Altered MRP is associated with multidrug resistance and reduced drug accumulation in human SW-1573 cells.

We have analysed the contribution of several parameters, e.g. drug accumulation, MDR1 P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and topoisomerase (topo) II, to drug resistance in a large set of drug-resistant variants of the human non-small-cell lung cancer cell line SW-1573 derived by selection with low concentrations of doxorubicin or vincristine. Selection with either drug nearly always resulted in MDR clones. The resistance of these clones could be explained by reduced drug accumulation and was associated with a decrease rather than an increase in the low MDR1 mRNA level. To test whether a decrease in MDR1 mRNA indirectly affected resistance in these cells, we introduced a MDR1-specific hammerhead ribozyme into wild-type SW-1573 cells. Although this led to a substantial reduction in MDR1 mRNA, it did not result in resistance. In all resistant clones we found an altered form of the multidrug resistance-associated protein (MRP), migrating slightly slower during SDS-polyacrylamide gel electrophoresis than MRP in parental cells. This altered MRP was also present in non-P-gp MDR somatic cell hybrids of the SW-1573 cells, demonstrating a clear linkage with the MDR phenotype. Treatment of crude cellular membrane fractions with N-glycanase, endoglycosidase H or neuraminidase showed that the altered migration of MRP on SDS-PAGE is due to a post-translational modification. There was no detectable difference in sialic acid content. In most but not all doxorubicin-selected clones, this MDR phenotype was accompanied by a reduction in topo II alpha mRNA level. No reduction was found in the clones selected with vincristine. We conclude from these results that selection of the SW-1573 cell line for low levels of doxorubicin or vincristine resistance, predominantly results in MDR with reduced drug accumulation associated with the presence of an altered MRP protein. This mechanism can be accompanied by other resistance mechanisms, such as reduced topo II alpha mRNA in case of doxorubicin selection

Predicting sudden death in patients with mild to moderate chronic heart failure

Objectives: To explore the relation between non-invasive measures of cardiac function and sudden cardiac death, as well as the development and utility of an index integrating these variables to identify patients at increased risk of this mode of death. Design: UK-HEART (United Kingdom-heart failure evaluation and assessment of risk trial) was a prospective study conducted between December 1993 and April 2000. The study was specifically designed to identify non-invasive markers of death and mode of death among patients with chronic heart failure. Setting: 8 UK general hospitals. Main outcome measures: Death and mode of death. Results: 553 patients aged a mean (SD) of 63 (10) years, in New York Heart Association functional class 2.3 (0.02), recruited prospectively. After 2365 patient-years’ follow up, 201 patients had died (67 suddenly). Predictors of sudden death were greater cardiothoracic ratio, QRS dispersion, QT dispersion corrected for rate (QTc) across leads V1–V6 on the 12 lead ECG, and the presence of non-sustained ventricular tachycardia. The hazard ratio and 95% confidence intervals (CI) of sudden death for a 10% increase in cardiothoracic ratio was 1.43 (95% CI 1.20 to 1.71), for a 10% increase in QRS dispersion 1.11 (95% CI 1.04 to 1.19), for the presence of non-sustained ventricular tachycardia 2.03 (95% CI 1.27 to 3.25), and for a 10% increase in QTc dispersion across leads V1–V6 1.03 (95% CI 1.00 to 1.07) (all p < 0.04). An index derived from these four factors performed well in identifying patients specifically at increased risk of sudden death. Conclusions: Results show that an index derived from three widely available non-invasive investigations has the potential to identify ambulant patients with chronic heart failure at increased risk of sudden death. This predictive tool could be used to target more sophisticated investigations or interventions aimed at preventing sudden death

Identification and Selection of Cases and Controls in the Pneumonia Etiology Research for Child Health Project

Methods for the identification and selection of patients (cases) with severe or very severe pneumonia and controls for the Pneumonia Etiology Research for Child Health (PERCH) project were needed. Issues considered include eligibility criteria and sampling strategies, whether to enroll hospital or community controls, whether to exclude controls with upper respiratory tract infection (URTI) or nonsevere pneumonia, and matching criteria, among others. PERCH ultimately decided to enroll community controls and an additional human immunodeficiency virus (HIV)–infected control group at high HIV-prevalence sites matched on age and enrollment date of cases; controls with symptoms of URTI or nonsevere pneumonia will not be excluded. Systematic sampling of cases (when necessary) and random sampling of controls will be implemented. For each issue, we present the options that were considered, the advantages and disadvantages of each, the rationale for the methods selected for PERCH, and remaining implications and limitations

Can an outdoor learning environment improve children’s academic attainment? A quasi-experimental mixed methods study in Bangladesh

The present study adopted a quasi-experimental mixed method approach to investigate the influence of an improved school ground on children’s academic performance. In total, 123 children from two (intervention and control) primary schools in Bangladesh participated. In the intervention school, a barren school ground was redesigned with several behavior settings (e.g., gardens and amphitheater) for teaching and learning. Treatment group children (n = 29) received math and science classes outdoors, while a comparison group (n = 32) received usual indoor classes. A control school with no changes to the outdoor environment was included (n = 62). The redesigned school ground was associated with higher levels of academic attainment. Furthermore, all intervention schoolchildren perceived more opportunities to explore in the redesigned school ground. Qualitative insights suggest the diverse settings provided more opportunities to explore, experiment, and work collaboratively. These results highlight the potential for school ground design to contribute to improvement of children’s academic attainment in developing countries

Closed-loop separation control over a sharp edge ramp using Genetic Programming

We experimentally perform open and closed-loop control of a separating turbulent boundary layer downstream from a sharp edge ramp. The turbulent boundary layer just above the separation point has a Reynolds number $Re_{\theta}\approx 3\,500$ based on momentum thickness. The goal of the control is to mitigate separation and early re-attachment. The forcing employs a spanwise array of active vortex generators. The flow state is monitored with skin-friction sensors downstream of the actuators. The feedback control law is obtained using model-free genetic programming control (GPC) (Gautier et al. 2015). The resulting flow is assessed using the momentum coefficient, pressure distribution and skin friction over the ramp and stereo PIV. The PIV yields vector field statistics, e.g. shear layer growth, the backflow area and vortex region. GPC is benchmarked against the best periodic forcing. While open-loop control achieves separation reduction by locking-on the shedding mode, GPC gives rise to similar benefits by accelerating the shear layer growth. Moreover, GPC uses less actuation energy.Comment: 24 pages, 24 figures, submitted to Experiments in Fluid

A cost effectiveness analysis of salt reduction policies to reduce coronary heart disease in four Eastern Mediterranean countries.

BACKGROUND: Coronary Heart Disease (CHD) is rising in middle income countries. Population based strategies to reduce specific CHD risk factors have an important role to play in reducing overall CHD mortality. Reducing dietary salt consumption is a potentially cost-effective way to reduce CHD events. This paper presents an economic evaluation of population based salt reduction policies in Tunisia, Syria, Palestine and Turkey. METHODS AND FINDINGS: Three policies to reduce dietary salt intake were evaluated: a health promotion campaign, labelling of food packaging and mandatory reformulation of salt content in processed food. These were evaluated separately and in combination. Estimates of the effectiveness of salt reduction on blood pressure were based on a literature review. The reduction in mortality was estimated using the IMPACT CHD model specific to that country. Cumulative population health effects were quantified as life years gained (LYG) over a 10 year time frame. The costs of each policy were estimated using evidence from comparable policies and expert opinion including public sector costs and costs to the food industry. Health care costs associated with CHDs were estimated using standardized unit costs. The total cost of implementing each policy was compared against the current baseline (no policy). All costs were calculated using 2010 PPP exchange rates. In all four countries most policies were cost saving compared with the baseline. The combination of all three policies (reducing salt consumption by 30%) resulted in estimated cost savings of $235,000,000 and 6455 LYG in Tunisia;$39,000,000 and 31674 LYG in Syria; $6,000,000 and 2682 LYG in Palestine and$1,3000,000,000 and 378439 LYG in Turkey. CONCLUSION: Decreasing dietary salt intake will reduce coronary heart disease deaths in the four countries. A comprehensive strategy of health education and food industry actions to label and reduce salt content would save both money and lives

First Results from the AMoRE-Pilot neutrinoless double beta decay experiment

The Advanced Molybdenum-based Rare process Experiment (AMoRE) aims to search for neutrinoless double beta decay (0$\nu\beta\beta$) of $^{100}$Mo with $\sim$100 kg of $^{100}$Mo-enriched molybdenum embedded in cryogenic detectors with a dual heat and light readout. At the current, pilot stage of the AMoRE project we employ six calcium molybdate crystals with a total mass of 1.9 kg, produced from $^{48}$Ca-depleted calcium and $^{100}$Mo-enriched molybdenum ($^{48\textrm{depl}}$Ca$^{100}$MoO$_4$). The simultaneous detection of heat(phonon) and scintillation (photon) signals is realized with high resolution metallic magnetic calorimeter sensors that operate at milli-Kelvin temperatures. This stage of the project is carried out in the Yangyang underground laboratory at a depth of 700 m. We report first results from the AMoRE-Pilot $0\nu\beta\beta$ search with a 111 kg$\cdot$d live exposure of $^{48\textrm{depl}}$Ca$^{100}$MoO$_4$ crystals. No evidence for $0\nu\beta\beta$ decay of $^{100}$Mo is found, and a upper limit is set for the half-life of 0$\nu\beta\beta$ of $^{100}$Mo of $T^{0\nu}_{1/2} > 9.5\times10^{22}$ y at 90% C.L.. This limit corresponds to an effective Majorana neutrino mass limit in the range $\langle m_{\beta\beta}\rangle\le(1.2-2.1)$ eV

GATE : a simulation toolkit for PET and SPECT

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols, and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at the address http://www-lphe.epfl.ch/GATE/

High platelet reactivity in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Randomised controlled trial comparing prasugrel and clopidogrel

Background: Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives: To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients: Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results: At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions: Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit