The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Beyond Control-Flow: Extending Business Process Configuration to Roles and Objects

A configurable process model is an integrated representation of multiple variants of a business process. It is designed to be individualized to meet a particular set of requirements. As such, configurable process models promote systematic reuse of proven or common practices. Existing notations for configurable process modeling focus on capturing tasks and control-flow dependencies, neglecting equally important aspects of business processes such as data flow, material flow and resource management. This paper fills this gap by proposing an integrated meta-model for configurable processes with advanced features for capturing resources involved in the performance of tasks (through task-role associations) as well as flow of data and physical artifacts (through task-object associations). Although embodied as an extension of a popular process modeling notation, namely EPC, the meta-model is defined in an abstract and formal manner to make it applicable to other notations

Gestational age at delivery and special educational need: retrospective cohort study of 407,503 schoolchildren

<STRONG>Background</STRONG> Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation. <STRONG>Methods and Findings</STRONG> We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37–39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12–1.20; 33–36 wk adjusted OR 1.53, 95% CI 1.43–1.63; 28–32 wk adjusted OR 2.66, 95% CI 2.38–2.97; 24–27 wk adjusted OR 6.92, 95% CI 5.58–8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37–39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases. <STRONG>Conclusions</STRONG> Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery

The redshift evolution of bias and baryonic matter distribution

We study the distribution of baryonic and luminous matter within the framework of a hierarchical scenario. Using an analytical model for structure formation which has already been checked against observations for galaxies, Lyman-$\alpha$ clouds, clusters and reionization processes, we present its predictions for the bias of these objects. We describe its dependence on the luminosity (for galaxies or quasars) or the column density (for Lyman-$\alpha$ absorbers) of the considered objects. We also study its redshift evolution, which can exhibit an intricate behaviour. These astrophysical objects do not trace the dark matter density field, the Lyman-$\alpha$ forest clouds being undercorrelated and the bright galaxies overcorrelated, while the intermediate class of Lyman-limit systems is seen to sample the matter field quite well. We also present the distribution of baryonic matter over these various objects. We show that light does not trace baryonic mass, since bright galaxies which contain most of the stars only form a small fraction of the mass associated with virialized and cooled halos. We consider two cosmologies: a critical density universe and an open universe. In both cases, our results agree with observations and show that hierarchical scenarios provide a good model for structure formation and can describe a wide range of objects which spans at least the seven orders of magnitude in mass for which data exist. More detailed observations, in particular of the clustering evolution of galaxies, will constrain the astrophysical models involved.Comment: 13 pages, final version published in A&

Constraints on the Formation of the Galactic Bulge from Na, Al, and Heavy Element Abundances in Plaut's Field

We report chemical abundances of Na, Al, Zr, La, Nd, and Eu for 39 red giant branch (RGB) stars and 23 potential inner disk red clump stars located in Plaut-s low extinction window. We also measure lithium for a super Li-rich RGB star. The abundances were determined by spectrum synthesis of high resolution (R~25,000), high signal-to-noise (S/N~50-100 pixel-1) spectra obtained with the Blanco 4m telescope and Hydra multifiber spectrograph. For the bulge RGB stars, we find a general increase in the [Na/Fe] and [Na/Al] ratios with increasing metallicity, and a similar decrease in [La/Fe] and [Nd/Fe]. Additionally, the [Al/Fe] and [Eu/Fe] abundance trends almost identically follow those of the {\alpha}-elements, and the [Zr/Fe] ratios exhibit relatively little change with [Fe/H]. The consistently low [La/Eu] ratios of the RGB stars indicate that at least a majority of bulge stars formed rapidly (<1 Gyr) and before the main s-process could become a significant pollution source. In contrast, we find that the potential inner disk clump stars exhibit abundance patterns more similar to those of the thin and thick disks. Comparisons between the abundance trends at different bulge locations suggest that the inner and outer bulge formed on similar timescales. However, we find evidence of some abundance differences between the most metal-poor and metal-rich stars in various bulge fields. The data also indicate that the halo may have had a more significant impact on the outer bulge initial composition than the inner bulge composition. The [Na/Fe] and to a lesser extent [La/Fe] abundances further indicate that the metal-poor bulge, at least at ~1 kpc from the Galactic center, and thick disk may not share an identical chemistry.Comment: Accepted for publication in ApJ; 66 pages, 17 figures, 3 tables; prior to publication, data tables in electronic form will be made available upon reques

Mergers of multi-metallic globular clusters: The role of dynamics

Hubble Space Telescope observations of globular clusters (GCs) in the Antennae galaxy show clusters of clusters, or regions in the galaxy that span hundreds of parsecs, where many of the GCs are doomed to collide, and eventually merge. Several such objects appear likely to present a significant range in ages, hence possibly metallicities, and their merger could plausibly lead to multi-metallic GCs. Here we explore this process with direct-summation N-body simulations with GPU hardware. Our results reveal that colliding GCs with different metallicities and ages can produce a GC with multiplicity and occupation fractions not unlike those observed in multi-metallic clusters. In our simulations, the merged clusters have a phase with a larger amount of flattening than average, as a consequence of rapid rotation- thus suggesting that relatively recent mergers may play a role in producing highly flattened, multi-metallic clusters. We additionally explore the role of the King parameter of the cluster in the occupation fractions with a set of 160 direct-summation simulations and find that for equal size clusters the King parameter of the progenitor clusters determines the occupation fractions in the merger product, while in unequal size mergers the size of the clusters dominates the distribution of stars in the new GC. In particular, we find that the observed distribution of populations in Omega Cen can be described to some extent with our dynamical models.Comment: Accepted for publication MNRA

Evidence for MBM_B and MCM_C phases in the morphotropic phase boundary region of (1−x)[Pb(Mg1/3Nb2/3)O3]−xPbTiO3(1-x)[Pb(Mg_{1/3}Nb_{2/3})O_3]-xPbTiO_3 : A Rietveld study

We present here the results of the room temperature dielectric constant measurements and Rietveld analysis of the powder x-ray diffraction data on $(1-x)[Pb(Mg_{1/3}Nb_{2/3})O_3]-xPbTiO_3$(PMN-$x$PT) in the composition range $0.20 \leq x \leq 0.45$ to show that the morphotropic phase boundary (MPB) region contains two monoclinic phases with space groups Cm (or $M_B$ type) and Pm (or $M_C$ type) stable in the composition ranges $0.27 \leq x \leq 0.30$ and $0.31 \leq x \leq 0.34$, respectively. The structure of PMN-$x$PT in the composition ranges $0 \leq x \leq$ 0.26, and $0.35 \leq x \leq1$ is found to be rhombohedral (R3m) and tetragonal (P4mm), respectively. These results are compared with the predictions of Vanderbilt & Cohen's theory.Comment: 20 pages, 11 pdf figure

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages

Using interpretative phenomenological analysis to inform physiotherapy practice: An introduction with reference to the lived experience of cerebellar ataxia

The attached file is a pre-published version of the full and final paper which can be found at the link below.This article has been made available through the Brunel Open Access Publishing Fund.Qualitative research methods that focus on the lived experience of people with health conditions are relatively underutilised in physiotherapy research. This article aims to introduce interpretative phenomenological analysis (IPA), a research methodology oriented toward exploring and understanding the experience of a particular phenomenon (e.g., living with spinal cord injury or chronic pain, or being the carer of someone with a particular health condition). Researchers using IPA try to find out how people make sense of their experiences and the meanings they attach to them. The findings from IPA research are highly nuanced and offer a fine grained understanding that can be used to contextualise existing quantitative research, to inform understanding of novel or underresearched topics or, in their own right, to provoke a reappraisal of what is considered known about a specified phenomenon. We advocate IPA as a useful and accessible approach to qualitative research that can be used in the clinical setting to inform physiotherapy practice and the development of services from the perspective of individuals with particular health conditions.This article is available through the Brunel Open Access Publishing Fund