2,188 research outputs found

    Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss

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    AbstractThe mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss

    The influence of perfusion solution on renal graft viability assessment

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    BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

    ROSAT X-ray sources in the field of the LMC I.Total LMC gas from the background AGN spectral fits

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    We analyzed a sample of 26 background X-ray sources in a ~60 square degree field of the Large Magellanic Cloud observed with the ROSAT PSPC. The sample has been selected from previously classified and optically identified X-ray sources. In addition pointlike and spectrally hard sources with at least 100 to 200 observed counts have been used for the analysis. We performed X-ray spectral fitting and derived total hydrogen absorbing column densities due to LMC gas in the range 10^20 - 2. 10^21 cm^-2. We compared these columns with the HI columns derived from a 21-cm Parkes survey of the LMC. For 7 optically identified sources we find, within the uncertainties derived from the X-ray spectral fit, agreement for both columns. For further 19 sources we constrain the LMC columns from the X-ray spectral fit assuming that the powerlaw photon index is that of AGN type spectra. We derive for 20 sources gas columns which are within the uncertainties in agreement with the HI columns. We derive for two background sources (RX J0536.9-6913 and RX J0547.0-7040) hydrogen absorbing column densities due to LMC gas, which are in excess to the HI columns. These sources - located in regions of large (~3. 10^21 cm^-2) LMC HI column densities - could be seen through additional gas which may be warm and diffuse, cold or molecular. For 10 sources we derive upper limits for the gas columns additional to HI and constrain the molecular mass fraction to <(30-140)%.Comment: Accepted by A&

    The axial ratio of hcp iron at the conditions of the Earth's inner core

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    We present ab initio calculations of the high-temperature axial c/a ratio of hexagonal-close-packed (hcp) iron at Earth's core pressures, in order to help interpret the observed seismic anisotropy of the inner core. The calculations are based on density functional theory, which is known to predict the properties of high-pressure iron with good accuracy. The temperature dependence of c/a is determined by minimising the Helmholtz free energy at fixed volume and temperature, with thermal contributions due to lattice vibrations calculated using harmonic theory. Anharmonic corrections to the harmonic predictions are estimated from calculations of the thermal average stress obtained from ab initio molecular dynamics simulations of hcp iron at the conditions of the inner core. We find a very gradual increase of axial ratio with temperature. This increase is much smaller than found in earlier calculations, but is in reasonable agreement with recent high-pressure, high-temperature diffraction measurements. This result casts doubt on an earlier interpretation of the seismic anisotropy of the inner core

    Rapid inference of antibiotic resistance and susceptibility by genomic neighbour typing

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    Genomic neighbour typing can be used to infer the antimicrobial susceptibility and resistance of a bacterial sample based on the genomes of closest relatives. Combined with MinION sequencing, it can rapidly determine microbial resistance for clinical samples within 4 h. Surveillance of drug-resistant bacteria is essential for healthcare providers to deliver effective empirical antibiotic therapy. However, traditional molecular epidemiology does not typically occur on a timescale that could affect patient treatment and outcomes. Here, we present a method called 'genomic neighbour typing' for inferring the phenotype of a bacterial sample by identifying its closest relatives in a database of genomes with metadata. We show that this technique can infer antibiotic susceptibility and resistance for both Streptococcus pneumoniae and Neisseria gonorrhoeae. We implemented this with rapid k-mer matching, which, when used on Oxford Nanopore MinION data, can run in real time. This resulted in the determination of resistance within 10 min (91% sensitivity and 100% specificity for S. pneumoniae and 81% sensitivity and 100% specificity for N. gonorrhoeae from isolates with a representative database) of starting sequencing, and within 4 h of sample collection (75% sensitivity and 100% specificity for S. pneumoniae) for clinical metagenomic sputum samples. This flexible approach has wide application for pathogen surveillance and may be used to greatly accelerate appropriate empirical antibiotic treatment

    Electron energy loss and induced photon emission in photonic crystals

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    The interaction of a fast electron with a photonic crystal is investigated by solving the Maxwell equations exactly for the external field provided by the electron in the presence of the crystal. The energy loss is obtained from the retarding force exerted on the electron by the induced electric field. The features of the energy loss spectra are shown to be related to the photonic band structure of the crystal. Two different regimes are discussed: for small lattice constants aa relative to the wavelength of the associated electron excitations λ\lambda, an effective medium theory can be used to describe the material; however, for a∌λa\sim\lambda the photonic band structure plays an important role. Special attention is paid to the frequency gap regions in the latter case.Comment: 12 pages, 7 figure

    Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats.

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    Reduced glomerular filtration, hypertension and renal microvascular injury are hallmarks of chronic kidney disease, which has a global prevalence of ~10%. We have shown previously that the Fischer (F344) rat has lower GFR than the Lewis rat, and is more susceptible to renal injury induced by hypertension. In the early stages this injury is limited to the pre-glomerular vasculature. We hypothesized that poor renal hemodynamic function and vulnerability to vascular injury are causally linked and genetically determined. In the present study, normotensive F344 rats had a blunted pressure diuresis relationship, compared with Lewis rats. A kidney microarray was then interrogated using the Endeavour enrichment tool to rank candidate genes for impaired blood pressure control. Two novel candidate genes, P2rx7 and P2rx4, were identified, having a 7- and 3- fold increased expression in F344 rats. Immunohistochemistry localized P2X4 and P2X7 receptor expression to the endothelium of the pre-glomerular vasculature. Expression of both receptors was also found in the renal tubule; however there was no difference in expression profile between strains. Brilliant Blue G (BBG), a relatively selective P2X7 antagonist suitable for use in vivo, was administered to both rat strains. In Lewis rats, BBG had no effect on blood pressure, but increased renal vascular resistance, consistent with inhibition of some basal vasodilatory tone. In F344 rats BBG caused a significant reduction in blood pressure and a decrease in renal vascular resistance, suggesting that P2X7 receptor activation may enhance vasoconstrictor tone in this rat strain. BBG also reduced the pressure diuresis threshold in F344 rats, but did not alter its slope. These preliminary findings suggest a physiological and potential pathophysiological role for P2X7 in controlling renal and/or systemic vascular function, which could in turn affect susceptibility to hypertension-related kidney damage

    Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke.

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    Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; &lt;4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation
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