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

Data Acquisition and Presentation in Scanning Nuclear Microprobe Analysis

The data acquisition is a very important part of the scanning nuclear microprobe instrument. To make full use of the potential of the technique an adequate system for acquiring, storing, processing and presenting the data is a prerequisite. Various principles applied are presented including the list mode approach, which facilitates flexible off-line data processing. As in the case of the electron probe the beam-induced effects in the sample may be substantial and the list mode acquisition can then also be used to monitor and correct for any such effects. A comprehensive system for scanning nuclear microprobe control and data acquisition, based on a combination of a VMEbus computer system and a μVax-II computer, is described in some detail

Staging laparoscopy for proximal pancreatic cancer in a magnetic resonance imaging-driven practice: what's it worth?

AbstractBackgroundPreoperative imaging is often inadequate in excluding unresectable pancreatic cancer. Accordingly, many groups employ staging laparoscopy (SL), although none have evaluated SL after preoperative magnetic resonance imaging (MRI). We performed a retrospective, indirect cost-effectiveness analysis of SL after MRI for pancreatic head lesions.MethodsAll MRI scans administered for proximal pancreatic cancer between 2004 and 2008 were reviewed and the clinical course of each patient determined. We queried our billing database to render average total costs for all inpatients with proximal pancreatic cancer who underwent pancreaticoduodenectomy, palliative bypass or an endoscopic stenting procedure. We then performed an indirect evaluation of the cost of routine SL.ResultsThe average costs of hospitalization for patients undergoing pancreaticoduodenectomy, open palliative bypass and endoscopic palliation were: US$26122.43, US$21957.18 and US$11304.00, respectively. The calculated cost of SL without laparotomy was US$2966.25 or US$1538.61 prior to laparotomy. The calculated cost of treating unresectable disease by outpatient laparoscopy followed by endoscopy was US$5943.17. Routine SL would increase our costs by US$76967.46 (3.6%).ConclusionsStaging laparoscopy becomes cost-effective by diverting unresectable patients from operative to endoscopic palliation. Given the paucity of missed metastases on MRI, the yield of SL is marginal and its cost-effectiveness is poor. Future studies should address the utility of SL by both examining this issue prospectively and investigating the cost-effectiveness of endoscopic vs. surgical palliation in a manner that takes account of survival and quality of life data

The Quality and Outcomes of Care Provided to Patients with Cirrhosis by Advanced Practice Providers

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153696/1/hep30695.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153696/2/hep30695_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153696/3/hep30695-sup-0001-TableS1-S6.pd

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

Run 2 Upgrades to the CMS Level-1 Calorimeter Trigger

The CMS Level-1 calorimeter trigger is being upgraded in two stages to maintain performance as the LHC increases pile-up and instantaneous luminosity in its second run. In the first stage, improved algorithms including event-by-event pile-up corrections are used. New algorithms for heavy ion running have also been developed. In the second stage, higher granularity inputs and a time-multiplexed approach allow for improved position and energy resolution. Data processing in both stages of the upgrade is performed with new, Xilinx Virtex-7 based AMC cards.Comment: 10 pages, 7 figure

Internal and external cooling methods and their effect on body temperature, thermal perception and dexterity

© 2018 The Authors. Published by PLOS. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1371/journal.pone.0191416© 2018 Maley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity. Methods Ten male participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14C (CV14), evaporative cooling vest (CVEV), arm immersion in 10C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout. Results Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P0.05). Conclusion The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.This project is financially supported by the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Measurement of event shapes in deep inelastic scattering at HERA

Inclusive event-shape variables have been measured in the current region of the Breit frame for neutral current deep inelastic ep scattering using an integrated luminosity of 45.0 pb^-1 collected with the ZEUS detector at HERA. The variables studied included thrust, jet broadening and invariant jet mass. The kinematic range covered was 10 < Q^2 < 20,480 GeV^2 and 6.10^-4 < x < 0.6, where Q^2 is the virtuality of the exchanged boson and x is the Bjorken variable. The Q dependence of the shape variables has been used in conjunction with NLO perturbative calculations and the Dokshitzer-Webber non-perturbative corrections (`power corrections') to investigate the validity of this approach.Comment: 7+25 pages, 6 figure

Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA

Inclusive photoproduction of D*+- mesons has been measured for photon-proton centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of 37 pb^-1. Total and differential cross sections as functions of the D* transverse momentum and pseudorapidity are presented in restricted kinematical regions and the data are compared with next-to-leading order (NLO) perturbative QCD calculations using the "massive charm" and "massless charm" schemes. The measured cross sections are generally above the NLO calculations, in particular in the forward (proton) direction. The large data sample also allows the study of dijet production associated with charm. A significant resolved as well as a direct photon component contribute to the cross section. Leading order QCD Monte Carlo calculations indicate that the resolved contribution arises from a significant charm component in the photon. A massive charm NLO parton level calculation yields lower cross sections compared to the measured results in a kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure