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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood–brain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 ± 0.03 for M6G alone to 0.17 ± 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood–brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Nociception evoked prostaglandin (PG) release in the spinal cord considerably contributes to the induction of hyperalgesia and allodynia. To evaluate the relative contribution of cyclooxygenase-1 (COX-1) and COX-2 in this process we assessed the effects of the selective COX-1 inhibitor SC560 and the selective COX-2 inhibitor celecoxib on formalin-evoked nociceptive behaviour and spinal PGE2 release. SC560 (10 and 20 mg/kg) significantly reduced the nociceptive response and completely abolished the formalin-evoked PGE2 raise. In contrast, celecoxib (10 and 20 mg/kg) was ineffective in both regards, i.e. the flinching behaviour was largely unaltered and the formalin-induced PGE2 raise as assessed using microdialysis was only slightly, not significantly reduced. This suggests that the formalin-evoked rapid PG release was primarily caused by COX-1 and was independent of COX-2. Mean free spinal cord concentrations of celecoxib during the formalin assay were 32.0 ± 4.5 nm, thus considerably higher than the reported IC50 for COX-2 (3–7 nm). Therefore, the lack of efficacy of celecoxib is most likely not to be a result of poor tissue distribution. COX-2 mRNA and protein expression in the spinal cord were not affected by microdialysis alone but the mRNA rapidly increased following formalin injection and reached a maximum at 2 h. COX-2 protein was unaltered up to 4 h after formalin injection. The time course of COX-2 up-regulation suggests that the formalin-induced nociceptive response precedes COX-2 protein de novo synthesis and may therefore be unresponsive to COX-2 inhibition. Considering the results obtained with the formalin model it may be hypothesized that the efficacy of celecoxib in early injury evoked pain may be less than that of unselective NSAIDs.
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  • 3
    ISSN: 1365-2486
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering , Geography
    Notes: Temperate forest ecosystems have recently been identified as an important net sink in the global carbon budget. The factors responsible for the strength of the sinks and their permanence, however, are less evident. In this paper, we quantify the present carbon sequestration in Thuringian managed coniferous forests. We quantify the effects of indirect human-induced environmental changes (increasing temperature, increasing atmospheric CO2 concentration and nitrogen fertilization), during the last century using BIOME-BGC, as well as the legacy effect of the current age-class distribution (forest inventories and BIOME-BGC). We focused on coniferous forests because these forests represent a large area of central European forests and detailed forest inventories were available.The model indicates that environmental changes induced an increase in biomass C accumulation for all age classes during the last 20 years (1982–2001). Young and old stands had the highest changes in the biomass C accumulation during this period. During the last century mature stands (older than 80 years) turned from being almost carbon neutral to carbon sinks. In high elevations nitrogen deposition explained most of the increase of net ecosystem production (NEP) of forests. CO2 fertilization was the main factor increasing NEP of forests in the middle and low elevations.According to the model, at present, total biomass C accumulation in coniferous forests of Thuringia was estimated at 1.51 t C ha−1 yr−1 with an averaged annual NEP of 1.42 t C ha−1 yr−1 and total net biome production of 1.03 t C ha−1 yr−1 (accounting for harvest). The annual averaged biomass carbon balance (BCB: biomass accumulation rate-harvest) was 1.12 t C ha−1 yr−1 (not including soil respiration), and was close to BCB from forest inventories (1.15 t C ha−1 yr−1). Indirect human impact resulted in 33% increase in modeled biomass carbon accumulation in coniferous forests in Thuringia during the last century. From the forest inventory data we estimated the legacy effect of the age-class distribution to account for 17% of the inventory-based sink. Isolating the environmental change effects showed that these effects can be large in a long-term, managed conifer forest.
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In Huntington's disease (HD), neuronal loss is most prominent in the striatum leading to emotional, cognitive and progressive motor dysfunction. The R6/2 mice, transgenic for exon 1 of the HD gene, develop a neurological phenotype with similarities to these features of HD. In striatal tissue, electrically evoked release of tritiated acetylcholine (ACh) and dopamine (DA) were compared in wild-type (WT) and R6/2 mice. In R6/2 mice, the evoked release of ACh, its M2 autoreceptor-mediated maximum inhibition and its dopamine D2 heteroreceptor-mediated maximum inhibition was diminished to 51%, 74% and 87% of controls, respectively. Also, the activities of choline acetyltransferase and of synaptosomal high-affinity choline uptake decreased progressively with age in these mice. In the DA release model, however, electrical stimulation elicited equal amounts of [3H]-DA both in WT and R6/2 mice. Moreover, high-affinity DA uptake into striatal slices was similar in WT and R6/2 mice. In order to confirm these findings in vivo, intrastriatal levels of extracellular DA were measured by intracerebral microdialysis in freely moving mice: striatal DA levels were found to be equal in WT and R6/2 mice. In conclusion, in the transgenic R6/2 mice changes occur mainly in striatal cholinergic neurones and their pre-synaptic modulation, but not in the dopaminergic afferent terminals. Whether similar events also contribute to the pathogenesis of HD in humans has to be established.
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    International journal of dermatology 37 (1998), S. 0 
    ISSN: 1365-4632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 31 (1998), S. 820-822 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: Superscrew dislocations are visible in back-reflection synchrotron white-beam X-ray topographs of basal-cut SiC wafers in striking contrast as black rings surrounding white circles, even though such topographs suffer from extensive harmonic contamination. The contributions to the synchrotron white-beam topograph of each member of its series of harmonic reflections, {\bf g}=(0006n), where n=3 to 16, were calculated. Through intensity considerations and comparison with a {\bf g}=00018 topograph taken with Cu Kα1 radiation, the {\bf g}=00024 harmonic was determined to be the most important contributor. The contrast of features lying deep beneath the crystal's surface was attributed to higher harmonics with larger penetration depths.
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  • 7
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 34 (2001), S. 20-26 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: Contrast is associated with micropipes in X-ray topographs of SiC crystals obtained with prismatic reflections, representing an apparent violation of the g·b = 0 invisibility criterion. This is explained as a population of basal-plane dislocations with Burgers vectors of the set b = {\textstyle{1 \over 3}}〈11{\bar{2}}0〉 that occur in a high density within a few micrometers of the micropipes, below the resolution of X-ray topography. These basal-plane dislocations could be observed under an electron microscope. The presence of the surfaces of the micropipes influences the dislocation images in the topographs taken with prismatic reflections, often resulting in a band of light contrast along the axes of the micropipes.
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  • 8
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 55 (1999), S. 272-275 
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: RCC1, the regulator of chromosome condensation, is the guanine nucleotide-exchange factor (GEF) of the GTP-binding protein Ran. Its GEF activity on Ran makes it a key element in nucleo-cytoplasmic transport and cell-cycle regulation. Crystals of human RCC1 suitable for X-ray analysis have been obtained using the seeding technique in hanging drops with sodium citrate as a precipitant. The crystals diffract to 1.7 Å at 100 K and belong to the space group P1, with unit-cell parameters a = 49.5, b = 84.3, c = 84.9 Å, α = 113.0, β = 103.9,γ = 103.3°. The Matthews parameter (Vm) and the self-rotation function are consistent with three molecules in the unit cell, which is confirmed by the averaged single isomorphous replacement (SIR) electron-density map.
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  • 9
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 32 (1999), S. 516-524 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: A kinematic (geometrical) diffraction simulation model has been developed to provide understanding of direct dislocation images on synchrotron white-beam X-ray topographs, and has been successfully applied to illustrate the contrast formation mechanisms involved in images of micropipe-related superscrew dislocations in silicon carbide crystals. The coincidence of the simulations with the contrast features of the superscrew dislocation images, recorded using a series of synchrotron topography techniques, shows that this model is capable of revealing the detailed diffraction behavior of the highly distorted region around the dislocation core and determining the quantitative characteristics of the dislocations. The simulation technique is thus demonstrated to be a simple but efficient method for interpretation of synchrotron topographs, and may be applied to explain the topographic contrast characters of general crystal defects.
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