Assessing depleted uranium (DU) contamination of soil, plants and earthworms at UK weapons testing sites

Depleted uranium (DU) weapons testing programmes have been conducted at two locations within the UK. An investigation was therefore carried out to assess the extent of any environmental contamination arising from these test programmes using both alpha spectrometry and mass spectrometry techniques. Uranium isotopic signatures indicative of DU contamination were observed in soil, plant and earthworm samples collected in the immediate vicinity of test firing points and targets, but contamination was found to be localised to these areas. The paper demonstrates the superiority of the 235U:238U ratio over the 234U:238U ratio for identifying and quantifying DU contamination in environmental samples and also describes the respective circumstances under which alpha spectrometry or mass spectrometry may be the more appropriate analytical tool

Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: A randomized clinical trial

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level. Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months. Conclusions and Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration: ClinicalTrials.gov identifier: NCT01696370

Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era

BACKGROUND: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery. METHODS: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses. RESULTS: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant. CONCLUSION: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors

A high fat breakfast attenuates the suppression of appetite and acylated ghrelin during exercise at simulated altitude.

High-altitude exposure induces a negative energy balance by increasing resting energy expenditure and decreasing energy intake. This diminished energy intake is likely caused by altitude-induced anorexia and can have detrimental effects for those travelling to high-altitude. We aimed to investigate whether altering the macronutrient composition of breakfast could attenuate altitude-induced anorexia and augment energy intake at high-altitude. Twelve healthy men (aged 26 (8) years, body mass index 23.9 (2.7) kg·m(-2)) completed two, 305min experimental trials at 4300m simulated altitude (~11.7% O2). After an overnight fast, participants entered a normobaric hypoxic chamber and rested for one hour, before receiving either a high fat (HF; 60% fat, 25% carbohydrate) or an isocaloric high carbohydrate (HC; 60% carbohydrate, 25% fat) breakfast. One hour after breakfast, participants performed 60min of treadmill walking at 50% of relative V̇O2max. An ad-libitum buffet meal was consumed 1h 30min after exercise. Appetite perceptions, blood samples and substrate oxidation rates were measured throughout. A significantly higher area under the curve for composite appetite score was observed during exercise in HF (40 (12) mm·h(-1)) compared with HC (30 (17) mm·h(-1), P=0.036). During exercise, lower insulin concentrations (P=0.013) and elevated acylated ghrelin concentrations (P=0.048) were observed in HF compared with HC. After exercise there was no significant difference in composite appetite score (P=0.356), acylated ghrelin (P=0.229) or insulin (P=0.513) between conditions. Energy intake at the buffet did not significantly differ between conditions (P=0.384). A HF breakfast attenuated appetite suppression during exercise at 4300m simulated altitude, however ad-libitum energy intake did not increase

A Novel Extracellular Hsp90 Mediated Co-Receptor Function for LRP1 Regulates EphA2 Dependent Glioblastoma Cell Invasion

Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897)). We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling.We find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2(S897), lamellipodia formation, and concomitant GBM cell motility and invasion. Furthermore, eHsp90 promotes the recruitment of LRP1 to EphA2 in an AKT dependent manner. A finding supported by biochemical methodology and the dual expression of LRP1 and P-EphA2(S897) in primary and recurrent GBM tumor specimens. Moreover, hypoxia mediated facilitation of GBM motility and invasion is dependent upon eHsp90-LRP1 signaling. Hypoxia dramatically elevated surface expression of both eHsp90 and LRP1, concomitant with eHsp90 dependent activation of src, AKT, and EphA2.We herein demonstrate a novel crosstalk mechanism involving eHsp90-LRP1 dependent regulation of EphA2 function. We highlight a dual role for eHsp90 in transducing signaling via LRP1, and in facilitating LRP1 co-receptor function for EphA2. Taken together, our results demonstrate activation of the eHsp90-LRP1 signaling axis as an obligate step in the initiation and maintenance of AKT signaling and EphA2 activation, thereby implicating this pathway as an integral component contributing to the aggressive nature of GBM

Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe