Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

Implementation fidelity of a self-management course for epilepsy: method and assessment.

BACKGROUND: Complex interventions such as self-management courses are difficult to evaluate due to the many interacting components. The way complex interventions are delivered can influence the effect they have for patients, and can impact the interpretation of outcomes of clinical trials. Implementation fidelity evaluates whether complex interventions are delivered according to protocol. Such assessments have been used for one-to-one psychological interventions; however, the science is still developing for group interventions. METHODS: We developed and tested an instrument to measure implementation fidelity of a two-day self-management course for people with epilepsy, SMILE(UK). Using audio recordings, we looked at adherence and competence of course facilitators. Adherence was assessed by checklists. Competence was measured by scoring group interaction, an overall impression score and facilitator "didacticism". To measure "didacticism", we developed a novel way to calculate facilitator speech using computer software. Using this new instrument, implementation fidelity of SMILE(UK) was assessed on three modules of the course, for 28% of all courses delivered. RESULTS: Using the instrument for adherence, scores from two independent raters showed substantial agreement with weighted Kappa of 0.67 and high percent agreement of 81.2%. For didacticism, the results from both raters were highly correlated with an intraclass coefficient of 0.97 (p < 0.0001). We found that the courses were delivered with a good level of adherence (> 50% of scored items received the maximum of 2 points) and high competence. Groups were interactive (mean score: 1.9-2.0 out of 2) and the overall impression was on average assessed as "good". Didacticism varied from 42% to 93% of total module time and was not associated with the other competence scores. CONCLUSION: The instrument devised to measure implementation fidelity was reproducible and easy to use. The courses for the SMILE(UK) study were delivered with a good level of adherence to protocol while not compromising facilitator competence. TRIAL REGISTRATION: ISRCTN57937389 .

A disease, disorder, illness or condition: How to label epilepsy?

The International League Against Epilepsy (ILAE) is an important source of guidance for health professionals when it comes to epilepsy. Their latest recommendation that epilepsy should no longer be called a "disorder," but a "disease" has though caused controversy. The ILAE contends the change will improve epilepsy's image. Some clinicians and other organizations fear the change may not though be accepted by patients as in common parlance "disease" can be associated with "contagiousness"/"infection." To allow practicing clinicians to make informed judgements about what language they use, we completed the first study to assess the preferences of those with epilepsy and significant others and explore if any of their characteristics were associated with preference. Via epilepsy interest groups and associations in England, Wales, Scotland and the Republic of Ireland, 971 patients and significant others were surveyed. Participants identified which of four labels for epilepsy ("disorder," "illness," "disease," "condition") they favoured and rated each using a Likert-scale. Patients' median age was 39; 69% had experienced seizures in the prior year. "Condition" was favoured by most patients (74.3%) and significant others (71.2%). Only 2.2% of patients and 1.2% of significant others chose "disease"; it received a median Likert-rating indicating "strongly dislike." Multinomial logistic regression found it was not possible to reliably distinguish between participants favouring the different terms on the basis of demographics. The ILAE's position is at odds with what most patients and carers want and we discuss the implications of this.

Which outcomes should we measure in adult epilepsy trials? The views of people with epilepsy and informal carers.

OBJECTIVE: So that informed treatment decisions can be made, clinical trials need to evaluate treatments against domains that are important to people with epilepsy (PWE), their carers, and clinicians. Health professionals have identified domains of importance to them via the International League Against Epilepsy's Commission on Outcome Measurement (COME). However, patients and carers have not been systematically asked. METHODS: Via the membership of the British Epilepsy Association, we recruited and surveyed 352 PWE and 263 of their informal carers. They were presented with 10 outcome domains (including the 5 identified by COME) and asked to rate their importance using a 9-point Likert scale. They were also asked to identify any additional domains of importance. RESULTS: The patients' mean age was 49years, the median number of years since diagnosis was 20, and 65% had experienced seizures in the prior 12months. Most carers were the spouse or parent. Patients' and carers' mean ratings indicated that their outcome priorities were similar, as were those of patients who had and had not experienced recent seizures. There was consensus among patients that 6 domains were of critical importance. These included the 5 identified by COME (namely, and in order of importance, the effects of the treatment on "Seizure severity", "Seizure frequency", "Quality of life", "Cognitive function", and "Adverse events"), as well as one additional domain ("Independence/need for support"). There was consensus among carers that the 5 COME domains were also critically important. They, however, identified 3 further domains as critically important. These were the effects of the treatment on patient "Depression", "Anxiety", and "Independence/need for support". CONCLUSIONS: Our study found some overlap between the priorities of PWE, carers, and health professionals. They, however, highlight additional areas of importance to patients and carers. Our results could inform a core outcome set for epilepsy that represents the domains that should be reported as a minimum by all trials. This could promote trials which produce meaningful results and consistency in measurement and reporting.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

Simulation of special bubble detectors for PICASSO.

The PICASSO project is a cold dark matter (CDM) search experiment relying on the superheated droplet technique. The detectors use superheated freon liquid droplets (active material) dispersed and trapped in a polymerised gel. This detection technique is based on the phase transition of superheated droplets at about room temperature and ambient pressure. The phase transition is induced by nuclear recoils when an atomic nucleus in the droplets interacts with incoming subatomic particles. This includes CDM particles candidate as the neutralino (a yet-to-discover particle predicted in extensions of the standard model of particle physics). Simulations performed to understand the detector response to neutrons and alpha particles are presented along with corresponding data obtained at the Montreal Laboratory.

Direct dark matter search using large-mass superheated droplet detectors in the PICASSO experiment.

The PICASSO experiment investigates the presence and nature of dark matter in the Universe. The experiment is based on the detection of acoustic signals generated in explosive phase transitions induced by dark matter particles. This technique is an alternative more traditional detection technique like scintillation and ionisation, which are largely employed for dark matter search. One of the main advantages of this technique, besides its sensitivity to very low nuclear recoil energies (few keV), is its excellent background suppression features. A pilot experiment consisting of six superheated droplet detectors (40 g of active mass) is presently taking data at the Sudbury Neutrino Observatory (SNO) at a depth of 2000 m. We discuss the operation, calibration and data acquisition of the experiment and also the ongoing work to increase the sensitivity and the active mass of the detectors.

Are "Theory of Mind" Skills in People with Epilepsy Related to How Stigmatised They Feel? An Exploratory Study.

Feelings of stigma are one of the main burdens reported by people with epilepsy (PWE). Adults with temporal or frontal lobe epilepsy and children with idiopathic generalised epilepsy are at risk of Theory of Mind (ToM) deficits. ToM refers to social cognitive skills, including the ability to understand the thoughts, intentions, beliefs, and emotions of others. It has been proffered that ToM deficits may contribute to the feelings of stigma experienced by PWE. In this study we tested this for the first time. We also determined the association between clinical and demographic factors and ToM performance. Five hundred and three PWE were recruited via epilepsy organisations and completed measures online. Feelings of stigma were measured using Jacoby's Stigma Scale, whilst the Reading the Mind in the Eyes Test and the Faux Pas Test measured ToM. The median age of participants was 37 years, their median years living with epilepsy were 15, and 70% had experienced seizures in the prior 12 months. Feelings of stigma held a negligible, negative, and nonsignificant association with ToM performance (r s -0.02 and -0.05). Our results indicate that the ToM model for understanding epilepsy stigma has limited utility and alternative approaches to understanding and addressing epilepsy-related stigma are required.

A pilot study of cognitive behavioural therapy and relaxation for migraine headache: a randomised controlled trial.

Headache is being viewed more commonly in a biopsychosocial framework, which introduces the possible utilisation of psychological treatment options, such as cognitive behavioural therapy and relaxation. No such treatments have been trialled in the UK. We conducted a randomised controlled pilot trial, comparing a brief guided self-help CBT and relaxation treatment with standard medical care (SMC), in a UK NHS setting. Participants were recruited from specialist headache clinics across London. Participants were randomised to receive either treatment or standard medical care. Our objective was to provide design information necessary for a future definitive trial of the SHE treatment, including, recruitment/retention rates, acceptability of randomisation, treatment fidelity and estimations of mean and variances of outcome measures. From the initial 275 patients identified, 73 were randomised. There was no difference in drop-out rates between SMC and treatment groups. Of the 36 participants randomised to receive treatment, 72% attended all sessions. Findings show that a future definitive trial of the SHE treatment is feasible, with small modifications of protocol, within a UK NHS context.

'Seizure First Aid Training' for people with epilepsy who attend emergency departments, and their family and friends: study protocol for intervention development and a pilot randomised controlled trial.

INTRODUCTION: People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. METHODS AND ANALYSIS: To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12 months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12 months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12 months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the intervention's effect on the outcome measures. ETHICS AND DISSEMINATION: Ethical approval: NRES Committee North West-Liverpool East (Reference number 15/NW/0225). The project's findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ISRCTN13 871 327.

Benz[f]isoquinoline analogues as high-affinity sigma ligands.

This paper describes the synthesis of some conformationally restricted 4-phenylpiperidine analogues and their affinities for the guinea pig cerebellum sigma recognition site ([3H]-DTG) and the rat striatum dopamine D2 receptor ([3H]-(-)-sulpiride) in order to develop potent selective sigma ligands as tools in the investigation of this site in psychosis. It was found that both hexa- and octahydrobenz[f]isoquinolines with lipophilic N-substituents had high affinities for the sigma site. Notably, trans-3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline (26) had an affinity of 0.25 nM making it the highest affinity sigma ligand reported to date. Moreover, it is at least 10,000-fold selective over the D2 receptor and could prove to be a valuable tool in the study of sigma sites. Other analogues such as 1H-indeno[2,1-c]pyridines and 1H-benzo[3,4]cyclohepta[1,2-c]pyridines also displayed high sigma site affinity.

The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor.

1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a-adrenoceptor or native alpha 1A-adrenoceptor. Since it has previously been shown that the receptor is not the alpha 1B- or alpha 1D-adrenoceptor, the functional alpha 1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the alpha 1-adrenoceptors currently defined by pharmacological means.

The effects of tamsulosin, a high affinity antagonist at functional alpha 1A- and alpha 1D-adrenoceptor subtypes.

1. The actions of the alpha 1-adrenoceptor antagonist tamsulosin have been examined at functional alpha 1-adrenoceptor subtypes and compared with those at the human prostate receptor. 2. At the alpha 1D-adrenoceptors of the rat aorta, tamsulosin acted as a competitive antagonist with a high affinity (pKB = 10.1). 3. At the alpha 1B-adrenoceptor of the rat spleen and rabbit corpus cavernosum penis, tamsulosin again acted as a competitive antagonist but with a significantly lower affinity (pKB = 8.9-9.2). 4. Tamsulosin acted as an unsurmountable antagonist of the alpha 1A-adrenoceptor-mediated responses of the rat and human vas deferens, reducing maximal responses to phenylephrine by 20% and 50%, respectively, at an antagonist concentration of 1 nM. Responses of depolarized (100 mM KCl) rat vas deferens preparations were unaffected by 10 nM tamsulosin but this concentration reduced maximal responses to 5-hydroxytryptamine (5-HT) in this tissue. 5. When longer antagonist incubation periods (> or = 60 min) were used, tamsulosin behaved as a competitive antagonist on the human prostate with a significantly higher affinity (pKB = 10.0) than obtained at the alpha 1B-adrenoceptor. 6. The data demonstrate that tamsulosin is a high affinity antagonist at functional alpha 1-adrenoceptors with a selectivity alpha 1D > or = alpha 1A > alpha 1B. In some tissues the compound exhibits an additional unsurmountable antagonist action, the clinical significance of which is unknown.

Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype.

Degenerate primers, suitable for polymerase chain reaction studies and based on the conserved structure of G protein-coupled receptors, were used to isolate cDNA clones encoding putative G protein-coupled receptors from a human hippocampal cDNA library. One clone isolated by this approach (AC1) encoded a putative receptor with 39% amino acid sequence identity to the serotonin 5HT1A receptor and 47% identity to the 5HT1D receptor. When expressed transiently in the human embryonic kidney cell line 293, AC1 cDNA-encoded receptor displayed high affinity (Kd = 15 nM) and saturability for [3H]serotonin, suggesting that AC1 encodes a 5HT1-like receptor. However, 5-carboxamidotryptamine demonstrated low affinity (pKi = 5.15) compared with serotonin (pKi = 8.14), consistent with the observed binding of the putative 5HT1E receptor. The excellent correlation observed between the pharmacology of the expressed receptor encoded by AC1 and the human brain 5HT1E binding site confirms that AC1 encodes a 5HT1E receptor and establishes a fifth 5HT1-like receptor subtype.