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Minimal Effects (minimal + effects)
Selected AbstractsEffects of Cyclosporine on Osteoclast Activity: Inhibition of Calcineurin Activity With Minimal Effects on Bone Resorption and Acid Transport Activity,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2003John P Williams Abstract Cyclosporine results in rapid and profound bone loss in transplant patients, an effect ascribed to osteoclasts. Cyclosporine, complexed with the appropriate immunophilin, inhibits calcineurin (the calcium/calmodulin dependent serine/threonine phosphatase) activity. We tested the hypothesis that cyclosporine inhibits calcineurin activity in osteoclasts, resulting in stimulation of osteoclast activity. We compared the effects of cyclosporine A and the calmodulin antagonist, tamoxifen, on bone resorption by avian osteoclasts. Tamoxifen inhibits bone resorption ,60%, whereas cyclosporine A only inhibited bone resorption 12%. One-hour treatment with 100 nM cyclosporine inhibited osteoclast calcineurin activity 70% in whole cell lysates, whereas 10 ,M tamoxifen only inhibited calcineurin activity 25%. We compared the effects of cyclosporine A and tamoxifen on acid transport activity in isolated membrane vesicles and in isolated membrane vesicles obtained from osteoclasts treated with cyclosporine A or tamoxifen under conditions that inhibit calcineurin activity. Direct addition of cyclosporine A in the acid transport assay, or pretreatment of cells with cyclosporine A followed by membrane isolation, had no effect on acid transport activity in membrane vesicles. In contrast, direct addition of tamoxifen to membranes inhibits acid transport activity, an effect that can be prevented by addition of exogenous calmodulin. Furthermore, acid transport activity was also inhibited in membrane vesicles isolated from cells treated with tamoxifen. In conclusion, cyclosporine A inhibits osteoclast calcineurin activity; however, calcineurin inhibition does not correspond to a significant effect on acid transport activity in isolated membrane vesicles or bone resorption by osteoclasts. [source] A New Era of Minimal Effects?JOURNAL OF COMMUNICATION, Issue 1 2010A Response to Bennett, Iyengar This article takes up Bennett and Iyengar's (2008) call for debate about the future of political communication effects research. We outline 4 key criticisms. First, Bennett and Iyengar are too quick to dismiss the importance of attitude reinforcement, long recognized as an important type of political media influence. Second, the authors take too narrow a view of the sources of political information, remaining fixated on news. Third, they offer an incomplete portrayal of selective exposure, exaggerating the extent to which individuals avoid attitude-discrepant information. Finally, they lean toward determinism when describing the role technologies play in shaping our political environment. In addition, we challenge Bennett and Iyengar's assertion that only brand new theory can serve to help researchers understand today's political communication landscape. We argue that existing tools, notably the Elaboration Likelihood Model (ELM), retain much utility for examining political media effects. Contrary to Bennett and Iyengar's claims, the ELM suggests that the contemporary political information environment does not necessarily lead to minimal effects. [source] Minimal effects of wind turbines on the distribution of wintering farmland birdsJOURNAL OF APPLIED ECOLOGY, Issue 6 2008Claire L. Devereux Summary 1Energy production from wind power is increasing rapidly in Europe to help combat the threats from global warming. For example, the European Commission have set a target for 20% of EU energy to come from renewable sources by 2020. In recent decades, biodiversity on European farmland has fallen dramatically due to agricultural intensification. Agri-environment schemes (AES) have been implemented across the EU, in part at least, to combat these declines. Significant numbers of turbines are, and will be, built on farmland. There is, therefore, a potential conflict between wind turbines and AES on farmland. 2Various mechanisms potentially cause wind turbines to alter bird distribution including noise and physical structure. 3We show that turbine location (controlling for other effects such as boundary location and crop type) did not affect the distribution of four functional groups of wintering farmland birds (seed-eaters, corvids, gamebirds and Eurasian skylarks) at differing distances from wind turbines ranging from 0,150 m to 600,750 m. The only species for which distribution was related to the presence of wind turbines was the largest and least manoeuvrable (common pheasant Phasianus colchicus L.). 4In a further analysis of data collected at 0,75 m and 75,150 m from turbines, we found no evidence to suggest that farmland birds in our study avoided areas close to wind turbines. 5Synthesis and applications. This is the first evidence suggesting that the present and future location of large numbers of wind turbines on European farmland is unlikely to have detrimental effects on farmland birds (at least for those species included in our study). This should be welcome news for nature conservationists, wind energy companies and policy-makers. However, our work is only a first step, as there may be potential influences of wind turbines on bird distribution during the breeding season. [source] An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupusARTHRITIS & RHEUMATISM, Issue 5 2008Frances Rena Bahjat Objective To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk),dependent signaling, could modulate disease in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling. Methods R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24,34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined. Results When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody. Conclusion We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders. [source] Evaluation of a bedside blood ketone sensor: the effects of acidosis, hyperglycaemia and acetoacetate on sensor performanceDIABETIC MEDICINE, Issue 7 2004A. S. A. Khan Abstract Aims To assess the performance of a handheld bedside ketone sensor in the face of likely metabolic disturbances in diabetic ketoacidosis, namely: pH, glucose and acetoacetate. Methods The effects of pH (7.44,6.83), glucose (5,50 mmol/l) and acetoacetate (0,5 mmol/l) were examined in venous blood to investigate the accuracy of betahydroxybutyrate measurement (0,5 mmol/l) by a handheld ketone sensor. Sensor results were compared with a reference method. Linear regression models were fitted to the difference between the methods with the concentration of metabolite as the explanatory factor. Results Decreasing pH and increasing glucose had no effect on the accuracy of the handheld ketone sensor; the gradients of the fitted lines were ,0.14 and ,0.003, respectively. The 95% confidence intervals were ,0.7,0.4 and ,0.01,0.004, respectively (P = 0.59 and 0.4, respectively). In the acetoacetate study, a positive relationship between the sensor and reference method results was found, the gradient was 0.09. The 95% confidence interval was 0.05,0.14 (P , 0.001), indicating that high concentrations of acetoacetate interfere with the sensor performance. Conclusions Acidosis and hyperglycaemia have minimal effects on the sensor performance. However, high concentrations of acetoacetate result in some overestimation of betahydroxybutyrate. This bedside ketone sensor provides useful data over a broad range of conditions likely to be encountered during moderate to severe diabetic ketoacidosis. [source] Destocking as a Drought,mitigation Strategy: Clarifying Rationales and Answering CritiquesDISASTERS, Issue 3 2002John Morton The idea of externally assisted emergency destocking of pastoralists has gained currency in recent years: increasing the incentives for pastoralists to sell animals, or removing the constraints to selling animals in the early stages of drought. We identify two separate rationales put forward by proponents of destocking: environmental benefits and purchasing power/welfare benefits. We consider whether specific recent critiques of ,new range ecology' and specifically of ,tracking policies' do in fact provide arguments against emergency destocking in pastoralist areas. We illustrate some of these themes with a case study of a successful destocking exercise in northern Kenya where a very specific form of support was requested and received by pastoralists themselves. The sorts of destocking that work are likely to have significant effects on pastoralist purchasing power at key points of the drought cycle, but minimal effects on the environment. Clarifying these points will make it easier to promote destocking as a drought,mitigation policy. [source] Thiol-reactive dyes for fluorescence labeling of proteomic samplesELECTROPHORESIS, Issue 14 2003Kamala Tyagarajan Abstract Covalent derivatization of proteins with fluorescent dyes prior to separation is increasingly used in proteomic research. This paper examines the properties of several commercially available iodoacetamide and maleimide dyes and discusses the conditions and caveats for their use in labeling of proteomic samples. The iodoacetamide dyes BODIPY TMR cadaverine IA and BODIPY Fl C1 -IA were highly specific for cysteine residues and showed little or no nonspecific labeling even at very high dye:thiol ratios. These dyes also showed minimal effects on pI's of standard proteins. Some iodoacetamide dyes, (5-TMRIA and eosin-5-iodoacetamide) and some maleimide dyes (ThioGlo I and Rhodamine Red C2 maleimide) exhibited nonspecific labeling at high dye:thiol ratios. Labeling by both iodoacetamide and maleimide dyes was inhibited by tris(2-carboxyethyl)phosphine (TCEP); interactions between TCEP and dye were also observed. Thiourea, an important component of sample solubilization cocktails, inhibited labeling of proteins with iodoacetamide dyes but not with maleimide dyes. Maleimide dyes may serve as an alternative for labeling proteins where it is essential to have thiourea in the solubilization buffer. Covalent derivatization by BODIPY TMR cadaverine IA, BODIPY Fl C1 -IA or Rhodamine Red C2 maleimide was also demonstrated to be compatible with in-gel digestion and peptide mass fingerprinting by matrix assisted laser desorption/ionization-mass spectrometry and allowed successful protein identification. [source] Adenosine A1 Antagonism Attenuates Atropine-resistant Hypoxic Bradycardia in RatsACADEMIC EMERGENCY MEDICINE, Issue 9 2003Justin L. Kaplan MD Abstract Objectives: To test the following hypotheses: Hypoxia induces bradycardia and hemodynamic compromise that are resistant to atropine but responsive to selective antagonism of the adenosine A1 receptor (A1AdoR). The mechanism for such attenuation is independent of the vagus nerve. Methods: Ten minutes after sham or actual bilateral cervical vagotomy, paralyzed ventilated rats were made hypoxic (5% fractional inspired oxygen, continued until death). Five minutes after beginning hypoxia, intravenous treatment with BG-9719, a selective A1AdoR antagonist (0.1 mg/kg); atropine (0.1 mg/kg); BG-9719 vehicle; or saline was initiated. These drug doses were based on pilot studies. Of the eight treatment groups (eight possible combinations of vagotomy status and drug/vehicle treatment), n= 8 in all except nonvagotomized, vehicle-treated rats (where n= 7). Results: Heart rate and left ventricular contractility decreased rapidly with hypoxia. Atropine had minimal effects in prolonging survival (from mean ± SEM of 15.5 ± 2.1 minutes to 20.2 ± 2.5 minutes, p = 0.94) and attenuating posthypoxic decreases in heart rate (p = 0.89) and contractility (p = 0.83) compared with saline. BG-9719 prolonged survival, however, from 14.4 ± 1.9 minutes (with vehicle treatment) to 37.2 ± 6.8 minutes (p < 0.001). Survival, heart rate, and contractility were preserved with BG-9719 compared with atropine and vehicle (p < 0.05, all comparisons). Vagotomy prevented the effects of BG-9719 on survival prolongation (p = 0.003), heart rate (p = 0.01), and contractility (p < 0.001) but did not affect those outcomes in saline-treated rats. Conclusions: Survival, heart rate, and contractility were better preserved with BG-9719 than atropine. A1AdoR selective antagonism, possibly because of its multiple mechanisms for attenuating hypoxic cardiac insufficiency, resulted in better hemodynamic and clinical outcomes. That attenuation seems to have a component of vagal mediation. [source] The role of peripheral Na+ channels in triggering the central excitatory effects of intravenous cocaineEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006P. Leon Brown Abstract While alterations in dopamine (DA) uptake appear to be a critical mechanism underlying locomotor and reinforcing effects of cocaine (COC), many centrally mediated physiological and affective effects of this drug are resistant to DA receptor blockade and are expressed more quickly following an intravenous (i.v.) injection than expected based on the dynamics of drug concentration in the brain. Because COC is also a potent local anesthetic, its rapid action on Na+ channels may be responsible for triggering these effects. We monitored temperatures in the nucleus accumbens, temporal muscle and skin together with conventional locomotion during a single i.v. injection of COC (1 mg/kg), procaine (PRO, 5 mg/kg; equipotential anesthetic dose), a short-acting local anesthetic drug that, like COC, interacts with Na+ channels, and cocaine methiodide (COC-MET, 1.31 mg/kg, equimolar dose), a quaternary COC derivative that is unable to cross the blood,brain barrier. In this way, we explored not only the importance of Na+ channels in general, but also the importance of central vs. peripheral Na+ channels specifically. COC induced locomotor activation, temperature increase in the brain and muscle, and a biphasic temperature fluctuation in skin. Though PRO did not induce locomotor activation, it mimicked, to a greater degree, the temperature effects of COC. Therefore, Na+ channels appear to be a key substrate for COC-induced temperature fluctuations in the brain and periphery. Similar to PRO, COC-MET had minimal effects on locomotion, but mimicked COC in its ability to increase brain and muscle temperature, and induce transient skin hypothermia. It appears therefore that COC's interaction with peripherally located Na+ channels triggers its central excitatory effects manifested by brain temperature increase, thereby playing a major role in drug sensing and possibly contributing to COC reinforcement. [source] Bacitracin is not a specific inhibitor of protein disulfide isomeraseFEBS JOURNAL, Issue 11 2010Anna-Riikka Karala To successfully dissect molecular pathways in vivo, there is often a need to use specific inhibitors. Bacitracin is very widely used as an inhibitor of protein disulfide isomerase (PDI) in vivo. However, the specificity of action of an inhibitor for a protein-folding catalyst cannot be determined in vivo. Furthermore, in vitro evidence for the specificity of bacitracin for PDI is scarce, and the mechanism of inhibition is unknown. Here, we present in vitro data showing that 1 mm bacitracin has no significant effect on the ability of PDI to introduce or isomerize disulfide bonds in a folding protein or on its ability to act as a chaperone. Where bacitracin has an effect on PDI activity, the effect is relatively minor and appears to be via competition of substrate binding. Whereas 1 mm bacitracin has minimal effects on PDI, it has significant effects on both noncatalyzed protein folding and on other molecular chaperones. These results suggest that the use of bacitracin as a specific inhibitor of PDI in cellular systems requires urgent re-evaluation. [source] Sliding mesh algorithm for CFD analysis of helicopter rotor,fuselage aerodynamicsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, Issue 5 2008R. Steijl Abstract The study of rotor,fuselage interactional aerodynamics is central to the design and performance analysis of helicopters. However, regardless of its significance, rotor,fuselage aerodynamics has so far been addressed by very few authors. This is mainly due to the difficulties associated with both experimental and computational techniques when such complex configurations, rich in flow physics, are considered. In view of the above, the objective of this study is to develop computational tools suitable for rotor,fuselage engineering analysis based on computational fluid dynamics (CFD). To account for the relative motion between the fuselage and the rotor blades, the concept of sliding meshes is introduced. A sliding surface forms a boundary between a CFD mesh around the fuselage and a rotor-fixed CFD mesh which rotates to account for the movement of the rotor. The sliding surface allows communication between meshes. Meshes adjacent to the sliding surface do not necessarily have matching nodes or even the same number of cell faces. This poses a problem of interpolation, which should not introduce numerical artefacts in the solution and should have minimal effects on the overall solution quality. As an additional objective, the employed sliding mesh algorithms should have small CPU overhead. The sliding mesh methods developed for this work are demonstrated for both simple and complex cases with emphasis placed on the presentation of the inner workings of the developed algorithms. Copyright © 2008 John Wiley & Sons, Ltd. [source] Expression of FGFR3 with the G380R Achondroplasia Mutation Inhibits Proliferation and Maturation of CFK2 Chondrocytic CellsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Janet E. Henderson Abstract A G380R substitution in the transmembrane-spanning region of FGFR3 (FGFR3Ach) results in constitutive receptor kinase activity and is the most common cause of achondroplastic dwarfism in humans. The epiphyseal growth plates of affected individuals are disorganized and hypocellular and show aberrant chondrocyte maturation. To examine the molecular basis of these abnormalities, we used a chondrocytic cell line, CFK2, to stably express the b variant of wild-type FGFR3 or the the constitutively active FGFR3Ach. Overexpression of FGFR3 had minimal effects on CFK2 proliferation and maturation compared with the severe growth retardation found in cells expressing FGFR3Ach. Cells expressing the mutant receptor also showed an abnormal apoptotic response to serum deprivation and failed to undergo differentiation under appropriate culture conditions. These changes were associated with altered expression of integrin subunits, which effectively led to a switch in substrate preference of the immature cell from fibronectin to type II collagen. These in vitro observations support those from in vivo studies indicating that FGFR3 mediates an inhibitory influence on chondrocyte proliferation. We now suggest that the mechanism is related to altered integrin expression. [source] CREB Cooperates with BMP-stimulated Smad signaling to enhance transcription of the Smad6 promoterJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004Andreia M. Ionescu Growth plate chondrocytes integrate a multitude of growth factor signals during maturation. PTHrP inhibits maturation through stimulation of PKA/CREB signaling while the bone morphogenetic proteins (BMPs) stimulate maturation through Smad mediated signaling. In this manuscript, we show that interactions between CREB and the BMP associated Smads are promoter specific, and demonstrate for the first time the requirement of CREB signaling for Smad mediated activation of a BMP responsive region of the Smad6 promoter. The 28 base pairs (bp) BMP responsive element of the Smad6 promoter contains an 11 bp Smad binding region and an adjacent 17 bp region in which we characterize a putative CRE site. PKA/CREB gain of function enhanced BMP stimulation of this reporter, while loss of CREB function diminished transcriptional activity. In contrast, ATF-2 and AP-1 transcription factors had minimal effects. Electrophoretic mobility shift assay (EMSA) confirmed CREB binding to the Smad6 promoter element. Mutations eliminating binding resulted in loss of transcriptional activity, while mutations that maintained CREB binding had continued reporter activation by CREB and BMP-2. The Smad6 gene was similarly regulated by CREB. Dominant negative CREB reduced BMP-2 stimulated Smad6 gene transcription by 50%, but markedly increased BMP-2 mediated stimulation of colX and Ihh expression. In contrast, PTHrP which activates CREB signaling, blocked the stimulatory effect of BMP-2 on colX and Ihh, but minimally inhibited the stimulatory effect of BMP on Smad6. These findings are the first to demonstrate a cooperative association between CREB and BMP regulated Smads in cells from vertebrates and demonstrate that promoter-specific rather than generalized interactions between PKA/CREB and BMP signaling regulate gene expression in chondrocytes. J. Cell. Physiol. 198: 428,440, 2004© 2003 Wiley-Liss, Inc. [source] A New Era of Minimal Effects?JOURNAL OF COMMUNICATION, Issue 1 2010A Response to Bennett, Iyengar This article takes up Bennett and Iyengar's (2008) call for debate about the future of political communication effects research. We outline 4 key criticisms. First, Bennett and Iyengar are too quick to dismiss the importance of attitude reinforcement, long recognized as an important type of political media influence. Second, the authors take too narrow a view of the sources of political information, remaining fixated on news. Third, they offer an incomplete portrayal of selective exposure, exaggerating the extent to which individuals avoid attitude-discrepant information. Finally, they lean toward determinism when describing the role technologies play in shaping our political environment. In addition, we challenge Bennett and Iyengar's assertion that only brand new theory can serve to help researchers understand today's political communication landscape. We argue that existing tools, notably the Elaboration Likelihood Model (ELM), retain much utility for examining political media effects. Contrary to Bennett and Iyengar's claims, the ELM suggests that the contemporary political information environment does not necessarily lead to minimal effects. [source] Role of fibrinogen-, factor VIII- and XIII-mediated clot propagation in gelatin haemodilutionACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2009A. A. SCHRAMKO Background: Gelatin solution impairs coagulation. The mechanism of coagulopathy is incompletely defined. The purpose of this study was to evaluate the capacity of single coagulation factors to reverse gelatin-promoted whole-blood coagulation disorders in vitro. Methods: Venous blood was withdrawn from 12 volunteers in a crossover study. Four percent succinylated gelatin was added to citrated whole-blood samples to make a 40 vol% end-concentration of gelatin. The baseline and 40 vol% samples, and samples with addition of fresh-frozen plasma (FFP), fibrinogen, coagulation factors XIII (FXIII) or VIII, together with the von Willebrand factor (FVIII+vWF), were analysed by thromboelastometry (ROTEM®). Coagulation was initiated by tissue thromboplastin (ExTEM®) with and without cytochalasin to determine the functional component of fibrinogen (FibTEM®). Results: Initiation of coagulation and fibrin formation were delayed at 40 vol% gelatin dilution. At this stage, the median (25th,75th percentiles) maximum clot firmness (MCF) was 76.3 (65.9,80.0) and 32.5 (27.4,45.0)% of the pre-dilution value in ExTEM® and FibTEM® thromboelastometry, respectively. Coagulation time was corrected by addition of fibrinogen and FFP in ExTEM® and FibTEM® analysis, whereas FVIII or FXIII had minimal effects. MCF was partly restored only by FFP in ExTEM®. In FibTEM® analysis, MCF improved more by fibrinogen than by FVIII+VWF, FXIII or FFP. Conclusions: Gelatin-induced whole-blood coagulation disorder in vitro is mainly dependent on the initial fibrinogen,fibrin interaction. The proposed mechanism might suggest not to reverse gelatin coagulopathy solely by fibrinogen administration. The administration of FFP, a mixture of different coagulation factors, reversed the gelatin-induced in vitro coagulopathy the best. [source] Dry-Aging Effects on Palatability of Beef Longissimus MuscleJOURNAL OF FOOD SCIENCE, Issue 2 2001R.E. Campbell ABSTRACT: Beef strip loins and short loins were vacuum aged for 7 or 14 d, then these cuts were dry aged for 7, 14, or 21 d. At 2, 9, and 16 d of post-dry-aging vacuum storage, strip steaks were analyzed for sensory, physical, and microbial differences. Controls were vacuum aged for 14 d. Dry aging for 14 and 21 d produced steaks with greater (P < 0.05) dry-aged flavor, tenderness, and juiciness than controls or steaks dry aged for 7 d. Shear forces were lower (P < 0.05) for steaks dry aged for 21 d. Time of vacuum storage before and after dry aging had minimal effects on development of dry-aged flavor attributes. [source] The effect of home-use fluoride gels on glass,ionomer, compomer and composite resin restorationsJOURNAL OF ORAL REHABILITATION, Issue 7 2003P. Dionysopoulos summary The purpose of this study was to investigate the resistance to dissolution by two home-use fluoride gels on the surface integrity of glass,ionomer, resin modified glass,ionomer, compomer and composite resin restorations. Class V cavities prepared in extracted teeth were restored with a glass,ionomer (Fuji II), a resin modified glass,ionomer (Vitremenr), two compomers (Dyract and F-2000) and a composite resin (Z-100). Groups of five specimens of each material were treated for 24 h with one of the following: (i) distilled water, (ii) neutral fluoride gel and (iii) acidulated phosphate fluoride (APF) gel. Surface degradation of the restorations was studied using standard electron microscopy (SEM), rated according to specific criteria and statistically analysed by the Wilcoxon test (rank sums). Acidulated phosphate fluoride was found to have a significant effect on all examined materials, while minimal effects resulted from the neutral fluoride gel compared with the control group. The effect of home-use fluoride gels on glass,ionomer, compomer and composite resin restorations. [source] Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturationJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2009Christine A. Clark Abstract While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP-13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP-2,treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP-2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE-luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP-responsive reporter, 12XSBE, by BMP-2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF-, to activate the TGF-,-responsive reporter, 4XSBE. Finally, PGE2 down-regulated BMP-mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 785,792, 2009 [source] SAFETY OF DEXTROAMPHETAMINE AND COCAINE COMBINATIONS IN COCAINE USERSALCOHOLISM, Issue 2008William Murff Two studies evaluated the safety and abuse liability of d-amphetamine in combination with cocaine in twenty cocaine-using research volunteers maintained in a controlled research laboratory. The first study tested low doses of d-amphetamine (15 mg) administered orally as a 1.5-hr pretreatment before low intranasal doses (48 mg) of cocaine. The study was double-blind, double-dummy, and placebo-controlled. A dose run-up procedure was employed to maximize safety. All drug effects were modest and the main finding of the study was diminished subjective effects of cocaine on a replicate determination of the original cocaine dose. The second study examined higher doses of d-amphetamine (30 mg, p.o.) and cocaine (96 mg, i.n.), alone and in combination, without a gradual dose run-up. Cocaine alone increased subjective mood, cocaine craving, and ratings indicating cocaine abuse potential. Again, replicate administration of cocaine produced lesser subjective effects than the first dose. D-amphetamine alone increased systolic and mean arterial pressures, but produced minimal effects on subjective mood. The combination of d-amphetamine and cocaine never produced effects greater than cocaine alone except for one subject who had an asymptomatic hypertensive episode. The data are interpreted in light of the possible use of stimulants for the treatment of cocaine dependence. [source] Pharmacodynamics of Carvedilol in Conscious, Healthy DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Sonya G. Gordon The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for >5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54,76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80,100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful. [source] Bilastine in allergic rhinoconjunctivitis and urticariaALLERGY, Issue 2010C. Bachert To cite this article: Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy 2010; 65 (Suppl. 93): 1,13. Abstract Allergic rhinoconjunctivitis and urticaria are increasing in prevalence in many developed countries. The role of histamine in such conditions is well documented and clinical guidelines recommend non-sedating H1 -receptor antagonists as first-line treatment choices. Bilastine is a novel non-sedating histamine H1 -receptor antagonist developed for the treatment of allergic rhinoconjunctivitis and urticaria. The aim of this review is to critique the scientific evidence relating to the pharmacological properties of bilastine and the clinical evidence regarding its potential as an antihistamine. In vitro binding studies and investigations in animal tissue have demonstrated the high specificity of bilastine for H1 -receptors, and preclinical animal studies have also yielded promising results in terms of a reduction of histamine-mediated inflammatory effects, including capillary permeability and bronchospasm. In pharmacodynamic studies bilastine was found to down-regulate histamine-induced flare and wheal responses in healthy volunteers. Preclinical and clinical pharmacokinetic studies showed that bilastine has dose-dependent kinetics following oral administration. Excretion is almost exclusively via urine and faeces as unchanged drug. Early clinical trials have shown that bilastine has similar efficacy to other second-generation H1 -receptor antagonists such as cetirizine, desloratadine, fexofenadine and levocetirizine, in terms of reducing allergic symptoms. Clinical findings also indicate that bilastine has a rapid onset of action and a 20 mg single dose is effective throughout a 24-h period. Furthermore, bilastine has been associated with improved quality of life in allergic rhinoconjunctivitis and urticaria patients. Adverse effects have generally been minimal in these studies and doses up to twice those proposed did not exhibit differences in adverse events compared to placebo. Moreover, in vivo investigations have found no evidence of accumulation of bilastine in the central nervous system, and various studies have confirmed minimal effects on psychomotor performance in healthy volunteers administered up to four times the usual dose. Clinical studies have also found no effect of bilastine on the QTc interval and other ECG parameters, even at supratherapeutic dosages, confirming the good cardiac safety profile of this newer antihistamine. Given its pharmacodynamic profile, which appears to be similar to other second-generation H1 -receptor antagonists, and its favourable safety and tolerability, bilastine has the attributes of a potentially clinically useful non-sedating antihistamine. Larger clinical studies are now necessary to fully elucidate the clinical potential of this novel antihistamine. [source] Microvascular Thrombosis Models in Venules and Arterioles In VivoMICROCIRCULATION, Issue 3 2005ROLANDO E. RUMBAUT MD ABSTRACT Platelets are intimately involved in hemostasis and thrombosis. Under physiological conditions, circulating platelets do not interact with microvascular walls. However, in response to microvascular injury, platelet adhesion and subsequent thrombus formation may be observed in venules and arterioles in vivo. Numerous intravital video microscopy techniques have been described to induce and monitor the formation of microvascular thrombi. The mechanisms of microvascular injury vary widely among different models. Some models induce platelet activation with minimal effects on endothelium, others induce endothelial inflammation or injury, while other models lead to thrombus formation associated with endothelial denudation. The molecular mechanisms mediating platelet,vessel wall adhesive interactions differ among various models. In some instances, differences in responses between venules and arterioles are described that cannot be explained solely by hemodynamic factors. Several models for induction of microvascular thrombosis in vivo are outlined in this review, with a focus on the mechanisms of injury and thrombus formation, as well as on differences in responses between venules and arterioles. Recognizing these characteristics should help investigators select an appropriate model for studying microvascular thrombosis in vivo. [source] A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenograftsMOLECULAR CARCINOGENESIS, Issue 2 2010Donghang Zheng Abstract Deregulation of insulin-like growth factor-1 receptor (IGF-1R) and focal adhesion kinase (FAK) signaling pathways plays an important role in cancer cell proliferation and metastasis. In pancreatic cancer cells, the crosstalk and compensatory mechanisms between these two pathways reduce the efficacy of the treatments that target only one of the pathways. Ablation of IGF-1R signaling by siRNA showed minimal effects on the survival and growth of pancreatic cancer cells. An increased activity of FAK pathway was seen in these cells after IGF-1R knockdown. Further inhibition of FAK pathway using Y15 significantly decreased cell survival, adhesion, and promoted apoptosis. The combination of Y15 treatment and IGF-1R knockdown also showed significant antitumor effect in vivo. The current study demonstrates the importance of dual inhibition of both these signaling pathways as a novel strategy to decrease both in vitro and in vivo growth of human pancreatic cancer. © 2009 Wiley-Liss, Inc. [source] The Role of Leptin in the Control of Body WeightNUTRITION REVIEWS, Issue 2002Rudolph L. Leibel M.D. Physiologic responses to high and low leptin concentrations are strikingly asymmetrical. High concentrations often produce minimal effects, whereas low concentrations provoke strong counterregulatory responses. A model and rationale for the physiology is presented. [source] Nickel and zinc hyperaccumulation by Alyssum murale and Thlaspi caerulescens (Brassicaceae) do not enhance survival and whole-plant growth under drought stressPLANT CELL & ENVIRONMENT, Issue 3 2003S. N. WHITING ABSTRACT Nickel and Zn hyperaccumulation by Alyssum murale and Thlaspi caerulescens bear substantial energetic costs and should confer benefits to the plant. This research determined whether metal hyperaccumulation can increase osmotic adjustment and resistance to water stress (drought). Alyssum murale and Thlaspi caerulescens treated with low or high concentrations of Ni or Zn were exposed to moderate (,0·4 MPa) and severe (,1·0 MPa) water stresses using aqueous polyethylene glycol. In the absence of metals both water deficits inhibited shoot growth. Nickel and Zn hyperaccumulation did not ameliorate growth inhibition by either level of water stress. The water stress did not induce major changes in shoot metal concentrations of these constitutive hyperaccumulators. Moreover, metal hyperaccumulation had minimal effects on the osmolality of leaf-sap extracts, relative water content of the shoots, or rate of evapotranspiration. It is concluded that Ni or Zn hyperaccumulation does not augment whole-plant capacity for drought resistance in A. murale and T. caerulescens. [source] Low free energy cost of very long loop insertions in proteinsPROTEIN SCIENCE, Issue 2 2003Michelle Scalley-Kim Abstract Long insertions into a loop of a folded host protein are expected to have destabilizing effects because of the entropic cost associated with loop closure unless the inserted sequence adopts a folded structure with amino- and carboxy-termini in close proximity. A loop entropy reduction screen based on this concept was used in an attempt to retrieve folded sequences from random sequence libraries. A library of long random sequences was inserted into a loop of the SH2 domain, displayed on the surface of M13 phage, and the inserted sequences that did not disrupt SH2 function were retrieved by panning using beads coated with a phosphotyrosine containing SH2 peptide ligand. Two sequences of a library of 2 × 108 sequences were isolated after multiple rounds of panning, and were found to have recovery levels similar to the wild-type SH2 domain and to be relatively intolerant to further mutation in PCR mutagenesis experiments. Surprisingly, although these inserted sequences exhibited little nonrandom structure, they do not significantly destabilize the host SH2 domain. Additional insertion variants recovered at lower levels in the panning experiments were also found to have a minimal effect on the stability and peptide-binding function of the SH2 domain. The additional level of selection present in the panning experiments is likely to involve in vivo folding and assembly, as there was a rough correlation between recovery levels in the phage-panning experiments and protein solubility. The finding that loop insertions of 60,80 amino acids have minimal effects on SH2 domain stability suggests that the free energy cost of inserting long loops may be considerably less than polymer theory estimates based on the entropic cost of loop closure, and, hence, that loop insertion may have provided an evolutionary route to multidomain protein structures. [source] Use of Patient and Hospital Variables in Interpreting Patient Satisfaction Data for Performance Improvement PurposesAMERICAN JOURNAL OF ORTHOPSYCHIATRY, Issue 3 2004Elise E. Lessing PhD Satisfaction scores of 349 patients being discharged from a state psychiatric hospital were examined in relation to available norms for the instrument used and selected patient and hospital variables. Mean item scores fell within the less-than-satisfied category on both total and factor scores. Regression analyses indicated minimal effects of patient attributes. Two hospital factors (restraint rate on patient's unit and accessibility of psychosocial groups) significantly predicted satisfaction, with the former having an unexpected positive relationship to satisfaction. Clinicians were able to use the survey data to improve care, but patients' tendency toward undifferentiated positive or negative responding hindered the prioritizing of change efforts. [source] The effects of paced breathing on respiratory resistance are minimal in healthy individualsPSYCHOPHYSIOLOGY, Issue 5 2009Thomas Ritz Abstract Paced breathing has been criticized for its presumed influences on autonomic and respiratory regulation, among that on respiratory resistance. It has been speculated that excessive pulmonary stretch receptor activation through high tidal volume (VT) would be the mechanism underlying such influences. However, the idea of airway dilation by paced breathing has remained untested. We analyzed inspiratory and expiratory resistance measured by forced oscillations in 26 healthy participants during baseline and two paced breathing conditions, regular pacing with instructions to alter rate only and pacing with additional instructions to alter volume randomly throughout the task. In each condition, four 3-min paced breathing trials at 8, 10.5, 13, and 18 breaths/min were administered. Despite pronounced changes in respiration rates and VT across pacing trials, neither inspiratory nor expiratory resistance were changed significantly under the regular paced breathing condition. A small reduction in resistance was only observed under conditions of variable volume at 18 breaths/min. Thus, regular paced breathing at different speeds across a range of naturally occurring breathing frequencies has only minimal effects on resistance of the airway passages. [source] Remedial options for chlorinated volatile organics in a partially anaerobic aquiferREMEDIATION, Issue 4 2004Xiujin Qiu A laboratory study was conducted for the selection of appropriate remedial technologies for a partially anaerobic aquifer contaminated with chlorinated volatile organics (VOCs). Evaluation of in situ bioremediation demonstrated that the addition of electron donors to anaerobic microcosms enhanced biological reductive dechlorination of tetrachloroethene (PCE), trichloroethene (TCE), and 1,1,1-trichloroethane (1,1,1-TCA) with half-lives of 20, 22, and 41 days, respectively. Nearly complete reductions of PCE, TCE, 1,1,1-TCA, and the derivative cis-dichloroethene were accompanied by a corresponding increase in chloride concentrations. Accumulation of vinyl chloride, ethene, and ethane was not observed; however, elevated levels of 14CO2 (from 14C-TCE spiked) were recovered, indicating the occurrence of anaerobic oxidation. In contrast, very little degradation of 1,2-dichloropropane (1,2-DCP) and 1,1-dichlorethane (1,1-DCA) was observed in the anaerobic microcosms, but nutrient addition enhanced their degradation in the aerobic biotic microcosms. The aerobic degradation half-lives for 1,2-DCP and 1,1-DCA were 63 and 56 days, respectively. Evaluation of in situ chemical oxidation (ISCO) demonstrated that chelate-modified Fenton's reagent was effective in degrading aqueous-phase PCE, TCE, 1,1,1-TCA, 1,2-DCP, etc.; however, this approach had minimal effects on solid-phase contaminants. The observed oxidant demand was 16 g-H2O2/L-groundwater. The oxidation reaction rates were not highly sensitive to the molar ratio of H2O2:Fe2+:citrate. A ratio of 60:1:1 resulted in slightly faster removal of chemicals of concern (COCs) than those of 12:1:1 and 300:1:1. This treatment resulted in increases in dissolved metals (Ca, Cr, Mg, K, and Mn) and a minor increase of vinyl chloride. Treatment with zero-valent iron (ZVI) resulted in complete dechlorination of PCE, and TCE to ethene and ethane. ZVI treatment reduced 1,1,1-TCA only to 1,1-DCA and chloroethane (CA) but had little effect on reducing the levels of 1,2-DCP, 1,1-DCA, and CA. The longevity test showed that one gram of 325-mesh iron powder was exhausted in reaction with > 22 mL of groundwater. The short life of ZVI may be a barrier to implementation. The ZVI surface reaction rates (ksa) were 1.2 × 10,2 Lm,2h,1, 2 × 10,3 Lm,2h,1, and 1.2 × 10,3 Lm,2h,1 for 1,1,1-TCA, TCE, and PCE, respectively. Based upon the results of this study, in situ bioremediation appeared to be more suitable than ISCO and ZVI for effectively treating the groundwater contamination at the site. © 2004 Wiley Periodicals, Inc. [source] REVIEW ARTICLE: Maternal Transmission of Asthma RiskAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009Robert H. Lim Maternal asthma significantly increases the risk of asthma in offspring, but the mechanisms remain poorly defined. We review animal models used to study the maternal effect, focusing on a murine model developed in our laboratory. Mother mice rendered allergic to ovalbumin produce offspring that are more susceptible to allergic sensitization, seen as airway hyperresponsiveness and allergic airway inflammation after a sensitization protocol, which has minimal effects on newborns from normal mothers. Mechanistic analyses identify a role for interleukin-4 (based on pre-mating injection of neutralizing antibodies), dendritic cells and allergen-specific T cells (based on adoptive transfer experiments). Other maternal exposures (e.g. pollutant exposure and non-pulmonary allergy) can increase asthma susceptibility in offspring. This observation implies that the maternal transmission of asthma represents a final common pathway to various types of inflammatory stimuli. Identification of the shared molecular mechanisms in these models may allow better prevention and therapy. Current knowledge, gaps in knowledge and future directions are discussed. [source] | ||||||||||||||||||||||