way for delivering drugs in human colitis. Methods: Colitis was induced in CD1 mice by trinitrobenzene sulfonic acid. Individual groups were either treated with CBD intraperitoneally (10 mg/kg), orally (20 mg/kg) or intrarectally (20 mg/kg). Colitis was evaluated by macroscopic scoring, histopathology and the myeloperoxidase (MPO) assay. Results: Intraperitoneal treatment of mice with CBD led to improvement of colonic inflammation. Intrarectal treatment with CBD also led to a significant improvement of disease parameters and to a decrease in MPO activity while oral treatment, using the same dose as per rectum, had no ameliorating effect on colitis. Conclusion: The data of this study indicate that in addition to intraperitoneal application, intrarectal delivery of cannabinoids may represent a useful therapeutic administration route for the treatment of colonic inflammation. Copyright (C) 2012 S. Karger AG, Base

The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

Background: The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives: To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS) in different regions of the rat intestine. Materials and Methods: Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results: EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist) and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist), methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist) there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist) induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions: The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions. Keywords: Electric Stimulation Therapy; Serotonin 5-HT1 Receptor Antagonists; Intestine, Smal

The feasibility of using pedometers and brief advice to increase activity in sedentary older women:a pilot study

Background: People over the age of 70 carry the greatest burden of chronic disease, disability and health care use. Participation in physical activity is crucial for health, and walking accounts for much of the physical activity undertaken by sedentary individuals. Pedometers are a useful motivational tool to encourage increased walking and they are cheap and easy to use. The aim of this pilot study was to evaluate the feasibility of the use of pedometers plus a theory-based intervention to assist sedentary older women to accumulate increasing amounts of physical activity, mainly through walking. Methods: Female participants over the age of 70 were recruited from primary care and randomised to receive either pedometer plus a theory-based intervention or a theory-based intervention alone. The theory-based intervention consisted of motivational techniques, goal-setting, barrier identification and self-monitoring with pedometers and daily diaries. The pedometer group were further randomised to one of three target groups: a 10%, 15% or 20% monthly increase in step count to assess the achievability and acceptability of a range of targets. The primary outcome was change in daily activity levels measured by accelerometry. Secondary outcome measures were lower limb function, health related quality of life, anxiety and depression. Results: 54 participants were recruited into the study, with an average age of 76. There were 9 drop outs, 45 completing the study. All participants in the pedometer group found the pedometers easy to use and there was good compliance with diary keeping (96% in the pedometer group and 83% in the theory-based intervention alone group). There was a strong correlation (0.78) between accelerometry and pedometer step counts i.e. indicating that walking was the main physical activity amongst participants. There was a greater increase in activity (accelerometry) amongst those in the 20% target pedometer group compared to the other groups, although not reaching statistical significance (p = 0.192). Conclusion: We have demonstrated that it is feasible to use pedometers and provide theory-based advice to community dwelling sedentary older women to increase physical activity levels and a larger study is planned to investigate this further.Publisher PDFPeer reviewe

What You Find Depends on How You Measure It: Reactivity of Response Scales Measuring Predecisional Information Distortion in Medical Diagnosis

“Predecisional information distortion” occurs when decision makers evaluate new information in a way that is biased towards their leading option. The phenomenon is well established, as is the method typically used to measure it, termed “stepwise evolution of preference” (SEP). An inadequacy of this method has recently come to the fore: it measures distortion as the total advantage afforded a leading option over its competitor, and therefore it cannot differentiate between distortion to strengthen a leading option (“proleader” distortion) and distortion to weaken a trailing option (“antitrailer” distortion). To address this, recent research introduced new response scales to SEP. We explore whether and how these new response scales might influence the very proleader and antitrailer processes that they were designed to capture (“reactivity”). We used the SEP method with concurrent verbal reporting: fifty family physicians verbalized their thoughts as they evaluated patient symptoms and signs (“cues”) in relation to two competing diagnostic hypotheses. Twenty-five physicians evaluated each cue using the response scale traditional to SEP (a single response scale, returning a single measure of distortion); the other twenty-five did so using the response scales introduced in recent studies (two separate response scales, returning two separate measures of distortion: proleader and antitrailer). We measured proleader and antitrailer processes in verbalizations, and compared verbalizations in the single-scale and separate-scales groups. Response scales did not appear to affect proleader processes: the two groups of physicians were equally likely to bolster their leading diagnosis verbally. Response scales did, however, appear to affect antitrailer processes: the two groups denigrated their trailing diagnosis verbally to differing degrees. Our findings suggest that the response scales used to measure information distortion might influence its constituent processes, limiting their generalizability across and beyond experimental studies

Spin qubits with electrically gated polyoxometalate molecules

Spin qubits offer one of the most promising routes to the implementation of quantum computers. Very recent results in semiconductor quantum dots show that electrically-controlled gating schemes are particularly well-suited for the realization of a universal set of quantum logical gates. Scalability to a larger number of qubits, however, remains an issue for such semiconductor quantum dots. In contrast, a chemical bottom-up approach allows one to produce identical units in which localized spins represent the qubits. Molecular magnetism has produced a wide range of systems with tailored properties, but molecules permitting electrical gating have been lacking. Here we propose to use the polyoxometalate [PMo12O40(VO)2]q-, where two localized spins-1/2 can be coupled through the electrons of the central core. Via electrical manipulation of the molecular redox potential, the charge of the core can be changed. With this setup, two-qubit gates and qubit readout can be implemented.Comment: 9 pages, 6 figures, to appear in Nature Nanotechnolog

Identification of the factors associated with outcomes in a condition management programme

<p>Background: A requirement of the Government’s Pathways to Work (PtW) agenda was to introduce a Condition Management Programme (CMP). The aim of the present study was to identify the differences between those who engaged and made progress in this telephone-based biopsychosocial intervention, in terms of their health, and those who did not and to determine the client and practitioner characteristics and programme elements associated with success in a programme aimed at improving health.</p> <p>Methods: Data were obtained from the CMP electronic spreadsheets and clients paper-based case records. CMP standard practice was that questionnaires were administered during the pre- and post-assessment phases over the telephone. Each client’s record contains their socio-demographic data, their primary health condition, as well as the pre- and post-intervention scores of the health assessment tool administered. Univariate and multivariate statistical analysis was used to investigate the relationships between the database variables. Clients were included in the study if their records were available for analysis from July 2006 to December 2007.</p> <p> Results: On average there were 112 referrals per month, totalling 2016 referrals during the evaluation period. The majority (62.8%) of clients had a mental-health condition. Successful completion of the programme was 28.5% (575 “completers”; 144 “discharges”). Several factors, such as age, health condition, mode of contact, and practitioner characteristics, were significant determinants of participation and completion of the programme. The results showed that completion of the CMP was associated with a better mental-health status, by reducing the number of clients that were either anxious, depressed or both, before undertaking the programme, from 74% to 32.5%.</p> <p>Conclusions: Our findings showed that an individual's characteristics are associated with success in the programme, defined as completing the intervention and demonstrating an improved health status. This study provides some evidence that the systematic evaluation of such programmes and interventions could identify ways in which they could be improved.</p&gt

Loss of p53 results in protracted electrographic seizures and development of an aggravated epileptic phenotype following status epilepticus

The p53 tumor suppressor is a multifunctional protein, which regulates cell cycle, differentiation, DNA repair and apoptosis. Experimental seizures up-regulate p53 in the brain, and acute seizure-induced neuronal death can be reduced by genetic deletion or pharmacologic inhibition of p53. However, few long-term functional consequences of p53 deficiency have been explored. Here, we investigated the development of epilepsy triggered by status epilepticus in wild-type and p53-deficient mice. Analysis of electroencephalogram (EEG) recordings during status epilepticus induced by intra-amygdala kainic acid (KA) showed that seizures lasted significantly longer in p53-deficient mice compared with wild-type animals. Nevertheless, neuronal death in the hippocampal CA3 subfield and the neocortex was significantly reduced at 72 h in p53-deficient mice. Long-term continuous EEG telemetry recordings after status epilepticus determined that the sum duration of spontaneous seizures was significantly longer in p53-deficient compared with wild-type mice. Hippocampal damage and neuropeptide Y distribution at the end of chronic recordings was found to be similar between p53-deficient and wild-type mice. The present study identifies protracted KA-induced electrographic status as a novel outcome of p53 deficiency and shows that the absence of p53 leads to an exacerbated epileptic phenotype. Accordingly, targeting p53 to protect against status epilepticus or related neurologic insults may be offset by deleterious consequences of reduced p53 function during epileptogenesis or in chronic epilepsy