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Sensitive System (sensitive + system)
Selected AbstractsInhibition of T-cell activation in vitro in human peripheral blood mononuclear cells by pimecrolimus and glucocorticosteroids and combinations thereofEXPERIMENTAL DERMATOLOGY, Issue 8 2007Anthony Winiski Abstract:, Pimecrolimus is an ascomycin macrolactam derivative that has been recently approved for the topical treatment of atopic dermatitis. In this study we report for the first time on a direct comparison of the inhibitory activity of pimecrolimus and the glucocorticosteroids betamethasone 17-valerate, dexamethasone and hydrocortisone at the level of T-cell proliferation and cytokine production. Stimulated human peripheral blood mononuclear cell (PBMC) systems were used that are either sensitive or resistant to calcineurin inhibitors or glucocorticosteroids. Pimecrolimus and the glucocorticosteroids inhibited dose-dependently T-cell proliferation and cytokine production in a sensitive system (anti-CD3 mAb-stimulated PBMC) with the following rank order of potency: pimecrolimus , betamethasone 17-valerate , dexamethasone > hydrocortisone. In resistant systems (anti-CD3 plus anti-CD28- or Staphylococcal enterotoxin B-stimulated PBMC), pimecrolimus or the glucocorticosteroids alone exerted either no effect, or only a partial inhibitory effect. However, combinations of pimecrolimus with a glucocorticosteroid synergistically and strongly inhibited T-cell proliferation. Taken together, the data indicate that medium potency glucocorticosteroids, such as betamethasone 17-valerate and dexamethasone, are as potent T-cell inhibitors as pimecrolimus. Furthermore, the experimental evidence suggests that combinations of glucocorticosteroids and pimecrolimus could be used clinically to achieve superior therapeutic efficacy, when monotherapy with the individual agents is unsatisfactory. [source] Baseflow and peakflow chemical responses to experimental applications of ammonium sulphate to forested watersheds in north-central West Virginia, USA,HYDROLOGICAL PROCESSES, Issue 12 2002Pamela J. Edwards Abstract Stream water was analysed to determine how induced watershed acidification changed the chemistry of peakflow and baseflow and to compare the relative timing of these changes. Two watersheds in north-central West Virginia, WS3 and WS9, were subjected to three applications of ammonium sulphate fertilizer per year to induce acidification. A third watershed, WS4, was the control. Samples were collected for 8 years from WS9 and for 9 years from WS3. Prior to analyses, concentration data were flow adjusted, and the influence of natural background changes was removed by accounting for the chemical responses measured from WS4. This yielded residual values that were evaluated using robust locally weighted regression and Mann,Kendall tests. On WS3, analyte responses during baseflow and peakflow were similar, although peakflow responses occurred soon after the first treatment whereas baseflow responses lagged 1,2 years. This lag in baseflow responses corresponded well with the mean transit time of baseflow on WS3. Anion adsorption on WS3 apparently delayed increases in SO4 leaching, but resulted in enhanced early leaching losses of Cl and NO3. Leaching of Ca and Mg was strongly tied, both by timing and stoichiometrically, to NO3 and SO4 leaching. F -factors for WS3 baseflow and peakflow indicated that the catchment was insensitive to acid neutralizing capacity reductions both before and during treatment, although NO3 played a large role in reducing the treatment period F -factor. By contrast, the addition of fertilizer to WS9 created an acid sensitive system in both baseflow and peakflow. On WS9, baseflow and peakflow responses also were similar to each other, but there was no time lag after treatment for baseflow. Changes in concentrations generally were not as great on WS9 as on WS3, and several ions showed no significant changes, particularly for peakflow. The lesser response to treatment on WS9 is attributed to the past abusive farming and site preparation before larch planting that resulted in poor soil fertility, erosion, and consequently, physical and chemical similarities between upper and lower soil layers. Even with fertilizer-induced NO3 and SO4 leaching increases, base cations were in low supplies and, therefore, unavailable to leach via charge pairing. The absence of a time lag in treatment responses for WS9 baseflow indicates that it has substantially different flow paths than WS3. The different hydrologies on these nearby watersheds illustrates the importance of understanding watershed hydrology when establishing a monitoring programme to detect ecosystem change. Published in 2002 by John Wiley & Sons, Ltd. [source] Concurrent determination of thalidomide in rat blood, brain and bile using multiple microdialysis coupled to liquid chromatographyBIOMEDICAL CHROMATOGRAPHY, Issue 7 2005Yu-Jen Huang Abstract A rapid and sensitive system of liquid chromatography coupled with microdialysis was developed for the simultaneous determination of unbound thalidomide in rat blood, brain and bile for pharmacokinetic study. Microdialysis probes were concurrently inserted into the jugular vein toward the right atrium, the brain striatum and the bile duct of the anesthetized Sprague,Dawley rats for biological ,uid sampling after the administration of thalidomide (5 mg kg,1) through the femoral vein. Thalidomide and dialysates were separated using a Zorbax ODS C18 column and a mobile phase comprising acetonitrile,methanol,0.1 mm 1-octanesulufonic acid (32:3:65, v/v/v, pH 5.3) at ,ow rate of 1 mL min,1. The UV wavelength was set at 220 nm. The concentration,response relationship was linear (r2 > 0.995) over a concentration range of 0.025,25 µg mL,1. The intra-assay and inter-assay precision and accuracy of thalidomide fell within 7%. The average in vivo recoveries were 0.31 ± 0.02,0.046 ± 0.004 and 0.57 ± 0.02 (n = 6), respective to the dialysates of blood, brain and bile, with thalidomide at concentrations 2, 5 and 10 µg mL,1. The disposition of thalidomide in the blood, brain and bile ,uid suggests that there is a rapid thalidomide exchange and equilibration between the blood and brain systems. In addition, thalidomide undergoes hepatobiliary excretion. Copyright © 2005 John Wiley & Sons, Ltd. [source] A new era for small molecule screening: from new targets, such as JAK2 V617F, to complex cellular screensJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2009Stefan N. ConstantinescuArticle first published online: 21 JAN 200 Traditionally reserved to research and development in pharmaceutical companies, screening of small molecule libraries is rapidly becoming an approach undertaken by academic laboratories. Novel cellular assays, sensitive systems to probe function, emerging new molecular targets are just some of the reasons explaining this shift. Targets of small molecules identified in cellular screens begin to be amenable to identification by elegant genetic approaches, such as probing toxicity of candidate small molecules on libraries of genetically modified yeast strains. Several new targets, such as JAK2 V617F, an activated JAK2 (Janus Kinase 2) mutant genetically associated with the majority of human myeloproliferative neoplasms, are being actively pursued. In this Review Series, we will learn how libraries of small molecules are harnessed to identify novel molecules, that alone or in combination, have the ability to alter cell fate, cell signalling, gene expression or response to extracellular cues. [source] | ||||||||||