The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats.

The hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions but little is known about neurocognitive performance in the presence of ALM. HcrtR antagonists are hypothesized to induce sleep by disfacilitation of wake-promoting systems whereas GABAA receptor modulators such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. To test the hypothesis that less functional impairment results from HcrtR antagonist-induced sleep, we evaluated the performance of rats in the Morris Water Maze in the presence of ALM vs. ZOL. Performance in spatial reference memory (SRM) and spatial working memory (SWM) tasks were assessed during the dark period after equipotent sleep-promoting doses (100 mg/kg, po) following undisturbed and sleep deprivation (SD) conditions. ALM-treated rats were indistinguishable from vehicle (VEH)-treated rats for all SRM performance measures (distance traveled, latency to enter, time within, and number of entries into, the target quadrant) after both the undisturbed and 6 h SD conditions. In contrast, rats administered ZOL showed impairments in all parameters measured compared to VEH or ALM in the undisturbed conditions. Following SD, ZOL-treated rats also showed impairments in all measures. ALM-treated rats were similar to VEH-treated rats for all SWM measures (velocity, time to locate the platform and success rate at finding the platform within 60 s) after both the undisturbed and SD conditions. In contrast, ZOL-treated rats showed impairments in velocity and in the time to locate the platform. Importantly, ZOL rats only completed the task 23-50% of the time while ALM and VEH rats completed the task 79-100% of the time. Thus, following equipotent sleep-promoting doses, ZOL impaired rats in both memory tasks while ALM rats performed at levels comparable to VEH rats. These results are consistent with the hypothesis that less impairment results from HcrtR antagonism than from GABAA-induced inhibition

Assessment of mood in aphasia following stroke: validation of the Dynamic Visual Analogue Mood Scales (D-VAMS)

OBJECTIVES: To validate a non-verbal self-report measure of mood - the Dynamic Visual Analogue Mood Scales (D-VAMS) - against the Hospital Anxiety and Depression Scale (HADS) and assess its suitability as an outcome measure or screening measure for depressed mood following stroke. DESIGN: Cross-sectional observational cohort study. PARTICIPANTS: Forty-six stroke survivors (24% with aphasia) recruited from online, from stroke clubs and via an NHS rehabilitation service. METHODS: A set of seven bipolar scales was developed enabling users to report mood by modifying facial expression images using a slider. Participants completed a tablet/computer task, reporting their mood on these scales mixed randomly with versions which used only words. The HADS was then completed, followed by a repeat run of the two versions in a different, random sequence. RESULTS: Exploratory factor analysis identified one factor consistent with pleasantness of mood accounting for 80% of the variance. Internal consistency of D-VAMS was high ( α = 0.95), and there was a high correlation between face-only D-VAMS scores and HADS total scores ( r = -0.80, P < 0.001), as well as HADS-D/HADS-A subscale scores ( r = -0.73, P < 0.001; r = -0.71, P < 0.001). D-VAMS showed good sensitivity and specificity against HADS, with means of 85%/77% (sensitivity/specificity) against the HADS-D and 80%/77% against the HADS-A across nine cut-offs. CONCLUSION: D-VAMS is a valid and reliable measure likely suitable for assessment of depressed mood in aphasia following stroke. Though D-VAMS performed well as a screening measure in this study sample, further study is needed in the acute stage post-stroke

Optimization of the feeding rate of Anopheles farauti s.s. colony mosquitoes in direct membrane feeding assays

Background: Direct membrane feeding assays (DMFA) are an important tool to study parasite transmission to mosquitoes. Mosquito feeding rates in these artificial systems require optimization, as there are a number of factors that potentially influence the feeding rates and there are no standardized methods that apply to all anopheline species. Methods: A range of parameters prior to and during direct membrane feeding (DMF) were evaluated for their impact on Anopheles farauti sensu stricto feeding rates, including the starving conditions and duration of starving prior to feeding, membrane type, DMF exposure time, mosquito age, feeding in the light versus the dark, blood volume, mosquito density and temperature of water bath. Results: The average successful DMFA feeding rate for An. farauti s.s. colony mosquitoes increased from 50 to 85% when assay parameters were varied. Overnight starvation and Baudruche membrane yielded the highest feeding rates but rates were also affected by blood volume in the feeder and the mosquito density in the feeding cups. Availability of water during the pre-feed starvation period did not significantly impact feeding rates, nor did the exposure duration to blood in membrane feeders, the age of mosquitoes (3, 5 and 7 days post-emergence), feeding in the light versus the dark, or the temperature (34 °C, 38 °C, 42 °C and 46 °C) of the water bath. Conclusion: Optimal feeding conditions in An. farauti s.s. DMFA were to offer 50 female mosquitoes in a cup (with a total surface area of ~ 340 cm2 with 1 mosquito/6.8 cm2) that were starved overnight 350–500 µL of blood (collected in heparin-coated Vacutainer tubes) per feeder in feeders with a surface area ~ 5 cm2 (with a maximum capacity of 1.5 mL of blood) via a Baudruche membrane, for at least 10–20 min

A new high-throughput method for simultaneous detection of drug resistance associated mutations in Plasmodium vivax dhfr, dhps and mdr1 genes

<p>Abstract</p> <p>Background</p> <p>Reports of severe cases and increasing levels of drug resistance highlight the importance of improved <it>Plasmodium vivax </it>case management. Whereas monitoring <it>P. vivax </it>resistance to anti-malarial drug by <it>in vivo </it>and <it>in vitro </it>tests remain challenging, molecular markers of resistance represent a valuable tool for high-scale analysis and surveillance studies. A new high-throughput assay for detecting the most relevant markers related to <it>P. vivax </it>drug resistance was developed and assessed on Papua New Guinea (PNG) patient isolates.</p> <p>Methods</p> <p><it>Pvdhfr, pvdhps </it>and <it>pvmdr1 </it>fragments were amplified by multiplex nested PCR. Then, PCR products were processed through an LDR-FMA (ligase detection reaction - fluorescent microsphere assay). 23 SNPs, including <it>pvdhfr </it>57-58-61 and 173, <it>pvdhps </it>382-383, 553, 647 and <it>pvmdr1 </it>976, were simultaneously screened in 366 PNG <it>P. vivax </it>samples.</p> <p>Results</p> <p>Genotyping was successful in 95.4% of the samples for at least one gene. The coexistence of multiple distinct haplotypes in the parasite population necessitated the introduction of a computer-assisted approach to data analysis. Whereas 73.1% of patients were infected with at least one wild-type genotype at codons 57, 58 and 61 of <it>pvdhfr</it>, a triple mutant genotype was detected in 65.6% of the patients, often associated with the 117T mutation. Only one patient carried the 173L mutation. The mutant 647P <it>pvdhps </it>genotype allele was approaching genetic fixation (99.3%), whereas 35.1% of patients were infected with parasites carrying the <it>pvmdr1 </it>976F mutant allele.</p> <p>Conclusions</p> <p>The LDR-FMA described here allows a discriminant genotyping of resistance alleles in the <it>pvdhfr</it>, <it>pvdhps</it>, and <it>pvmdr1 </it>genes and can be used in large-scale surveillance studies.</p

Differentiating normal and problem gambling: a grounded theory approach.

A previous study (Ricketts &amp; Macaskill, 2003) delineated a theory of problem gambling based on the experiences of treatment seeking male gamblers and allowed predictions to be made regarding the processes that differentiate between normal and problem gamblers. These predictions are the focus of the present study, which also utilised a grounded theory approach, but with a sample of male high frequency normal gamblers. The findings suggest that there are common aspects of gambling associated with arousal and a sense of achievement. The use of gambling to manage negative emotional states differentiated normal and problem gambling. Perceived self-efficacy , emotion management skills and perceived likelihood of winning money back were intervening variables differentiating problem and normal gamblers.</p

Non-perturbative dynamics of hot non-Abelian gauge fields: beyond leading log approximation

Many aspects of high-temperature gauge theories, such as the electroweak baryon number violation rate, color conductivity, and the hard gluon damping rate, have previously been understood only at leading logarithmic order (that is, neglecting effects suppressed only by an inverse logarithm of the gauge coupling). We discuss how to systematically go beyond leading logarithmic order in the analysis of physical quantities. Specifically, we extend to next-to-leading-log order (NLLO) the simple leading-log effective theory due to Bodeker that describes non-perturbative color physics in hot non-Abelian plasmas. A suitable scaling analysis is used to show that no new operators enter the effective theory at next-to-leading-log order. However, a NLLO calculation of the color conductivity is required, and we report the resulting value. Our NLLO result for the color conductivity can be trivially combined with previous numerical work by G. Moore to yield a NLLO result for the hot electroweak baryon number violation rate.Comment: 20 pages, 1 figur

An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the <i>HLA-DRB1</i> locus

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (&gt;700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis

Behavioural activation therapy for depression after stroke (BEADS): a study protocol for a feasibility randomised controlled pilot trial of a psychological intervention for post-stroke depression

Background There is currently insufficient evidence for the clinical and cost-effectiveness of psychological therapies for treating post-stroke depression. Methods/Design BEADS is a parallel group feasibility multicentre randomised controlled trial with nested qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression. We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness. The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic evaluation will be undertaken from the National Health Service and personal social service perspective, with a supplementary analysis from the societal perspective. A value of information analysis will be completed to identify the areas in which future research will be most valuable. Discussion The feasibility outcomes from this trial will provide the data needed to inform the design of a definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural activation for treating post-stroke depression