Properties of Cyclic-Nucleotide Gated Channels Mediating Olfactory Transduction - Activation, Selectivity, and Blockage

Cyclic nucleotide-gated channels (cng channels) in the sensory membrane of olfactory receptor cells, activated after the odorant-induced increase of cytosolic cAMP concentration, conduct the receptor current that elicits electrical excitation of the receptor neurons. We investigated properties of cng channels from frog and rat using inside-out and outside-out membrane patches excised from isolated olfactory receptor cells. Channels were activated by cAMP and cGMP with activation constants of 2.5-4.0-mu-M for cAMP and 1.0-1.8 for cGMP. Hill coefficients of dose-response curves were 1.4-1.8, indicating cooperativity of ligand binding. Selectivity for monovalent alkali cations and the Na/Li mole-fraction behavior identified the channel as a nonselective cation channel, having a cation-binding site of high field strength in the pore. Cytosolic pH effects suggest the presence of an additional titratable group which, when protonated, inhibits the cAMP-induced current with an apparent pK of 5.0-5.2. The pH effects were not voltage dependent. Several blockers of Ca2+ channels also blocked olfactory cng channels. Amiloride, D 600, and diltiazem inhibited the cAMP-induced current from the cytosolic side. Inhibition constants were voltage dependent with values of, respectively, 0.1, 0.3, and 1 mM at - 60 mV, and 0.03, 0.02, and 0.2 mM at + 60 mV. Our results suggest functional similarity between frog and rat cng channels, as well as marked differences to cng channels from photoreceptors and other tissues

Comparison of Allen Carr's Easyway programme with a specialist behavioural and pharmacological smoking cessation support service: a randomized controlled trial.

BACKGROUND AND AIMS: A combination of behavioural and pharmacological support is judged to be the optimal approach for assisting smoking cessation. Allen Carr's Easyway (ACE) is a single-session pharmacotherapy-free programme that has been in operation internationally for 38 years. We compared the effectiveness of ACE with specialist behavioural and pharmacological support delivered to the national standard in England. DESIGN: A two-arm, parallel-group, single-blind, randomized controlled trial. SETTING: London, UK, between February 2017 and May 2018. PARTICIPANTS: A total of 620 participants (310 in ACE and 310 in the combined behavioural and pharmacological support condition) were included in the analysis. Adult (≥ 18 years) smokers wanting to quit were randomized in a 1 : 1 ratio. Mean age for the total sample was 40.8 years, with 53.4% being male. Participant baseline characteristics (ethnicity, educational level, number of previous quit attempts, nicotine dependence) were evenly balanced between treatment groups. INTERVENTION AND COMPARATOR: The intervention was the ACE method of stopping smoking. This centres on a 4.5-6-hour session of group-based support, alongside subsequent text messages and top-up sessions if needed. It aims to make it easy to stop smoking by convincing smokers that smoking provides no benefits for them. The comparator was a specialist stop smoking service (SSS) providing behavioural and pharmacological support in accordance with national standards. MEASUREMENTS: The primary outcome was self-reported continuous abstinence for 26 weeks from the quit/quit re-set date verified by exhaled breath carbon monoxide measurement < 10 parts per million (p.p.m.). Primary analysis was by intention to treat. Secondary outcomes were: use of pharmacotherapy, adverse events and continuous abstinence up to 4 and 12 weeks. FINDINGS: A total of 468 participants attended treatment (255 ACE versus 213 SSS, P < 0.05). Of those who did attend treatment, 100 completed 6-month measures (23.7% ACE versus 20.7% SSS). Continuous abstinence to 26 weeks was 19.4% (60 of 310) in the ACE intervention and 14.8% (46 of 310) in the SSS intervention [risk difference for ACE versus SSS 4.5% (95% confidence interval (CI) = -1.4 to 10.4%, odds ratio (OR) = 1.38)]. The Bayes factor for superiority of the ACE condition was 1.24. CONCLUSION: There was no clear evidence of a difference in the efficacies of the Allen Carr's Easyway (ACE) and specialist smoking cessation support involving behavioural support and pharmacotherapy

Study protocol for a randomised controlled trial of Allen Carr's Easyway programme versus Lambeth and Southwark NHS for smoking cessation.

INTRODUCTION: Smoking is a major cause of ill health and is associated with several diseases including cancer, coronary heart disease and stroke. Many psychological and pharmacological smoking cessation treatments are available and although they are undoubtedly the most cost-effective health interventions available, many people still fail to maintain cessation in the longer term. Recently, National Institute for Health and Care Excellence called for comparative studies to determine the short-term and long-term effectiveness of Allen Carr's Easyway (ACE) method of stopping smoking. This study will compare the efficacy of the ACE programme and a 1-1 counselling service available via the National Health Service. METHODS AND ANALYSIS: A two-arm, parallel-group, blinded, randomised controlled trial will be conducted with people who smoke tobacco cigarettes, are aged ≥18 years and are motivated to quit. Exclusion criteria comprise self-reported mental health condition, pregnancy or respiratory disease such as chronic obstructive pulmonary disease or emphysema. The primary treatment outcome is smoking cessation 26 weeks after treatment. Participants will be analysed on an intention to treat basis at the point of randomisation. Before being randomised, the research team will not inform participants which two treatments are being compared. Once randomised researchers will be blinded to participant condition, and participants will be blinded to the condition they are not assigned to. Logistic regression will be used to estimate the effectiveness of the treatment condition on smoking cessation at 26 weeks. The following covariates will be included: baseline quit efficacy (at inclusion), age (at inclusion), gender and baseline nicotine dependency. ETHICS AND DISSEMINATION: Approval was granted by London-Fulham Research Ethics Committee (ref: 16/LO/1657). The study's findings will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier number: NCT02855255. ISRCTN registration number: ISRCTN23584477; Pre-results

Diagnostic performance of the specific uptake size index for semi-quantitative analysis of I-123-FP-CIT SPECT: harmonized multi-center research setting versus typical clinical single-camera setting

Introduction: The specific uptake size index (SUSI) of striatal FP-CIT uptake is independent of spatial resolution in the SPECT image, in contrast to the specific binding ratio (SBR). This suggests that the SUSI is particularly appropriate for multi-site/multi-camera settings in which camera-specific effects increase inter-subject variability of spatial resolution. However, the SUSI is sensitive to inter-subject variability of striatum size. Furthermore, it might be more sensitive to errors of the estimate of non-displaceable FP-CIT binding. This study compared SUSI and SBR in the multi-site/multi-camera (MULTI) setting of a prospective multi-center study and in a mono-site/mono-camera (MONO) setting representative of clinical routine. Methods: The MULTI setting included patients with Parkinson’s disease (PD, n = 438) and healthy controls (n = 207) from the Parkinson Progression Marker Initiative. The MONO setting included 122 patients from routine clinical patient care in whom FP-CIT SPECT had been performed with the same double-head SPECT system according to the same acquisition and reconstruction protocol. Patients were categorized as “neurodegenerative” (n = 84) or “non-neurodegenerative” (n = 38) based on follow-up data. FP-CIT SPECTs were stereotactically normalized to MNI space. SUSI and SBR were computed for caudate, putamen, and whole striatum using unilateral ROIs predefined in MNI space. SUSI analysis was repeated in native patient space in the MONO setting. The area (AUC) under the ROC curve for identification of PD/“neurodegenerative” cases was used as performance measure. Results: In both settings, the highest AUC was achieved by the putamen (minimum over both hemispheres), independent of the semi-quantitative method (SUSI or SBR). The putaminal SUSI provided slightly better performance with ROI analysis in MNI space compared to patient space (AUC = 0.969 vs. 0.961, p = 0.129). The SUSI (computed in MNI space) performed slightly better than the SBR in the MULTI setting (AUC = 0.993 vs. 0.991, p = 0. 207) and slightly worse in the MONO setting (AUC = 0.969 vs. AUC = 0.976, p = 0.259). There was a trend toward larger AUC difference between SUSI and SBR in the MULTI setting compared to the MONO setting (p = 0.073). Variability of voxel intensity in the reference region was larger in misclassified cases compared to correctly classified cases for both SUSI and SBR (MULTI setting: p = 0.007 and p = 0.012, respectively). Conclusions: The SUSI is particularly useful in MULTI settings. SPECT images should be stereotactically normalized prior to SUSI analysis. The putaminal SUSI provides better diagnostic performance than the SUSI of the whole striatum. Errors of the estimate of non-displaceable count density in the reference region can cause misclassification by both SUSI and SBR, particularly in borderline cases. These cases might be identified by visual checking FP-CIT uptake in the reference region for particularly high variability

Universal magnetic structure of the half-magnetization phase in Cr-based spinels

Using an elastic neutron scattering technique under a pulsed magnetic field up to 30 T, we determined the magnetic structure in the half-magnetization plateau phase in the spinel CdCr$_2$O$_4$. The magnetic structure has a cubic $P4_3$32 symmetry, which is the same as that observed in HgCr$_2$O$_4$. This suggests that there is a universal field induced spin-lattice coupling mechanism at work in the Cr-based spinels.Comment: 4 pages, 4 figure

Re-entrant hidden order at a metamagnetic quantum critical end point

Magnetization measurements of URu2Si2 in pulsed magnetic fields of 44 T reveal that the hidden order phase is destroyed before appearing in the form of a re-entrant phase between ~ 36 and 39 T. Evidence for conventional itinerant electron metamagnetism at higher temperatures suggests that the re-entrant phase is created in the vicinity of a quantum critical end point.Comment: 8 pages, including 3 figures (Physical Review Letters, in press) a systematic error in the field calibration has been fixed since the original submission of this manuscrip

From interacting particle systems to random matrices

In this contribution we consider stochastic growth models in the Kardar-Parisi-Zhang universality class in 1+1 dimension. We discuss the large time distribution and processes and their dependence on the class on initial condition. This means that the scaling exponents do not uniquely determine the large time surface statistics, but one has to further divide into subclasses. Some of the fluctuation laws were first discovered in random matrix models. Moreover, the limit process for curved limit shape turned out to show up in a dynamical version of hermitian random matrices, but this analogy does not extend to the case of symmetric matrices. Therefore the connections between growth models and random matrices is only partial.Comment: 18 pages, 8 figures; Contribution to StatPhys24 special issue; minor corrections in scaling of section 2.

E1gE_{1g} model of superconducting UPt3_3

The phase diagram of superconducting UPt$_3$ is explained in a Ginzburg-Landau theory starting from the hypothesis that the order parameter is a pseudo-spin singlet which transforms according to the $E_{1g}$ representation of the $D_{6h}$ point group. We show how to compute the positions of the phase boundaries both when the applied field is in the basal plane and when it is along the c-axis. The experimental phase diagrams as determined by longitudinal sound velocity data can be fit using a single set of parameters. In particular the crossing of the upper critical field curves for the two field directions and the apparent isotropy of the phase diagram are reproduced. The former is a result of the magnetic properties of UPt$_3$ and their contribution to the free energy in the superconducting state. The latter is a consequence of an approximate particle-hole symmetry. Finally we extend the theory to finite pressure and show that, in contrast to other models, the $E_{1g}$ model explains the observed pressure dependence of the phase boundaries.Comment: RevTex, 29 pages, 18 PostScript figures in a uuencoded, gzipped tar file. PostScript version of paper, tar file of PostScript figures and individual PostScript figures are also available via anonymous ftp at ftp://nym.physics.wisc.edu/anonymou/papers/upt3