Dopamine D_2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism

Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits (α4β2*) functionally interact with G-protein-coupled dopamine (DA) D_2 receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9'Ala) rendering 4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D_2-receptor agonist. When challenged with the D_(2)R agonist, quinpirole (0.5–10 mg/kg), Leu9'Ala mice, but not wild-type (WT) littermates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole-induced DA depletion did not differ between Leu9'Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c-Fos expression in choline acetyltransferase (ChAT)-positive interneurons. Highlighting the importance of the cholinergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson’s disease, and the data suggest that a D_(2)R–α4*-nAChR functional interaction regulates cholinergic interneuron activity.—Zhao-Shea, R., Cohen, B. N., Just, H., McClure-Begley, T., Whiteaker, P., Grady, S. R., Salminen, O., Gardner, P. D., Lester, H. A., Tapper, A. R. Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic-dependent mechanism

Review article: the diagnostic approach and current management of chylous ascites

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138889/1/apt14284.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138889/2/apt14284_am.pd

Demonstration of FPGA acceleration of Monte Carlo simulation

We present results from a stand-alone simulation of electron single Coulomb scattering as implemented completely on an Field Programmable Gate Array (FPGA) architecture and compared with an identical simulation on a standard CPU. FPGA architectures offer unprecedented speed-up capability for Monte Carlo simulations, however with the caveats of lengthy development cycles and resource limitation, particularly in terms of on-chip memory and DSP blocks. As a proof of principle of acceleration on an FPGA, we chose a single scattering process of electrons in water at an energy of 6 MeV. The initial code-base was implemented in C++ and optimised for CPU processing. To measure the potential performance gains of FPGAs compared to modern multi-core CPUs we computed 100M histories of a 6 MeV electron interacting in water. Without performing any hardware-specific optimisation, the results show that the FPGA implementation is over 110 times faster than an optimised parallel implementation running on 12 CPU-cores, and over 270 times faster than a sequential single-core CPU implementation. The results on both architectures were statistically equivalent. The successful implementation and acceleration results are very encouraging for the future exploitation of more sophisticated Monte Carlo simulation on FPGAs for High Energy Physics applications

A feasibility randomised controlled trial of a motivational interviewing-based intervention for weight loss maintenance in adults

Background Obesity has significant health and NHS cost implications. Relatively small reductions in weight have clinically important benefits, but long-term weight loss maintenance (WLM) is challenging. Behaviour change interventions have been identified as key for WLM. Motivation is crucial to supporting behaviour change, and motivational interviewing (MI) has been identified as a successful approach to changing health behaviours. The study was designed as an adequately powered, pragmatic randomised controlled trial (RCT); however, owing to recruitment issues, the study became a feasibility trial. Objectives To assess recruitment, retention, feasibility, acceptability, compliance and delivery of a 12-month intervention to support WLM. Secondary objectives were to assess the impact of the intervention on body mass index (BMI) and other secondary outcomes. Design Three-arm individually randomised controlled trial comprising an intensive arm, a less intensive arm and a control arm. Setting Community setting in South Wales and the East Midlands. Participants Individuals aged 18�70 years with a current or previous BMI of ??30 kg/m2 who could provide evidence of at least 5% weight loss during the previous 12 months. Intervention Participants received individually tailored MI, which included planning and self-monitoring. The intensive arm received six face-to-face sessions followed by nine telephone sessions. The less intensive arm received two face-to-face sessions followed by two telephone sessions. The control arm received a leaflet advising them on healthy lifestyle. Main outcome measures Feasibility outcomes included numbers recruited, retention and adherence. The primary effectiveness outcome was BMI at 12 months post randomisation. Secondary outcomes included waist circumference, waist-to-hip ratio, physical activity, proportion maintaining weight loss, diet, quality of life, health service resource usage, binge eating and well-being. A process evaluation assessed intervention delivery, adherence, and participants� and practitioners� views. Economic analysis aimed to assess cost-effectiveness in terms of quality-adjusted life-years (QALYs). Results A total of 170 participants were randomised. Retention was good (84%) and adherence was excellent (intensive, 83%; less intensive, 91%). The between-group difference in mean BMI indicated the intensive arm had BMIs 1.0?kg/m2 lower than the controls [95% confidence interval (CI) �2.2 kg/m2 to 0.2?kg/m2]. Similarly, a potential difference was found in weight (average difference of 2.8?kg, 95% CI �6.1 kg to 0.5?kg). The intensive arm had odds of maintaining on average 43% [odds ratio(OR) 1.4, 95% CI 0.6 to 3.5] higher than controls. None of these findings were statistically significant. Further analyses controlling for level of adherence indicated that average BMI was 1.2?kg/m2 lower in the intensive arm than the control arm (95% CI �2.5?kg/m2 to 0.0?kg/m2). The intensive intervention led to a statistically significant difference in weight (mean �3.7?kg, 95% CI �7.1?kg to �0.3?kg). The other secondary outcomes showed limited evidence of differences between groups. The intervention was delivered as planned, and both practitioners and participants were positive about the intervention and its impact. Although not powered to assess cost-effectiveness, results of this feasibility study suggest that neither intervention as currently delivered is likely to be cost-effective in routine practice. Conclusion This is the first trial of an intervention for WLM in the UK, the intervention is feasible and acceptable, and retention and adherence were high. The main effectiveness outcome showed a promising mean difference in the intensive arm. Owing to the small sample size, we are limited in the conclusions we can draw. However, findings suggest that the intensive intervention may facilitate long-term weight maintenance and, therefore, further testing in an effectiveness trial may be indicated. Research examining WLM is in its infancy, further research is needed to develop our understanding of WLM and to expand theory to inform the development of interventions to be tested in rigorously designed RCTs with cost-effectiveness assessed

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

L1 track finding for a time multiplexed trigger

At the HL-LHC, proton bunches will cross each other every 25. ns, producing an average of 140 pp-collisions per bunch crossing. To operate in such an environment, the CMS experiment will need a L1 hardware trigger able to identify interesting events within a latency of 12.5. μs. The future L1 trigger will make use also of data coming from the silicon tracker to control the trigger rate. The architecture that will be used in future to process tracker data is still under discussion. One interesting proposal makes use of the Time Multiplexed Trigger concept, already implemented in the CMS calorimeter trigger for the Phase I trigger upgrade. The proposed track finding algorithm is based on the Hough Transform method. The algorithm has been tested using simulated pp-collision data. Results show a very good tracking efficiency. The algorithm will be demonstrated in hardware in the coming months using the MP7, which is a μTCA board with a powerful FPGA capable of handling data rates approaching 1. Tb/s.This project has received funding from the European Union׳s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 317446

Projections of the healthcare costs and disease burden due to hepatitis C infection under different treatment policies in Malaysia, 2018-2040

The World Health Organisation (WHO) has set ambitious goals to reduce the global disease burden associated with, and eventually eliminate, viral hepatitis

The design, construction and performance of the MICE scintillating fibre trackers

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2011 ElsevierCharged-particle tracking in the international Muon Ionisation Cooling Experiment (MICE) will be performed using two solenoidal spectrometers, each instrumented with a tracking detector based on diameter scintillating fibres. The design and construction of the trackers is described along with the quality-assurance procedures, photon-detection system, readout electronics, reconstruction and simulation software and the data-acquisition system. Finally, the performance of the MICE tracker, determined using cosmic rays, is presented.This work was supported by the Science and Technology Facilities Council under grant numbers PP/E003214/1, PP/E000479/1, PP/E000509/1, PP/E000444/1, and through SLAs with STFC-supported laboratories. This work was also supportedby the Fermi National Accelerator Laboratory, which is operated by the Fermi Research Alliance, under contract No. DE-AC02-76CH03000 with the U.S. Department of Energy, and by the U.S. National Science Foundation under grants PHY-0301737,PHY-0521313, PHY-0758173 and PHY-0630052. The authors also acknowledge the support of the World Premier International Research Center Initiative (WPI Initiative), MEXT, Japan

VISTA Milky Way public survey

We propose a public IR variability survey, named \Vista Variables in the Vía Láctea" (V V V ), of the Milky Way bulge and an adjacent section of the mid-plane where star formation activity is high. This would take 1920 hours, covering ~ 109 point sources within an area of 520 sq deg, including 33 known globular clusters and ~ 350 open clusters. The final products will be a deep IR atlas in 5 passbands and a catalogue of ~ 106 variable point sources. These will produce a 3-D map of the surveyed region (unlike single-epoch surveys that only give 2-D maps) using well-understood primary distance indicators such as RR Lyrae stars. It will yield important information on the ages of the populations. The observations will be combined with data from MACHO, OGLE, EROS, VST, SPITZER, HST, CHANDRA, INTEGRAL, and ALMA for a complete understanding of the variable sources in the inner Milky Way. Several important implications for the history of the Milky Way, for globular cluster evolution, for the population census of the bulge and center, and for pulsation theory would follow from this survey