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Synergistic
Terms modified by Synergistic Selected AbstractsIrritants in combination with a synergistic or additive effect on the skin response: an overview of tandem irritation studiesCONTACT DERMATITIS, Issue 6 2006Francisca Kartono Sodium lauryl sulfate (SLS) has often been chosen as a model for irritant contact dermatitis (ICD) to study the effect of irritants in combination (1,14). Recently ,tandem', or sequential, exposures with SLS have been performed to study the mechanism of skin barrier impairment in ICD (1,6, 15). The assessment of reactions have been documented with visual scoring, transepidermal water loss (TEWL), skin colour reflectance measurements, skin blood flow; among which TEWL has been noted as the most sensitive value (16). The matched control groups were treated with either a single exposure to a single irritant or in tandem with the same irritant repeatedly. Synergistic and additive effects have been reported for various tandem pairs of irritants, however, the mechanism for both remains unclear. The results of tandem irritation studies were evaluated to define and investigate the responses produced and deduce a possible mechanism of action. Clinical ramifications, albeit complex, are discussed. [source] Synergistic, antagonistic and additive effects of multiple stressors: predation threat, parasitism and pesticide exposure in Daphnia magnaJOURNAL OF APPLIED ECOLOGY, Issue 6 2008Anja Coors Summary 1Predation and parasitism are important factors in the ecology and evolution of natural populations and may, along with other environmental factors, interact with the impact of anthropogenic pollutants. 2Our study aimed at identifying potential interactions between three stressors (predation threat, parasitism and pesticide exposure) and at exploring the predictability of their joint effects by using the model of independent action. We assessed in a full-factorial design the impacts of these stressors on key life-history traits and population growth rate of the water flea Daphnia magna. 3When applied as single stressors, predation threat and parasite challenge induced varying stressor-specific adaptive responses. The pesticide carbaryl was applied at a generally sublethal concentration, which caused low mortality only in first-brood offspring. 4Pesticide exposure interacted synergistically with parasite challenge regarding survival, which suggests immunomodulatory activity of the pesticide. Predation threat by phantom midge larvae showed antagonistic interactions for amount of first-brood offspring with both parasite challenge and carbaryl exposure. All stressors additively affected age and size at maturity, which added up to a considerable delay in the onset of reproduction in the three-stressor combination. The intrinsic rate of natural increase, r, reflected the non-additive and additive effects on single endpoints and showed significant synergistic interactions for all two-stressor combinations. The combination of all stressors resulted in a dramatic reduction of r compared to the stressor-free control. 5The model of independent action proved useful in quantitatively predicting effects of additively acting stressors, and in visualizing the occurrence and magnitude of non-additive effects in accordance with results of analysis of variances. 6Synthesis and applications. Cumulative additive effects and non-additive interactions of natural antagonists and pollutants are shown to result in considerable impacts on ecologically relevant parameters. As a starting point for an environmentally more realistic risk assessment of chemicals, it may be a valuable strategy to screen for non-additive effects among many stress factors simultaneously in simplified experimental designs by using the model of independent action. [source] STEVIOSIDE AS A REPLACEMENT OF SUCROSE IN PEACH JUICE: SENSORY EVALUATIONJOURNAL OF SENSORY STUDIES, Issue 5 2001GIUSEPPINA PAOLA PARPINELLO ABSTRACT The suitability of stevioside as a sweetener in peach juice was investigated. Comparison between stevioside and sucrose in terms of sweetness, sweet and bitter aftertastes were determined both in water and peach juice. The results demonstrated that 160 mg/L of stevioside may replace 34 g/L of sucrose in juice, with a 25% decrease in calories, without affecting the sensory characteristics of the product. Synergistic and inhibitory effects between sucrose and stevioside were also monitored at different stevioside concentration. A new juice formulation sweetened with a binary mixture of stevioside (160 mg/L) and sucrose (56 g/L) was not significantly different in terms of desirability from a reference product sweetened with 9% sucrose. [source] Synergistic or additive corrosion inhibition of mild steel by a mixture of HEDP and metasilicate at pH 7 and 11MATERIALS AND CORROSION/WERKSTOFFE UND KORROSION, Issue 11 2004D. Mohammedi Abstract Electrochemical measurements (steady-state current-voltage curves and AC impedance) were coupled with mass-loss measurements, SEM examinations, and EDSX analyses to investigate the inhibition of corrosion of a carbon steel by a mixture of phosphonic acid HEDP (acid 1, hydroxyethylene, 1-1 diphosphonic) and sodium metasilicate pentahydrate Na2SiO3. 5H2O in an industrial hard water containing 3.10,3 M Ca2+ ions. At pH 7, HEDP and Ca2+ act in a synergistic manner, by formation of a HEDP and calcium containing layer. Addition of silicate at this pH value, allows to reach an efficiency of 94% due to an additive inhibition effect. At pH 11, metasilicate, HEDP, and Ca2+ ions reinforce the passive layer in a synergistic way. The mixture (1.7 · 10,5 M HEDP + 2.6 · 10 -3 M SiO2,3) in the Ca2+ containing electrolyte is shown to be able to inhibit efficaciously the corrosion of iron at room temperature, considering uniform corrosion at pH 7 or pitting corrosion at pH 11. [source] Influence of several non-nutrient additives on nonspecific immunity and growth of juvenile turbot, Scophthalmus maximus L.AQUACULTURE NUTRITION, Issue 5 2008Y. LI Abstract The effects of three non-nutrient additives on nonspecific immunity and growth of juvenile turbot (Scophthalmus maximus L.) were studied in this feeding experiment. The five treatments are basal diet alone, basal diets containing three different additives [0.4 g kg,1 of xylo-oligosaccharides (XOS), 1.3 g kg ,1 of yeast cell wall and 0.8 g kg ,1 of bile acids] individually or in combination. Two hundred and twenty-five turbots (average initial weight 151.3 ± 11.3 g) were randomly allotted in five treatments with three replicates within each treatment in a 72-day period. Comparing with basal diet group, activities of C3, C4, phagocyte, lysozyme, specific growth rate and feed conversion rate in yeast cell wall, XOS and the combined groups was enhanced significantly (P < 0.05); however, these parameters in bile acid groups were increased slightly (P > 0.05) except for phagocyte (P < 0.05); superoxide dismutase activity in additive groups was not significantly increased (P > 0.05) except for the combined group (P < 0.05). In conclusion, supplementation of yeast cell wall and XOS enhanced the nonspecific immunity of juvenile turbot. Synergistic or additive effect of the three additives was not observed. [source] Rhythm Management in Pediatric Heart FailureCONGENITAL HEART DISEASE, Issue 4 2006Charles I. Berul MD ABSTRACT There are several options now available for the management of arrhythmias and ventricular dysfunction in pediatric patients with heart failure. A hybrid approach that combines the expertise of heart failure and electrophysiology specialists may be well suited for the optimal management of these complex patients. Medical and device therapies may be synergistic in decreasing the morbidity and mortality in pediatric heart failure. Pediatric electrophysiology can now potentially offer therapies that can help prevent both arrhythmic and pump failure deaths, as well as improve functional capacity and quality of life. These therapies and the available supporting data relevant to pediatrics will be the focus of this review. [source] Stress Resistance and Environmental Dependency of Inbreeding Depression in Drosophila melanogasterCONSERVATION BIOLOGY, Issue 4 2000Jesper Dahlgaard Two important issues are whether stress and inbreeding effects are independent as opposed to synergistic, and whether inbreeding effects are general across stresses as opposed to stress-specific. We found that inbreeding reduced resistance to acetone and desiccation in adult Drosophila melanogaster, whereas resistance to knockdown heat stress was not affected. Inbred flies, however, experienced a greater proportional decrease in productivity than outbreds following heat stress. Correlations using line means indicated that all resistance traits were uncorrelated in the inbred as well as in the outbred flies. Recessive, deleterious alleles therefore did not appear to have any general deleterious effects on stress resistance. Inbreeding within a specific environment and selection for resistant genotypes may therefore purge a population of deleterious genes specific to only one environmental stress. Resumen: Tanto la endogamia como el estrés ambiental pueden tener efectos adversos sobre la adaptabilidad afectando la conservación de especies en peligro de extinción. Dos temas importantes son determinar si los efectos del estrés y la endogamia son independientes en lugar de ser sinérgicos, y determinar si los efectos de la endogamia son generales para distintos tipos de estrés o si son específicos para un tipo determinado de estrés. Encontramos que la endogamia reduce la resistencia a la acetona y la desecación en adultos de Drosophila melanogaster, mientras que la resistencia al efecto demoledor del estrés por calor no fue afectada. Sin embargo, las moscas endogámicas experimentaron una disminución proporcionalmente mayor en la productividad que aquellas moscas sin endogamia después de experimentar un estrés por calor. Las correlaciones obtenidas usando líneas medias indicaron que las características de resistencia no estuvieron correlacionadas ni en moscas con endogamia, ni en moscas sin ella. Aparentemente los alelos nocivos recesivos no tuvieron ningún efecto nocivo general en la resistencia al estrés. La endogamia dentro de un ambiente específico y la selección por genotipos resistentes podrían, por lo tanto, eliminar una población de genes nocivos específicos a un solo estrés ambiental. [source] Combined effects of two stressors on Kenyan coral reefs are additive or antagonistic, not synergisticCONSERVATION LETTERS, Issue 2 2010Emily S. Darling Abstract A challenge for conservation science is predicting the impacts of co-occurring human activities on ecological systems. Multiple anthropogenic and natural stressors impact ecosystems globally and are expected to jeopardize their ecological functions and the success of conservation and management initiatives. The possibility that two or more stressors interact synergistically is of particular concern, but such nonadditive effects remain largely unidentified in nature. A long-term data set of hard coral cover from Kenyan reefs was used to examine the independent and interactive effects of two stressors: fishing and a temperature anomaly in 1998 that caused mass coral bleaching and mortality. While both stressors decreased coral cover, fishing by 51% and bleaching by 74%, they did not interact synergistically. Instead, their combined effect was antagonistic or weakly additive. The observed nonsynergistic response may be caused by the presence of one dominant stressor, bleaching, and cotolerance of coral taxa to both bleaching and fishing stressors. Consequently, coral bleaching has been the dominant driver of coral loss on Kenyan reefs and while marine reserves offer many benefits to reef ecosystems, they may not provide corals with a refuge from climate change. [source] Irritants in combination with a synergistic or additive effect on the skin response: an overview of tandem irritation studiesCONTACT DERMATITIS, Issue 6 2006Francisca Kartono Sodium lauryl sulfate (SLS) has often been chosen as a model for irritant contact dermatitis (ICD) to study the effect of irritants in combination (1,14). Recently ,tandem', or sequential, exposures with SLS have been performed to study the mechanism of skin barrier impairment in ICD (1,6, 15). The assessment of reactions have been documented with visual scoring, transepidermal water loss (TEWL), skin colour reflectance measurements, skin blood flow; among which TEWL has been noted as the most sensitive value (16). The matched control groups were treated with either a single exposure to a single irritant or in tandem with the same irritant repeatedly. Synergistic and additive effects have been reported for various tandem pairs of irritants, however, the mechanism for both remains unclear. The results of tandem irritation studies were evaluated to define and investigate the responses produced and deduce a possible mechanism of action. Clinical ramifications, albeit complex, are discussed. [source] Interaction of vitamins C and E as better cosmeceuticalsDERMATOLOGIC THERAPY, Issue 5 2007Karen E Burke ABSTRACT:, Although many cosmeceutical formulations contain vitamin C and/or vitamin E, very few are actually effective in topical application. First because there is only a low concentration, second because the stability is compromised as soon as the product is opened and exposed to air and light, and third because the form of the molecule (an ester or a mixture of isomers) is not absorbed or metabolized effectively by the skin. However, when a stable formulation delivers a high concentration of the nonesterified, optimal isomer of the antioxidant, vitamins C and E do indeed inhibit the acute ultraviolet (UV) damage of erythema, sunburn, and tanning as well as chronic UV photoaging and skin cancer. Both are highly effective depigmenting agents. Topical vitamin C also increases collagen synthesis in both young and old fibroblasts. Because vitamin C regenerates oxidized vitamin E, the combination in a cosmeceutical formulation is synergistic , particularly in UV protection. [source] Predicting the number of ecologically harmful exotic species in an aquatic systemDIVERSITY AND DISTRIBUTIONS, Issue 2 2008Anthony Ricciardi ABSTRACT Most introduced species apparently have little impact on native biodiversity, but the proliferation of human vectors that transport species worldwide increases the probability of a region being affected by high-impact invaders , i.e. those that cause severe declines in native species populations. Our study determined whether the number of high-impact invaders can be predicted from the total number of invaders in an area, after controlling for species,area effects. These two variables are positively correlated in a set of 16 invaded freshwater and marine systems from around the world. The relationship is a simple linear function; there is no evidence of synergistic or antagonistic effects of invaders across systems. A similar relationship is found for introduced freshwater fishes across 149 regions. In both data sets, high-impact invaders comprise approximately 10% of the total number of invaders. Although the mechanism driving this correlation is likely a sampling effect, it is not simply the proportional sampling of a constant number of repeat-offenders; in most cases, an invader is not reported to have strong impacts on native species in the majority of regions it invades. These findings link vector activity and the negative impacts of introduced species on biodiversity, and thus justify management efforts to reduce invasion rates even where numerous invasions have already occurred. [source] Follow-up of an exercise-based treatment for children with reading difficultiesDYSLEXIA, Issue 2 2007David Reynolds Abstract This study reports the results of a long-term follow-up of an exercise-based approach to dyslexia-related disorders (Reynolds, Nicolson, & Hambly, Dyslexia, 2003; 9(1): 48,71). In the initial study, children at risk of dyslexia were identified in 3 years of a junior school. One half then undertook a 6 month, home-based exercise programme. Evaluation after 6 months indicated that the exercise group improved significantly more than the controls on a range of cognitive and motor skills. Critics had suggested that the improvement might be attributable to artifactual issues including Hawthorne effects; an initial literacy imbalance between the groups; and inclusion of non-dyslexic participants. The present study evaluated the issue of whether the gains were maintained over the following 18 months, and whether they were in some sense artifactual as postulated by critics of the original study. Comparison of (age-adjusted) initial and follow-up performance indicated significant gains in motor skill, speech/language fluency, phonology, and working memory. Both dyslexic and non-dyslexic low achieving children benefited. There was also a highly significant reduction in the incidence of symptoms of inattention. Interestingly there were no significant changes in speeded tests of reading and spelling, but there was a significant improvement in (age-adjusted) reading (NFER). It is concluded that the gains were indeed long-lasting, and that the alternative hypotheses based on potential artifacts were untenable, and that the exercise treatment therefore achieved its applied purpose. Further research is needed to determine the underlying reasons for the benefits. Possible (and potentially synergistic) explanations include: improved cerebellar function (neural level); improved learning ability and/or attentional ability (cognitive level); improved self-esteem and self-efficacy (affective level); and improved parental/familial support (social level). Copyright © 2006 John Wiley & Sons, Ltd. [source] Quantifying the evidence for ecological synergiesECOLOGY LETTERS, Issue 12 2008Emily S. Darling Abstract There is increasing concern that multiple drivers of ecological change will interact synergistically to accelerate biodiversity loss. However, the prevalence and magnitude of these interactions remain one of the largest uncertainties in projections of future ecological change. We address this uncertainty by performing a meta-analysis of 112 published factorial experiments that evaluated the impacts of multiple stressors on animal mortality in freshwater, marine and terrestrial communities. We found that, on average, mortalities from the combined action of two stressors were not synergistic and this result was consistent across studies investigating different stressors, study organisms and life-history stages. Furthermore, only one-third of relevant experiments displayed truly synergistic effects, which does not support the prevailing ecological paradigm that synergies are rampant. However, in more than three-quarters of relevant experiments, the outcome of multiple stressor interactions was non-additive (i.e. synergies or antagonisms), suggesting that ecological surprises may be more common than simple additive effects. [source] Understanding biodiversity effects on prey in multi-enemy systemsECOLOGY LETTERS, Issue 9 2006Paolo Casula Abstract Biodiversity,ecosystem functioning theory would predict that increasing natural enemy richness should enhance prey consumption rate due to functional complementarity of enemy species. However, several studies show that ecological interactions among natural enemies may result in complex effects of enemy diversity on prey consumption. Therefore, the challenge in understanding natural enemy diversity effects is to predict consumption rates of multiple enemies taking into account effects arising from patterns of prey use together with species interactions. Here, we show how complementary and redundant prey use patterns result in additive and saturating effects, respectively, and how ecological interactions such as phenotypic niche shifts, synergy and intraguild predation enlarge the range of outcomes to include null, synergistic and antagonistic effects. This study provides a simple theoretical framework that can be applied to experimental studies to infer the biological mechanisms underlying natural enemy diversity effects on prey. [source] Effects of predator-induced visual and olfactory cues on 0+ perch (Perca fluviatilis L.) foraging behaviourECOLOGY OF FRESHWATER FISH, Issue 2 2006V. N. Mikheev Abstract,,, Foraging juvenile fish with relatively high food demands are usually vulnerable to various aquatic and avian predators. To compromise between foraging and antipredator activity, they need exact and reliable information about current predation risk. Among direct predator-induced cues, visual and olfactory signals are considered to be most important. Food intake rates and prey-size selectivity of laboratory-reared, naive young-of-the-year (YOY) perch, Perca fluviatilis, were studied in experiments with Daphnia magna of two size classes: 2.8 and 1.3 mm as prey and northern pike, Esox lucius, as predator. Neither total intake rate nor prey-size selectivity was modified by predator kairomones alone (water from an aquarium with a pike was pumped into the test aquaria) under daylight conditions. Visual presentation of pike reduced total food intake by perch. This effect was significantly more pronounced (synergistic) when visual and olfactory cues were presented simultaneously to foraging perch. Moreover, the combination of cues caused a significant shift in prey-size selection, expressed as a reduced proportion of large prey in the diet. Our observations demonstrate that predator-induced olfactory cues alone are less important modifiers of the feeding behaviour of naive YOY perch than visual cues under daylight conditions. However, pike odour acts as a modulatory stimulus enhancing the effects of visual cues, which trigger an innate response in perch. [source] Distribution of microbial populations and their relationship with environmental parameters in the coastal waters of Qingdao, ChinaENVIRONMENTAL MICROBIOLOGY, Issue 7 2010Min Wang Summary In order to understand the large-scale distribution of microbial populations simultaneously and their relationship with environmental parameters, flow cytometry was used to analyse samples collected from 46 stations in the coastal waters of Qingdao in spring, 2007. The distribution of virus was significantly and positively correlated with heterotrophic bacteria. Two groups of picophytoplankton (Synechococcus and picoeukaryotes) were detected; however, Prochlorococcus was not found. Picoeukaryotes and nanophytoplankton were abundant in the near-shore waters, whereas Synechococcus was abundant in the off-shore areas. No variation was found in vertical distribution of virus, heterotrophic bacteria, Synechococcus and nanophytoplankton abundances, except picoeukaryotes abundance in the bottom layer was dramatically lower than that in the upper layers. Correlation analyses indicated that the relationship between abiotic variables and heterotrophic bacteria, pico- and nanophytoplankton was closer than that between abiotic variables and virioplankton. Temperature and nutrients were the synchronous factors controlling the growth of heterotrophic bacteria, pico- and nanophytoplankton in the coastal waters of Qingdao in spring. The results suggested that synergistic and antagonistic effects existed among microbial groups. [source] Biodegradation during contaminant transport in porous media: 7.ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005Impact of multiple-degrader community dynamics Abstract The biodegradation and transport of phenanthrene in porous media containing multiple populations of phenanthrene degraders is examined with a series of miscible-displacement experiments. A long-term experiment was conducted with a soil containing an indigenous microbial community comprised of 25 identified phenanthrene-degrading isolates. The rate and magnitude of phenanthrene biodegradation oscillated throughout the six-month experiment. This behavior, at least in part, is attributed to multiple-population dynamics associated with the indigenous community of phenanthrene degraders, the composition of which changed during the experiment. This hypothesis is supported by the results of experiments conducted using sterilized porous media that were inoculated with selected isolates obtained from the indigenous soil community. The results of experiments conducted with sterilized soil inoculated with isolate A exhibited an initial extended period of steady phenanthrene effluent concentrations, followed by a uniform decline. The results of experiments conducted using sterilized sand for single-isolate systems with one of three selected isolates and for systems of two-isolate combinations, indicate the existence of apparent synergistic and antagonistic interactions among the isolates. For example, phenanthrene biodegradation was relatively extensive and occurred without a lag phase for isolate A alone. However, biodegradation was constrained when isolate A and B were combined, indicating an antagonistic interaction. Conversely, whereas extensive lag phases were exhibited by both isolates B and C for the single-isolate experiments, there was minimal lag when isolates B and C were combined, indicating a synergistic interaction. [source] Synergistic Combinations of Anticonvulsant Agents: What Is the Evidence from Animal Experiments?EPILEPSIA, Issue 3 2007Daniël M. Jonker Summary:,Purpose: Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use. Methods: Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis. Results: In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p < 0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p < 0.001). Conclusions: Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic,pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations. [source] Combined Ketogenic Diet and Vagus Nerve Stimulation: Rational Polytherapy?EPILEPSIA, Issue 1 2007Eric H. Kossoff Summary:,Objective: The concept of "rational polypharmacy" has been associated with anticonvulsant management for decades, but the term has not been applied to nonpharmacologic therapies. Methods: We conducted a multicenter, retrospective study of children who received concurrent diet (ketogenic or modified Atkins) and vagus nerve stimulation (VNS) treatment for medically intractable epilepsy. Results: Thirty children in total from six epilepsy centers were treated over a 6-yr period. The median age at the initiation of combination therapy was 10 yr (range, 4,24 yr). Sixteen (53%) received dietary therapy followed by VNS; no differences were noted between centers. After 3 months, 21 (70%) had seizure reduced by >50% over the previous single nonpharmacologic treatment, of whom 13 (62%) had improvement within the first month. A 5-min VNS off-time correlated with >90% seizure reduction (p = 0.02). The median duration of nonpharmacologic polytherapy was 12 months (range, 0.5,96 months); 17 (57%) remain on dual therapy at this time. No side effects were noted. Most patients who discontinued combination therapy did so because of a lack of efficacy rather than restrictiveness. Conclusions: In this small group, the combined use of diet and VNS appeared synergistic and yielded rapid benefits. It may be more effective with longer VNS off-times. Further prospective studies of this combination in refractory pediatric epilepsy are needed to help guide optimal use. [source] Pharmacodynamic and Pharmacokinetic Interaction Studies of Loreclezole with Felbamate, Lamotrigine, Topiramate, and Oxcarbazepine in the Mouse Maximal Electroshock Seizure ModelEPILEPSIA, Issue 3 2005Jarogniew J. Luszczki Summary:,Purpose: The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. Methods: Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. Results: With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. Conclusions: LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions. [source] Interactions Between Oxcarbazepine and Conventional Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic AnalysisEPILEPSIA, Issue 4 2003Jarogniew J. Luszczki Summary: ,Purpose: The aim of this study was to determine the types of interactions between oxcarbazepine (OCBZ) and conventional antiepileptic drugs (AEDs) against maximal electroshock-induced seizures (MES test) in mice, by using a method of isobolographic analysis. Methods: Adverse effects of combinations were evaluated in the chimney test (motor performance), also using the isobolographic method, which allowed determination of the median toxic dose (TD50) values for individual combinations; thus the protective indices could be determined. Results: OCBZ and phenytoin (PHT) at the fixed-ratio combination of 1:1 were significantly infraadditive (antagonistic) with respect to the antiseizure protection against MES and simultaneously additive in terms of side effects in the chimney test. Interestingly, combinations between OCBZ and clonazepam (CZP) in the MES test proved antagonistic or synergistic, depending on the proportion of both AEDs in the mixture. Low doses of OCBZ with high doses of CZP exerted antagonism. Conversely, high doses of OCBZ combined with low doses of CZP resulted in a synergistic interaction. Remaining combinations between OCBZ and phenobarbital, valproate, or carbamazepine were purely additive, either as regards the anticonvulsant activity against MES or in terms of motor impairment in the chimney test. Conclusions: The results of this study indicate that interaction of OCBZ and CZP at fixed-ratio combination of 1:1 might be profitable from a clinical point of view. Conversely, combinations of OCBZ with PHT may not be clinically efficient. [source] Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal TransductionEPILEPSIA, Issue 3 2003Daniël M. Jonker Summary: ,Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ,-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake. Methods: The in vivo concentration,response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point. Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration,EEG relation of TGB was described by the sigmoid- Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 ± 10 ,V, EC50 = 392 ± 20 ng/ml, and nH = 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism. Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage. [source] Superficial digital flexor tendon lesions in racehorses as a sequela to muscle fatigue: A preliminary studyEQUINE VETERINARY JOURNAL, Issue 6 2007M. T. Butcher Summary Reasons for performing study: Racing and training related lesions of the forelimb superficial digital flexor tendon are a common career ending injury to racehorses but aetiology and/or predisposing causes of the injury are not completely understood. Objectives: Although the injury takes place within the tendon, the lesion must be considered within the context of the function of the complete suspensory system of the distal limb, including the associated muscles. Methods: Both muscle and tendon function were investigated in vivo using implanted strain gauges in 3 Thoroughbred horses walking, trotting and cantering on a motorised treadmill. These data were combined with assessments of muscle architecture and fibre composition to arrive at an overview of the contribution of each muscle-tendon unit during locomotion. Results: The superficial digital flexor muscle has fatigue-resistant and high force production properties that allow its tendon to store and return elastic energy, predominantly at the trot. As running speed increases, deep digital flexor tendon force increases and it stabilises hyperextension of the fetlock, thus reinforcing the superficial digital flexor in limb load support. The deep digital flexor muscle has fast contracting properties that render it susceptible to fatigue. Conclusion: Based on these measurements and supporting evidence from the literature, it is proposed that overloading of the superficial digital flexor tendon results from fatigue of the synergistic, faster contracting deep digital flexor muscle. Potential relevance: Future research investigating distal limb system function as a whole should help refine clinical diagnostic procedures and exercise training approaches that will lead to more effective prevention and treatment of digital flexor tendon injuries in equine athletes. [source] Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2008Elin Lindhagen Abstract Objectives:, Gefitinib inhibits epidermal growth factor receptor (EGFR) signalling, but may also act by non-EGFR dependent mechanisms. We have investigated the activity of gefitinib in haematological tumour cells, in particular acute myeloblastic leukaemia (AML). Methods:, Cytotoxic activity of gefitinib, alone or in combination with standard anti-leukaemic drugs, was assessed by the short-term fluorometric microculture cytotoxicity assay in tumour cells from 117 patients representing five haematological and five non-haematological malignancies. In AML, the EGFR status was analysed by immunochemistry. Gefitinib-induced apoptosis was investigated in a subset of AML samples, as well as in the leukaemia cell line MV-4-11, using a multiparametric high content screening assay. To confirm activation of caspase-3 in cells treated with gefitinib, a blocking test was carried out in which MV4-11 cells were pretreated with the specific caspase inhibitor DEVD-FMK. Results:, Gefitinib showed highest cytotoxic activity in AML (n = 19) with many samples being sensitive at concentrations achievable in clinical practice (<10 ,M), and no difference between previously untreated and relapsed patients. No correlation between the activity of gefitinib and standard antileukaemic drugs (cytarabine, doxorubicin, etoposide) was observed. Combining gefitinib with these drugs resulted in mainly additive or synergistic (etoposide) effects, with no evidence of sequence dependency. The AML cells did not express the EGFR. Gefitinib induced apoptosis, which was at least partly mediated by activation of the caspase-3 pathway. Conclusion:,In vitro, gefitinib has significant cytotoxic activity in AML by inducing apoptosis through non-EGFR dependent pathways. [source] CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first ,-strand of chemokineEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2005Silvia Sebastiani Abstract In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first ,-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4+ T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines. [source] Recruitment of different subsets of antigen-presenting cells selectively modulates DNA vaccine-elicited CD4+ and CD8+ T lymphocyte responsesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004Abstract The immunogenicity of plasmid DNA vaccines may be limited by the availability of professional antigen-presenting cells (APC) at the site of inoculation. Here we demonstrate that the types of APC recruited to the injection site can selectively modulate CD4+ or CD8+ T lymphocyte responses elicited by an HIV-1 Env DNA vaccine in mice. Coadministration of plasmid GM-CSF with the DNA vaccine resulted in the recruitment of macrophages to the site of inoculation and specifically augmented vaccine-elicited CD4+ T lymphocyte responses. In contrast, coadministration of plasmid MIP-1, with the DNA vaccine resulted in the recruitment of dendritic cells to the injection site and enhanced vaccine-elicited CD8+ T lymphocyte responses. Interestingly, coadministration of both plasmid GM-CSF and plasmid MIP-1, with the DNA vaccine recruited both macrophages and dendritic cells and led to a synergistic and sustained augmentation of CD4+and CD8+ T lymphocyte responses. These data demonstrate the critical importance of locally recruited professional APC in determining the magnitude and nature of immune responses elicited by plasmid DNA vaccines. Moreover, these studies show that different subsets of professional APC can selectively modulate DNA vaccine-elicited T lymphocyte responses. [source] Fall-related brain injuries and the risk of dementia in elderly people: a population-based studyEUROPEAN JOURNAL OF NEUROLOGY, Issue 2 2005H. Luukinen Severe head injury in early adulthood may increase the risk of dementia in older age, but it is not known whether head injury in later life also increases the risk of dementia. A representative sample (82%) of persons aged 70 years or older with a Mini-Mental State Examination (MMSE) test score of ,26 (n = 325) were followed-up for 9 years to record all their fall-related head injuries resulting in traumatic brain injury (TBI). At the end of the follow-up period, 152 persons (81% of the surviving population) were examined for clinical dementia, according to DSM-IV criteria. Eight persons sustained a TBI and 34 developed dementia. Brain injury was associated with younger age at detection of dementia even when adjusted for sex and educational status (low educational status significantly associated with dementia); age-specific hazard ratio (95% confidence interval) 2.80 (1.35,5.81). In a population scoring ,28 points in the baseline MMSE an apolipoprotein E (ApoE) ,4 phenotype was also associated with younger age at the time of detecting dementia; 3.56 (1.35,9.34), and the effect of brain injury and ApoE ,4 phenotype was synergistic; 7.68 (2.32,25.3). We conclude that fall-related TBI predicts earlier onset of dementia and the effect is especially high amongst subjects who carry the ApoE ,4 allele. [source] Inter-hemispheric inhibition is impaired in mirror dystoniaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2009S. Beck Abstract Surround inhibition, a neural mechanism relevant for skilled motor behavior, has been shown to be deficient in the affected primary motor cortex (M1) in patients with focal hand dystonia (FHD). Even in unilateral FHD, however, electrophysiological and neuroimaging studies have provided evidence for bilateral M1 abnormalities. Clinically, the presence of mirror dystonia, dystonic posturing when the opposite hand is moved, also suggests abnormal interhemispheric interaction. To assess whether a loss of inter-hemispheric inhibition (IHI) may contribute to the reduced surround inhibition, IHI towards the affected or dominant M1 was examined in 13 patients with FHD (seven patients with and six patients without mirror dystonia, all affected on the right hand) and 12 right-handed, age-matched healthy controls (CON group). IHI was tested at rest and during three different phases of a right index finger movement in a synergistic, as well as in a neighboring, relaxed muscle. There was a trend for a selective loss of IHI between the homologous surrounding muscles in the phase 50 ms before electromyogram onset in patients with FHD. Post hoc analysis revealed that this effect was due to a loss of IHI in the patients with FHD with mirror dystonia, while patients without mirror dystonia did not show any difference in IHI modulation compared with healthy controls. We conclude that mirror dystonia may be due to impaired IHI towards neighboring muscles before movement onset. However, IHI does not seem to play a major role in the general pathophysiology of FHD. [source] The utility of behavioral models and modules in molecular analyses of social behaviorGENES, BRAIN AND BEHAVIOR, Issue 3 2008Andrew B. Barron It is extremely difficult to trace the causal pathway relating gene products or molecular pathways to the expression of behavior. This is especially true for social behavior, which being dependent on interactions and communication between individuals is even further removed from molecular-level events. In this review, we discuss how behavioral models can aid molecular analyses of social behavior. Various models of behavior exist, each of which suggest strategies to dissect complex behavior into simpler behavioral ,modules.' The resulting modules are easier to relate to neural processes and thus suggest hypotheses for neural and molecular function. Here we discuss how three different models of behavior have facilitated understanding the molecular bases of aspects of social behavior. We discuss the response threshold model and two different approaches to modeling motivation, the state space model and models of reinforcement and reward processing. The examples we have chosen illustrate how models can generate testable hypotheses for neural and molecular function and also how molecular analyses probe the validity of a model of behavior. We do not champion one model over another; rather, our examples illustrate how modeling and molecular analyses can be synergistic in exploring the molecular bases of social behavior. [source] Ammonia impairs neutrophil phagocytic function in liver disease,HEPATOLOGY, Issue 4 2008Debbie L. Shawcross Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38MAPK) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 ,M ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38MAPK modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n = 8) or an amino acid solution inducing hyperammonemia (n = 8). Cell volume and phagocytosis was analyzed by fluorescent-activated cell sorting using fluorescein isothiocyanate,labeled E. coli. p38MAPK phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38MAPK intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38MAPK agonist. Conclusion: Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38MAPK intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction. (HEPATOLOGY 2008.) [source] | |||||||||||||||||||||||||||||||||||||||||||||||||