Home About us Contact
|
Home About us Contact | ||
|
|
||
Independent Action (independent + action)
Selected AbstractsSignificance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysisENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2005Martijs J. Jonker Abstract In ecotoxicology, the state of the art for effect assessment of chemical mixtures is through multiple dose,response analysis of single compounds and their combinations. Investigating whether such data deviate from the reference models of concentration addition and/or independent action to identify overall synergism or antagonism is becoming routine. However, recent data show that more complex deviation patterns, such as dose ratio,dependent deviation and dose level,dependent deviation, need to be addressed. For concentration addition, methods to detect such deviation patterns exist, but they are stand-alone methods developed separately in literature, and conclusions derived from these analyses are therefore difficult to compare. For independent action, hardly any methods to detect such deviations from this reference model exist. This paper describes how these well-established mixture toxicity principles have been incorporated in a coherent data analysis procedure enabling detection and quantification of dose level,and dose ratio,specific synergism or antagonism from both the concentration addition and the independent action models. Significance testing of which deviation pattern describes the data best is carried out through maximum likelihood analysis. This analysis procedure is demonstrated through various data sets, and its applicability and limitations in mixture research are discussed. [source] Can the choice of endpoint lead to contradictory results of mixture-toxicity experiments?ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2005Nina Cedergreen Abstract Theoretically, the effect of two independently acting compounds in a mixture will depend on the slope of the dose-response curves of the individual compounds if evaluated in relation to the model of concentration addition (CA). In the present study, we explored development of the shape of the dose-response relationship for four different recommended endpoints (surface area, frond number, fresh weight-specific, and dry weight-specific relative growth rates [RGRA, RGRF, RGRFW, and RGRDW, respectively]) and for two differently acting herbicides (metsulfuron-methyl and terbuthylazine) over time (3,15 d) on the standard test plant Lemna minor to identify endpoints and experiment times for which predictions of independent action (IA) would depart the most from those of CA. After a test time of 6 d, predictions of IA based on RGRA and RGRFW showed antagonism in relation to CA. Based on RGRDW, synergy was predicted, whereas IA based on RGRF was indistinguishable from CA. To test the prediction of choice of endpoint giving different results in mixture-toxicity experiments, three endpoints and six combinations of independently acting herbicides were evaluated using isobolograms. The experiments showed that in four of six herbicide combinations, different conclusions were reached depending on endpoint. The contradictory isoboles did not follow the theory of IA and, therefore, are more likely to be related to differences in susceptibility of the physiological processes affecting each endpoint than to the shape of the dose-response curve. [source] Algal toxicity of nitrobenzenes: Combined effect analysis as a pharmacological probe for similar modes of interactionENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2005Rolf Altenburger Abstract An analysis regarding the effects of the mixture toxicity of different nitrobenzenes on the reproduction of the green alga Scenedesmus vacuolatus was undertaken using the concepts of concentration addition and response addition. Using lipophilicity-based quantitative structure-activity relationship (QSAR) modeling for nitrobenzenes, the assumption is held that mononitrobenzenes may exert narcotic effects as a common type of action, whereas dinitrobenzenes show a somewhat greater toxicity. From the literature, QSARs based on quantum chemical parameters suggest that some mononitrobenzenes may be effective through additional other modes of action. The toxicity of a mixture of 14 nitrobenzenes clearly exceeds the predicted combined effects, as expected for the sum of toxic units from a uniform narcotic mode of action. Moreover, the observed combined effect is smaller than that predicted from similarly acting compounds calculated on the basis of the parameterized dose-response functions using concentration addition. Further modeling of the combined effect, joining the models of concentration addition for components with anticipated similar modes of action and of response addition for those with independent action, led us to propose that not all nitrobenzenes follow the same mode of action. This idea is in line with the hypothesis derived from quantum chemical QSAR considerations. Most interestingly, the methodology introduced here uses combined effect analysis as a pharmacological probe to test for similarity in the mode of action of mixture components. [source] Dopaminergic signalling in the rodent neonatal suprachiasmatic nucleus identifies a role for protein kinase A and mitogen-activated protein kinase in circadian entrainmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2002Irina L. Schurov Abstract The circadian clock of the suprachiasmatic nuclei (SCN) of perinatal rodents is entrained by maternally derived cues. The SCN of neonatal Syrian hamsters express high-affinity D1 dopamine receptors, and the circadian activity,rest cycle of pups can be entrained by maternal injection of dopaminergic agonists. The present study sought to characterize the intracellular pathways mediating dopaminergic signalling in neonatal rodent SCN. Both dopamine and the D1 agonist SKF81297 caused a dose-dependent increase in phosphorylation of the transcriptional regulator Ca2+/cyclic AMP response element (CRE) binding protein (CREB) in suprachiasmatic GABA-immunoreactive (-IR) neurons held in primary culture. The D1 antagonist SCH23390 blocked this effect. Dopaminergic induction of pCREB-IR in GABA-IR neurons was also blocked by a protein kinase A (PKA) inhibitor, 5,24, and by the MAPK inhibitor, PD98059, whereas KN-62, an inhibitor of Ca2+/calmodulin-dependent (CAM) kinase II/IV was ineffective. Treatment with NMDA increased the level of intracellular Ca2+ in the cultured primary SCN neurons in Mg2+ -free medium, but SKF81297 did not. Blockade of CaM kinase II/IV with KN-62 inhibited glutamatergic induction of pCREB-IR in GABA-IR neurons, whereas 5,24 was ineffective, confirming the independent action of Ca2+ - and cAMP-mediated inputs on pCREB. SKF81297 caused an increase in pERK-IR in SCN cells, and this was blocked by 5,24, indicative of activation of MAPK via D1/cAMP. These results demonstrate that dopaminergic signalling in the neonatal SCN is mediated via the D1-dependent activation of PKA and MAPK, and that this is independent of the glutamatergic regulation via Ca2+ and CaM kinase II/IV responsible for entrainment to the light/dark cycle. [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] The infectivity of transmissible spongiform encephalopathy agent at low doses: the importance of phospholipidJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2006P. Gale Abstract The issue of whether the mechanism of infection is independent or co-operative for low doses of transmissible spongiform encephalopathy (TSE) agent is critical for risk assessment. The susceptibility (and hence ID50) of individuals with the same prion protein (PrP) genotype may vary considerably with a small proportion being very susceptible. Assuming independent action, the incubation period (IP) would continue to increase until the dose is below the ID50 of the most susceptible individuals in the experiment, at which point it would become constant. This may explain the observed increase in IP with decreasing dose below the apparent ID50 in experiments with untreated TSE agent. In contrast, IPs for autoclaved or NaOH-treated TSE agent increase greatly at doses Active conscience or administrative vanguard?: The Commissioner of Official Languages as an agent of changeCANADIAN PUBLIC ADMINISTRATION/ADMINISTRATION PUBLIQUE DU CANADA, Issue 2 2006C. Michael MacMillan Its ombudsman component is enhanced by extensive powers of independent action, which make it an important instrument for holding governmental institutions accountable. Developments in federal language policy since 1980 have given far greater importance to its policy advocacy role, which has been vigorously exercised in legal interventions. Its role as linguistic auditor general is perhaps overstated and may more accurately be described as an enhancement of the ombudsman role. Its significant policy advocacy role poses issues regarding the significance of federalism in regard to language matters. Increasingly the commission conducts its activities at the intersection point of constitutional jurisdictions and must navigate around them. In addressing this ongoing challenge, the Commissioner of Official Languages operates in the vanguard of public officials on the national unity front. Sommaire: Le poste de Commissaire aux langues officielles en tant que haut fonctionnaire du Parlement est une institution unique qui intègre de multiples rôles. Son rôle de médiateur comporte de vastes pouvoirs d'action indépendante, qui en font un instrument important en ce qui concerne l'imputabilité des institutions gouverne-mentales. Les nouveautés dans la politique linguistique fédérate depuis 1980 ont accordé une importance beaucoup plus grande à son rôle de défenseur de politiques vigoureusement exercé dans certaines interventions judiciaires. Son rôle de Vérificateur général linguistique est peut-être exagéré et pourrait être plus correctement décrit comme un rôle amélioré de protecteur du citoyen. Son rôle considerable de défenseur de politiques pose des problèmes concernant l'importance du fédéralisme face aux questions linguistiques. La Commission exerce de plus en plus ses activités au point d'intersection de juridictions constitutionnelles et doit en tenir compte. Face à ces défis permanents, le Commissaire aux langues officielles agit à l'avant-garde des agents publics sur le front de l'unité nationale. [source] Neuropharmacological basis of combining antidepressantsACTA PSYCHIATRICA SCANDINAVICA, Issue 2005J. de la Gándara Objective:, To review the neuropharmacological basis of antidepressant combination therapy. Method:, Literature searches and other relevant material were obtained and reviewed. Results:, The overall clinical aim of combining antidepressants is to increase the efficacy whilst minimizing the side effects. Although such prescriptions are frequently based on the previous experience and knowledge, a sound neuropharmacological basis to support these combinations is desirable. When combining antidepressants, it is important to combine mechanisms of action, rather than simply one drug with another, and to aim for synergistic effects. The possibilities of combining mechanisms of action should also be exploited to the full if necessary, and the potential exists for combining two independent actions that have synergistic effects on the serotonergic, noradrenergic and even the dopaminergic systems. Conclusion:, Unfortunately, there are still, as yet, insufficient data to categorically justify choosing one or other combination based only on the neuropharmacological evidence. [source] Modulation of growth hormone action by sex steroidsCLINICAL ENDOCRINOLOGY, Issue 4 2006Udo J. Meinhardt Summary Growth hormone (GH) is a major regulator of growth, somatic development and body composition. Sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness. This review addresses data of potential clinical relevance on how sex steroids modulate GH secretion and action, aiming to increase the understanding of sex steroid/GH interactions and leading to improved management of patients. Sex steroids regulate GH secretion directly as well as indirectly through IGF-I modulation. Testosterone stimulates GH secretion centrally, an effect dependent on prior aromatization to oestrogen. Oestrogen stimulates GH secretion indirectly by reducing IGF-I feedback inhibition. Whether oestrogen stimulates GH secretion centrally in females is unresolved. Gonadal steroids modify the metabolic effects of GH. Testosterone amplifies GH stimulation of IGF-I, sodium retention, substrate metabolism and protein anabolism while exhibiting similar but independent actions of its own. Oestrogen attenuates GH action by inhibiting GH-regulated endocrine function of the liver. This is a concentration-dependent phenomenon that arises invariably from oral administration of therapeutic doses of oestrogen, an effect that can be avoided by using a parenteral route. This strong modulatory effect of gonadal steroids on GH responsiveness provides insights into the biological basis of sexual dimorphism in growth, development and body composition and practical information for the clinical endocrinologist. It calls for an appraisal of the diagnostic criteria for GH deficiency of GH stimulation tests, which currently are based on arbitrary cut-offs that do not take into account the shifting baseline from the changing gonadal steroid milieu. In the management of GH deficiency in the hypopituitary female, oestrogen should be administered by a nonoral route. In hypopituitary men, androgens should be replaced concurrently to maximize the benefits of GH. In the general population, the metabolic consequences of long-term treatment of women with oral oestrogen compounds, including selective oestrogen receptor modulators, are largely unknown and warrant study. [source]
| | ||||||||||||