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Subsequent Application (subsequent + application)
Selected AbstractsRepaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetesDIABETIC MEDICINE, Issue 10 2005M. Hollingdal Abstract Aims/hypothesis First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes. Methods We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2,9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses. Results Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA1c did not reach statistical significance (P = 0.07). AUCins,0,12 min during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 ± 6.0 pmol/l/pulse vs. placebo, 31.4 ± 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 ± 2.4 pmol/l/min vs. placebo, 12.6 ± 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment. Conclusion/interpretation Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered. Diabet. Med. (2005) [source] The impact of diazepam's discovery on the treatment and understanding of status epilepticusEPILEPSIA, Issue 9 2009Howard P. Goodkin Summary The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of ,-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a ,2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive , subunit,containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA-mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABAA receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity-dependent, subunit-specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine-sensitive ,2 subunit,containing receptors and the preserved surface expression of the benzodiazepine-insensitive , subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE. [source] A domain decomposition method for modelling Stokes flow in porous materialsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, Issue 11 2002Guangli Liu Abstract An algorithm is presented for solving the Stokes equation in large disordered two-dimensional porous domains. In this work, it is applied to random packings of discs, but the geometry can be essentially arbitrary. The approach includes the subdivision of the domain and a subsequent application of boundary integral equations to the subdomains. This gives a block diagonal matrix with sparse off-block components that arise from shared variables on internal subdomain boundaries. The global problem is solved using a biconjugate gradient routine with preconditioning. Results show that the effectiveness of the preconditioner is strongly affected by the subdomain structure, from which a methodology is proposed for the domain decomposition step. A minimum is observed in the solution time versus subdomain size, which is governed by the time required for preconditioning, the time for vector multiplications in the biconjugate gradient routine, the iterative convergence rate and issues related to memory allocation. The method is demonstrated on various domains including a random 1000-particle domain. The solution can be used for efficient recovery of point velocities, which is discussed in the context of stochastic modelling of solute transport. Copyright © 2002 John Wiley & Sons, Ltd. [source] Reversible translocation of p115-RhoGEF by G12/13 -coupled receptorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2008Bruno H. Meyer Abstract G protein-coupled receptors (GPCRs) are important targets for medicinal agents. Four different G protein families, Gs, Gi, Gq, and G12, engage in their linkage to activation of receptor-specific signal transduction pathways. G12 proteins were more recently studied, and upon activation by GPCRs they mediate activation of RhoGTPase guanine nucleotide exchange factors (RhoGEFs), which in turn activate the small GTPase RhoA. RhoA is involved in many cellular and physiological aspects, and a dysfunction of the G12/13 -Rho pathway can lead to hypertension, cardiovascular diseases, stroke, impaired wound healing and immune cell functions, cancer progression and metastasis, or asthma. In this study, regulator of G protein signaling (RGS) domain-containing RhoGEFs were tagged with enhanced green fluorescent protein (EGFP) to detect their subcellular localization and translocation upon receptor activation. Constitutively active G,12 and G,13 mutants induced redistribution of these RhoGEFs from the cytosol to the plasma membrane. Furthermore, a pronounced and rapid translocation of p115-RhoGEF from the cytosol to the plasma membrane was observed upon activation of several G12/13 -coupled GPCRs in a cell type-independent fashion. Plasma membrane translocation of p115-RhoGEF stimulated by a GPCR agonist could be completely and rapidly reversed by subsequent application of an antagonist for the respective GPCR, that is, p115-RhoGEF relocated back to the cytosol. The translocation of RhoGEF by G12/13 -linked GPCRs can be quantified and therefore used for pharmacological studies of the pathway, and to discover active compounds in a G12/13 -related disease context. J. Cell. Biochem. 104: 1660,1670, 2008. © 2008 Wiley-Liss, Inc. [source] Active learning support vector machines for optimal sample selection in classificationJOURNAL OF CHEMOMETRICS, Issue 6 2004Simeone Zomer Abstract Labelling samples is a procedure that may result in significant delays particularly when dealing with larger datasets and/or when labelling implies prolonged analysis. In such cases a strategy that allows the construction of a reliable classifier on the basis of a minimal sized training set by labelling a minor fraction of samples can be of advantage. Support vector machines (SVMs) are ideal for such an approach because the classifier relies on only a small subset of samples, namely the support vectors, while being independent from the remaining ones that typically form the majority of the dataset. This paper describes a procedure where a SVM classifier is constructed with support vectors systematically retrieved from the pool of unlabelled samples. The procedure is termed ,active' because the algorithm interacts with the samples prior to their labelling rather than waiting passively for the input. The learning behaviour on simulated datasets is analysed and a practical application for the detection of hydrocarbons in soils using mass spectrometry is described. Results on simulations show that the active learning SVM performs optimally on datasets where the classes display an intermediate level of separation. On the real case study the classifier correctly assesses the membership of all samples in the original dataset by requiring for labelling around 14% of the data. Its subsequent application on a second dataset of analogous nature also provides perfect classification without further labelling, giving the same outcome as most classical techniques based on the entirely labelled original dataset. Copyright © 2004 John Wiley & Sons, Ltd. [source] The effect of drought and ultraviolet radiation on growth and stress markers in pea and wheatPLANT CELL & ENVIRONMENT, Issue 12 2001V. Alexieva Abstract It emerged recently that there is an inter-relationship between drought and ultraviolet-B (UV-B) radiation in plant responses, in that both stresses provoke an oxidative burst. The purpose of this investigation was to compare the effects and interaction of drought and UV-B in wheat and pea. The absence of changes in relative leaf water content (RWC) after UV-B treatments indicate that changes in water content were not involved. RWC was the main factor resulting in reduced growth in response to drought. Increases in anthocyanin and phenols were detected after exposure to UV-B. The increases do not appear to be of sufficient magnitude to act as a UV-B screen. UV-B application caused greater membrane damage than drought stress, as assessed by lipid peroxidation as well as osmolyte leakage. An increase in the specific activities of antioxidant enzymes was measured after UV-B alone as well as after application to droughted plants. Proline increased primarily in drought-stressed pea or wheat. Proline may be the drought-induced factor which has a protective role in response to UV-B. The physiological and biochemical parameters measured indicate the UV-B light has stronger stress effectors than drought on the growth of seedlings of both species. The two environmental stresses acted synergistically to induce protective mechanisms in that pre-application of either stress reduced the damage caused by subsequent application of the other stress. [source] A microfluidics approach for the isolation of nucleated red blood cells (NRBCs) from the peripheral blood of pregnant womenPRENATAL DIAGNOSIS, Issue 10 2008R. Huang Abstract Objective Nucleated red blood cells (NRBCs) have been identified in maternal circulation and potentially provide a resource for the monitoring and diagnosis of maternal, fetal, and neonatal health and disease. Past strategies used to isolate and enrich for NRBCs are limited to complex approaches that result in low recovery and less than optimal cell purity. Here we report the development of a high-throughput and highly efficient microfluidic device for isolating rare NRBCs from maternal blood. Material and Methods NRBCs were isolated from the peripheral blood of 58 pregnant women using a microfluidic process that consists of a microfluidic chip for size-based cell separation and a magnetic device for hemoglobin-based cell isolation. Results The microfluidic,magnetic combination removes nontarget red blood cells and white blood cells at a very high efficiency (,99.99%). The device successfully identified NRBCs from the peripheral blood of 58/58 pretermination samples with a mean of 37.44 NRBC/mL (range 0.37,274.36 NRBC/mL). These results were compared with those from previous studies. Conclusion The microfluidic device results in an approximate 10- to 20-fold enrichment of NRBCs over methods described previously. The reliability of isolation and the purity of the NRBC product have the potential to enable the subsequent application of molecular diagnostic assays. Copyright © 2008 John Wiley & Sons, Ltd. [source] A Historical Perspective and Future Outlook on Landscape Scale Restoration in the Northwest Wisconsin Pine BarrensRESTORATION ECOLOGY, Issue 2 2000Volker C. Radeloff Abstract The concurrent discussions of landscape scale restoration among restoration ecologists, and of historic disturbance pattern as a guideline for forest management among forest scientists, offer a unique opportunity for collaboration between these traditionally separated fields. The objective of this study was to review the environmental history, early restoration projects, and current plans to restore landscape patterns at broader scales in the 450,000 ha northwest Wisconsin Pine Barrens. The Pine Barrens offer an example of a landscape shaped by fire in the past. In northwestern Wisconsin historically the barrens were a mosaic of open prairie, savanna, and pine forests on very poor, sandy soils. The surrounding region of better soils was otherwise heavily forested. Six restoration sites have been managed since the middle of this century using prescribed burns to maintain the open, barrens habitat. However, these sites are not extensive enough to mimic the shifting mosaic of large open patches previously created by fire. Extensive clear-cuts may be used as a substitute for these large fire patches so that presettlement landscape patterns are more closely approximated in the current landscape. We suggest that such silvicultural treatments can be suitable to restore certain aspects of presettlement landscapes, such as landscape pattern and open habitat for species such as grassland birds. We are aware that the effects of fire and clear-cuts differ in many aspects and additional management tools, such as prescribed burning after harvesting, may assist in further approximating the effect of natural disturbance. However, the restoration of landscape pattern using clear-cuts may provide an important context for smaller isolated restoration sites even without the subsequent application of fire, in this formerly more open landscape. [source] Catalysts for water,gas shift processing of coal-derived syngases,ASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 4 2010San Shwe Hla Abstract Although the gasification of coal is an efficient means of producing syngas, the carbon content of coal is such that gasification produces significantly higher ratios of carbon oxides to hydrogen than those obtained by the steam reforming of natural gas. The CO:H2 ratio can be adjusted, and more hydrogen produced, by the subsequent application of the water,gas shift (WGS) reaction. This article presents a review of technologies associated with the catalytic WGS reaction in a fixed-bed reactor that might be incorporated into a coal gasification-based system for H2 production with CO2 capture. The main output from this review is the identification of key project areas requiring further research. The performance of existing, commercially available catalysts,designed for use in natural gas reforming processes,with coal-derived syngases is an important aspect of developing technologies for coal-based H2 production. This article presents an experimental assessment of the performance of selected commercially available WGS catalysts, two high-temperature catalysts (HT01 and HT02) and a sour shift catalyst (SS01), with such syngases. For the three commercial catalysts investigated in this study, CO reaction order is found to be in a range of 0.75,1. The effect of changes in H2O concentration over HT01 is insignificant, whereas H2O reaction orders determined using HT02 and SS01 are found to be significantly positive even at high H2O:C ratios. The CO conversion rate is significantly reduced by increasing CO2 concentration, whereas increasing H2 concentration also causes a slight reduction in CO conversion rate for the three commercial catalysts investigated. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd. [source] Multiple P2Y receptor subtypes in the apical membranes of polarized epithelial cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000H L McAlroy Apical ATP, ATP, UTP and UDP evoked transient increases in short circuit current (ISC, a direct measure of transepithelial ion transport) in confluent Caco-2 cells grown on permeable supports. These responses were mediated by a population of at least three pharmacologically distinct receptors. Experiments using cells grown on glass coverslips showed that ATP and UTP consistently increased intracellular free calcium ([Ca2+]i) whilst sensitivity to UDP was variable. Cross desensitization experiments suggested that the responses to UTP and ATP were mediated by a common receptor population. Messenger RNA transcripts corresponding to the P2Y2, P2Y4 and P2Y6 receptors genes were detected in cells grown on Transwell membranes by the reverse transcriptase,polymerase chain reaction. Identical results were obtained for cells grown on glass. Experiments in which ISC and [Ca2+]i were monitored simultaneously in cells on Transwell membranes, confirmed that apical ATP and UTP increased both parameters and showed that the UDP-evoked increase in ISC was accompanied by a [Ca2+]i -signal. Ionomycin consistently increased [Ca2+]i in such polarized cells but caused no discernible change in ISC. However, subsequent application of apical ATP or UTP evoked a small rise in ISC but no rise in [Ca2+]i. UDP evoked no such response. As well as evoking increases in [Ca2+]i, the ATP/UTP-sensitive receptors present in Caco-2 cells thus allow direct control over ion channels in the apical membrane. The UDP-sensitive receptors, however, appear to simply evoke a rise in [Ca2+]i. British Journal of Pharmacology (2000) 131, 1651,1658; doi:10.1038/sj.bjp.0703743 [source] Two-step radiosynthesis of [18F]N -succinimidyl-4-fluorobenzoate ([18F]SFB)JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2009Matthias Glaser Abstract The acylation reagent [18F]N -succinimidyl-4-fluorobenzoate (18F-SFB) has been prepared using a new two-step approach. The starting material p- [18F]fluorobenzaldehyde (18F-FBA) was obtained by an improved radiosynthesis with a decay-corrected radiochemical yield of 66±6 % (n=3). Reaction of 18F-FBA with (diacetoxyiodine)benzene and N -hydroxysuccinimide and preparative HPLC purification furnished 18F-SFB in an r.c.y. of 49±6 % (n=3), based on the starting radioactivity of 18F-FBA. The radiochemical purity of 18F-SFB was >99%. Alternatively, purification by solid phase extraction gave 18F-SFB with an r.c.y. of 77±9% (n=4) and a radiochemical purity of 89±5% (n=4). This radiochemical synthesis only used non-aqueous solvents, which simplifies the method and facilitates subsequent applications of 18F-SFB. Copyright © 2009 John Wiley & Sons, Ltd. [source] A new generation of protein display scaffolds for molecular recognitionPROTEIN SCIENCE, Issue 1 2006Ralf J. Hosse Abstract Engineered antibodies and their fragments are invaluable tools for a vast range of biotechnological and pharmaceutical applications. However, they are facing increasing competition from a new generation of protein display scaffolds, specifically selected for binding virtually any target. Some of them have already entered clinical trials. Most of these nonimmunoglobulin proteins are involved in natural binding events and have amazingly diverse origins, frameworks, and functions, including even intrinsic enzyme activity. In many respects, they are superior over antibody-derived affinity molecules and offer an ever-extending arsenal of tools for, e.g., affinity purification, protein microarray technology, bioimaging, enzyme inhibition, and potential drug delivery. As excellent supporting frameworks for the presentation of polypeptide libraries, they can be subjected to powerful in vitro or in vivo selection and evolution strategies, enabling the isolation of high-affinity binding reagents. This article reviews the generation of these novel binding reagents, describing validated and advanced alternative scaffolds as well as the most recent nonimmunoglobulin libraries. Characteristics of these protein scaffolds in terms of structural stability, tolerance to multiple substitutions, ease of expression, and subsequent applications as specific targeting molecules are discussed. Furthermore, this review shows the close linkage between these novel protein tools and the constantly developing display, selection, and evolution strategies using phage display, ribosome display, mRNA display, cell surface display, or IVC (in vitro compartmentalization). Here, we predict the important role of these novel binding reagents as a toolkit for biotechnological and biomedical applications. [source] | ||||||||||||||||