Activation of Wnt/β-Catenin Signalling Affects Differentiation of Cells Arising from the Cerebellar Ventricular Zone

Development of the cerebellum proceeds under the precise spatio-temporal control of several key developmental signalling pathways, including the Wnt/β-catenin pathway. We recently reported the activity of Wnt/β-catenin signalling in the perinatal cerebellar ventricular zone (VZ), a germinal centre in the developing cerebellum that gives rise to GABAergic and glial cells. In order to investigate the normal function of Wnt/β-catenin signalling in the VZ and the cell lineages it gives rise to, we used a combination of ex vivo cerebellar slice culture and in vivo genetic manipulation to dysregulate its activity during late embryonic development. Activation of the pathway at the cerebellar ventricular zone led to a reduction in the number of cells expressing the glial lineage markers Sox9 and GFAP and the interneuron marker Pax2, but had no consistent effect on either proliferation or apoptosis. Our findings suggest that activation of the Wnt/β-catenin pathway in the cerebellar ventricular zone causes a shift in the cell types produced, most likely due to disruption of normal differentiation. Thus, we propose that regulation of Wnt/β-catenin signalling levels are required for normal development of cells arising from the cerebellar ventricular zone during late embryogenesis

Single dose oral dexamethasone versus multi-dose prednisolone in the treatment of acute exacerbations of asthma in children who attend the emergency department: study protocol for a randomized controlled trial.

BACKGROUND: Asthma is a major cause of pediatric morbidity and mortality. In acute exacerbations of asthma, corticosteroids reduce relapses, subsequent hospital admission and the need for ß2-agonist therapy. Prednisolone is relatively short-acting with a half-life of 12 to 36 hours, thereby requiring daily dosing. Prolonged treatment course, vomiting and a bitter taste may reduce patient compliance with prednisolone. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours. It is used frequently in children with croup and bacterial meningitis, and is well absorbed orally. The purpose of this trial is to examine whether a single dose of oral dexamethasone (0.3 mg/kg) is clinically non-inferior to prednisolone (1 mg/kg/day for three days) in the treatment of exacerbations of asthma in children who attend the Emergency Department. METHODS/DESIGN: This is a randomized, non-inferiority, open-label clinical trial. After informed consent with or without assent, patients will be randomized to either oral dexamethasone 0.3 mg/kg stat or prednisolone 1 mg/kg/day for three days. The primary outcome measure is the comparison between the Pediatric Respiratory Assessment Measure (PRAM) across both groups on Day 4. The PRAM score, a validated, responsive and reliable tool to determine asthma severity in children aged 2 to 16 years, will be performed by a clinician blinded to treatment allocation. Secondary outcomes include relapse, hospital admission and requirement for further steroid therapy. Data will be analyzed on an intention-to-treat and a per protocol basis. With a sample size of 232 subjects (105 in each group with an estimated 10% loss to follow-up), we will be able to reject the null hypothesis - that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The Type I error probability associated with this test (of the null hypothesis) is 0.05. DISCUSSION: This clinical trial may provide evidence that a shorter steroid course using dexamethasone can be used in the treatment of acute pediatric asthma, thus eliminating the issue of compliance to treatment. REGISTRATION: ISRCTN26944158 and EudraCT Number 2010-022001-18

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial.

BACKGROUND: Children with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain. METHODS/DESIGN: This study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05. DISCUSSION: This clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20

Reliability Based Factors of Safety for VIV Fatigue Using NDP Riser High Mode VIV Tests

Understanding the level of conservatism in a riser system design for vortex-induced vibration (VIV) fatigue is an important issue for operators. This study represents a demonstration of the calibration methodology to derive consistent values for the Factor of Safety (FoS). The exercise is performed here based on medium scale VIV data and utilizing the most commonly used VIV prediction software by industry. The results emphasize the need for (i) a coherent approach to estimate the FoS to be used and (ii) monitoring/measurement of software improvements as this may increase risk of failure if the influence of such improvements on the FoS is not quantified.DeepStar (Consortium) (DeepStar Phase IX

Using Model Test Data to Assess VIV Factor of Safety for SCR and TTR in GOM

This paper presents results obtained as part of the DeepStar Phase 10 program on VIV Factors of Safety. The objective was to develop a general methodology to calibrate Factors of Safety for VIV-induced fatigue and to apply it to partially straked risers. This was achieved using reliability methods, accepted industry VIV prediction software and state-of-the-art model test experiments. Most oil companies use a Factor of Safety of 20 when predicting VIV damage using VIV software tools. There are numerous software tools currently in use in industry to predict VIV damage to straked risers and each of them will have different accuracy, and therefore an intrinsic level of conservatism. Understanding the level of conservatism in different VIV prediction software is therefore critical to determining what Factor of Safety to use. This study benchmarks the latest generation of industry accepted VIV design tools at the time of the study (2011): SHEAR7v4.6, VIVAv6.5 and VIVANAv3.7.24 against high quality VIV data from three separate straked riser experiments. A bias distribution (predicted to measured VIV damage results) is obtained for each software tool as a function of the strake coverage. A novel reliability framework approach is then developed to incorporate all uncertainties associated with VIV fatigue prediction into a limit state function, including variability in met-ocean conditions and variability in the fatigue resistance of the material characterized by a design S-N curve. The limit state function is analyzed using First Order Reliability Methods to develop Factors of Safety for target probabilities of failure. The general method is then applied on two case studies involving an SCR and TTR in Gulf of Mexico loop currents, but it can be easily extended to different locations and riser configurations. The resulting FoS range from about 1 to 15 for most software, and are lower than industry standards for VIV prediction. The FoS do not vary markedly for different riser configurations, indicating the possibility of reducing excess conservatism when predicting VIV damage on straked risers.DeepStar (Consortium)SHEAR7 JI

Scaling of magnetic fluctuations near a quantum phase transition

We use inelastic neutron scattering to measure the magnetic fluctuations in a single crystal of the heavy fermion alloy CeCu_5.9Au_0.1 close to the antiferromagnetic quantum critical point. The energy and temperature-dependent spectra obey (E/T) scaling at Q near (1,0,0). The neutron data and earlier bulk susceptibility are consistent with the form 1/X ~ f(Q)+(-iE+bT)^a, with an anomalous exponent a=0.8. We confirm the earlier observation of quasi-low dimensionality and show how both the magnetic fluctuations and the thermodynamics can be understood in terms of a quantum Lifshitz point.Comment: Latex file with two postscript figure

Tracing chemical evolution over the extent of the Milky Way's Disk with APOGEE Red Clump Stars

We employ the first two years of data from the near-infrared, high-resolution SDSS-III/APOGEE spectroscopic survey to investigate the distribution of metallicity and alpha-element abundances of stars over a large part of the Milky Way disk. Using a sample of ~10,000 kinematically-unbiased red-clump stars with ~5% distance accuracy as tracers, the [alpha/Fe] vs. [Fe/H] distribution of this sample exhibits a bimodality in [alpha/Fe] at intermediate metallicities, -0.9<[Fe/H]<-0.2, but at higher metallicities ([Fe/H]=+0.2) the two sequences smoothly merge. We investigate the effects of the APOGEE selection function and volume filling fraction and find that these have little qualitative impact on the alpha-element abundance patterns. The described abundance pattern is found throughout the range 5<R<11 kpc and 0<|Z|<2 kpc across the Galaxy. The [alpha/Fe] trend of the high-alpha sequence is surprisingly constant throughout the Galaxy, with little variation from region to region (~10%). Using simple galactic chemical evolution models we derive an average star formation efficiency (SFE) in the high-alpha sequence of ~4.5E-10 1/yr, which is quite close to the nearly-constant value found in molecular-gas-dominated regions of nearby spirals. This result suggests that the early evolution of the Milky Way disk was characterized by stars that shared a similar star formation history and were formed in a well-mixed, turbulent, and molecular-dominated ISM with a gas consumption timescale (1/SFE) of ~2 Gyr. Finally, while the two alpha-element sequences in the inner Galaxy can be explained by a single chemical evolutionary track this cannot hold in the outer Galaxy, requiring instead a mix of two or more populations with distinct enrichment histories.Comment: 18 pages, 17 figures. Accepted for publication in Ap

Recommendations of the LHC Dark Matter Working Group: Comparing LHC searches for dark matter mediators in visible and invisible decay channels and calculations of the thermal relic density

Weakly-coupled TeV-scale particles may mediate the interactions between normal matter and dark matter. If so, the LHC would produce dark matter through these mediators, leading to the familiar “mono-X” search signatures, but the mediators would also produce signals without missing momentum via the same vertices involved in their production. This document from the LHC Dark Matter Working Group suggests how to compare searches for these two types of signals in case of vector and axial-vector mediators, based on a workshop that took place on September 19/20, 2016 and subsequent discussions. These suggestions include how to extend the spin-1 mediated simplified models already in widespread use to include lepton couplings. This document also provides analytic calculations of the relic density in the simplified models and reports an issue that arose when ATLAS and CMS first began to use preliminary numerical calculations of the dark matter relic density in these models