Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

On the relationship between C and N fixation in nodulated alfalfa (Medicago sativa)

Legumes such as alfalfa (Medicago sativa L.) are vital N2-fixing crops accounting for a global N2 fixation of ~35 MtNyear-1. Although enzymatic and molecular mechanisms of nodule N2 fixation are now well documented, some uncertainty remains as to whether N2 fixation is strictly coupled with photosynthetic carbon fixation. That is, the metabolic origin and redistribution of carbon skeletons used to incorporate nitrogen are still relatively undefined. Here, we conducted isotopic labelling with both 15N2 and 13C-depleted CO2 on alfalfa plants grown under controlled conditions and took advantage of isotope ratio mass spectrometry to investigate the relationship between carbon and nitrogen turn-over in respired CO2, total organic matter and amino acids. Our results indicate that CO2 evolved by respiration had an isotopic composition similar to that in organic matter regardless of the organ considered, suggesting that the turn-over of respiratory pools strictly followed photosynthetic input. However, carbon turn-over was nearly three times greater than N turn-over in total organic matter, suggesting that new organic material synthesised was less N-rich than pre-existing organic material (due to progressive nitrogen elemental dilution) or that N remobilisation occurred to sustain growth. This pattern was not consistent with the total commitment into free amino acids where the input of new C and N appeared to be stoichiometric. The labelling pattern in Asn was complex, with contrasted C and N commitments in different organs, suggesting that neosynthesis and redistribution of new Asn molecules required metabolic remobilisation. We conclude that the production of new organic material during alfalfa growth depends on both C and N remobilisation in different organs. At the plant level, this remobilisation is complicated by allocation and metabolism in the different organs. Additional keywords: carbon exchange, carbon isotopes, nitrogen fixation, nitrogen 15 isotope

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

Protective behavioral strategies and future drinking behaviors: Effect of drinking intentions.

Alcohol use is common among United States and Swedish high school students and is related to negative consequences. Whereas drinking intentions are associated with future drinking behaviors, the use of protective behavioral strategies (PBS) is associated with decreased alcohol-related harm among young adults. The interactive effect of PBS and drinking intentions in predicting alcohol outcomes has not been examined. Further, because most PBS studies have been conducted among U.S. college students, PBS research among other populations is needed. The aims of this study were to evaluate longitudinally (a) the relationships between drinking intentions, PBS and alcohol outcomes, and (b) the moderating roles of drinking intentions and country in these relationships among United States and Swedish high school drinkers. Data were collected at baseline, 6- and 12-month follow-ups on 901 Swedish and 288 U.S. high school drinkers. Drinking intentions were associated with more alcohol use and consequences, and use of certain PBS was related to fewer alcohol-related consequences over time. Additionally, the negative prospective relationship between use of PBS and alcohol use, but not alcohol-related consequences, was moderated by intentions, such that the relationship was stronger among participants endorsing high drinking intentions. Country did not moderate these relationships. These results provide initial support for the generalizability of PBS college research to United States and Swedish high school students and suggest that interventions targeting the use of PBS may be most effective among high school drinkers endorsing high drinking intentions. (PsycINFO Database Record

Methods of Jet to Wire Speed Ratio Determination and Its Effect in Paper and Board Manufacture

Suihku/viira-nopeussuhde on perälaatikon huulisuihkun ja viiran välinen nopeusero. Se vaikuttaa suuresti paperin ja kartongin loppuominaisuuksiin, kuten formaatioon sekä kuituorientaatioon ja näin ollen paperin lujuusominaisuuksiin. Tämän johdosta on erityisen tärkeää tietää todellinen suihku/viira-nopeussuhde paperin- ja kartonginvalmistuksessa. Perinteinen suihku/viira-nopeussuhteen määritysmenetelmä perustuu perälaatikon kokonaispaineeseen. Tällä menetelmällä kuitenkin todellinen huulisuihkun nopeus saattaa usein jäädä tietämättä johtuen mahdollisesta virheellisestä painemittarin kalibroinnista sekä laskuyhtälön epätarkkuuksista. Tämän johdosta on kehitetty useita reaaliaikaisia huulisuihkun mittausmenetelmiä. Perälaatikon parametrien optimaaliset asetukset ovat mahdollista määrittää ja ylläpitää huulisuihkun nopeuden “on-line” määrityksellä. Perälaatikon parametrejä ovat mm. huulisuihku, huuliaukon korkeusprofiili, reunavirtaukset ja syöttövirtauksen tasaisuus. Huulisuihkun nopeuden on-line mittauksella paljastuu myös muita perälaatikon ongelmakohtia, kuten mekaaniset viat, joita on perinteisesti tutkittu aikaa vievillä paperin ja kartongin lopputuoteanalyyseillä.

Relationship between diet and reproductive success in the Israeli barn owl

The effect of diet on barn owl (Tyto alba) breeding biology has been well studied in the temperate regions but not in the more arid Middle East. In temperate regions, barn owls are darker colored and mainly prey upon Cricetidae rodents, whereas in arid regions, they are lighter colored and prey to a larger degree upon Muridae rodents. In this study we analyzed the diet and breeding success of 261 barn owl pairs nesting in Israel. The reproductive success of barn owls declined from March to August, and fledged more young when they consumed a larger proportion of social voles (Microtus socialis guentheri). Although the diet of the lighter colored barn owls in Israel comprises more Muridae than that of the darker morphs in temperate regions, in both regions the number of barn owl young increases with an increased proportion of voles in the diet.

The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

OBJECTIVE: Studies suggest that smoking may be a risk factor for the development of microvascular complications such as diabetic peripheral neuropathy (DPN). The objective of this study was to assess the relationship between smoking and DPN in persons with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: A systematic review of the PubMed, Embase, and Cochrane clinical trials databases was conducted for the period from January 1966 to November 2014 for cohort, cross-sectional and case-control studies that assessed the relationship between smoking and DPN. Separate meta-analyses for prospective cohort studies and case-control or cross-sectional studies were performed using random effects models. RESULTS: Thirty-eight studies (10 prospective cohort and 28 cross-sectional) were included. The prospective cohort studies included 5558 participants without DPN at baseline. During follow-up ranging from 2 to 10 years, 1550 cases of DPN occurred. The pooled unadjusted odds ratio (OR) of developing DPN associated with smoking was 1.26 (95% CI 0.86-1.85; I(2) = 74%; evidence grade: low strength). Stratified analyses of the prospective studies revealed that studies of higher quality and with better levels of adjustment and longer follow-up showed a significant positive association between smoking and DPN, with less heterogeneity. The cross-sectional studies included 27,594 participants. The pooled OR of DPN associated with smoking was 1.42 (95% CI 1.21-1.65; I(2) = 65%; evidence grade: low strength). There was no evidence of publication bias. CONCLUSIONS: Smoking may be associated with an increased risk of DPN in persons with diabetes. Further studies are needed to test whether this association is causal and whether smoking cessation reduces the risk of DPN in adults with diabetes.

Study and modelling of the effect of herbicides pulse exposure on freshwater microalgae

De plus en plus de substances chimiques sont émises et détectées dans l'environnement.Parmi ces substances, on trouve les herbicides qui sont utilisés en agriculture pour luttercontre la présence des mauvaises herbes. Après leur application sur les sols, les herbicidespeuvent être entrainés par les eaux de pluie jusque dans les ruisseaux et les rivières. Lesconcentrations de ces substances varient donc de manière importante dans les systèmesaquatiques en période de pluie ou en période de temps sec. Des pics élevés de concentrationssont suivis de période de concentrations très faibles ou nulles. Les herbicides présents dans lescours d'eau peuvent engendrer des effets toxiques sur les algues et les plantes aquatiques. Orles tests classiques d'écotoxicologie effectués en laboratoire sont réalisés en exposant lesespèces vivantes à des polluants de manière continue. Ils ne permettent donc pas d'évaluer leseffets des concentrations fluctuantes comme celles des herbicides. Le but de cette thèse estd'étudier et de modéliser les effets des concentrations fluctuantes d'herbicide sur les espècesde microalgues vertes Scenedesmus vacuolatus et Pseudokirchneriella subcapitata. Desexpériences en laboratoire ont également été effectuées dans le but de valider le modèle.Quatre herbicides ont été testés. Il s'agit de l'atrazine (utilisé jusqu'à récemment pour lemaïs), du diuron (utilisé dans la vigne), de l'isoproturon (utilisé pour les céréales) et du Smétolachlore(utilisé pour le maïs). Les résultats de ce travail de thèse indiquent que les effetsdes concentrations fluctuantes d'herbicide peuvent être modélisés sur des algues d'eau douce.Le modèle est relativement simple pour les inhibiteurs de la photosynthèse tels que l'atrazine,le diuron ou l'isoproturon. Il nécessite la connaissance de deux paramètres, le taux decroissance de l'algue sans polluant et la courbe dose-réponse pour chaque substance.Cependant, des expériences supplémentaires doivent être réalisées si la substance étudiéeinduit un délai de l'effet et du rétablissement ou si une algue est cultivée avec une autre alguedans le même milieu de croissance. Le modèle pourrait également être adapté pour tenircompte des mélanges de substances. Appliqué pour prédire les effets sur les algues descénarios réels, le modèle montre que les longs pics de concentrations jouent le rôle le plusimportant. Il est donc crucial de les mesurer lors du monitoring des cours d'eau. D'autre part,une évaluation du risque effectuée avec ce modèle montre que l'impact des pics deconcentrations sur les espèces les plus sensibles est total. Cela met en évidence, une fois deplus, l'importance de tenir compte de ces concentrations fluctuantes dans l'évaluation durisque environnemental des herbicides, mais également des autres polluants.

The effect of learning on the evolution of new courtship behavior: a simulation model

The fact that individuals learn can change the relationship between genotype and phenotype in the population, and thus affect the evolutionary response to selection. Here we ask how male ability to learn from female response affects the evolution of a novel male behavioral courtship trait under pre-existing female preference (sensory drive). We assume a courtship trait which has both a genetic and a learned component, and a two-level female response to males. With individual-based simulations we show that, under this scenario, learning generally increases the strength of selection on the genetic component of the courtship trait, at least when the population genetic mean is still low. As a consequence, learning not only accelerates the evolution of the courtship trait, but also enables it when the trait is costly, which in the absence of learning results in an adaptive valley. Furthermore, learning can enable the evolution of the novel trait in the face of gene flow mediated by immigration of males that show superior attractiveness to females based on another, non-heritable trait. However, rather than increasing monotonically with the speed of learning, the effect of learning on evolution is maximized at intermediate learning rates. This model shows that, at least under some scenarios, the ability to learn can drive the evolution of mating behaviors through a process equivalent to Waddington's genetic assimilation.

Epidermal growth factor secreted from submandibular salivary glands interferes with the lipolytic effect of adrenaline in mice

We had described that epidermal growth factor (EGF) interfered with the lipolytic effect of catecholamines in isolated adipocytes. Since catecholamines stimulate the release of EGF from submandibular salivary glands to blood plasma in male mice, we studied whether EGF affected also the lipolytic response to adrenaline in whole animals. We studied the effect of adrenaline in sialoadenectomized and sham-operated mice receiving or not a high dose of EGF following adrenaline injection. There was no difference in plasma EGF concentration between sham-operated and sialoadenectomized animals receiving saline. After adrenaline administration plasma EGF increased by 20-fold in sham-operated but did not increase in sialoadenectomized mice. Indeed, the increase was much higher (more than 100-fold) in mice receiving exogenous EGF. The effect of adrenaline on plasma concentration of both glycerol and nonesterified fatty acids was higher as lower was plasma EGF concentration. Isolated adipocytes obtained from sham-operated or sialoadenectomized mice had identical lipolytic response to adrenaline. The lipolytic response of adipocytes to isoproterenol was decreased by addition of EGF. To study whether the interference with the in vivo lipolytic effect of adrenaline had further metabolic consequences, we measured plasma b-hydroxybutyrate concentration in plasma. There was no difference in the response to adrenaline between sham-operated and sialoadenectomized mice in spite of the difference in plasma nonsterified fatty acid concentration. Studies in isolated hepatocytes indicated that ketogenesis run at near maximal rate in this range of substrate concentration. These results suggest that EGF in the physiological range decreases the lipolytic effect of adrenaline but does not compromise further metabolic events like the enhancement of ketogenesis.

Effect of diet composition and ration size on key enzyme activities of glycolysis-gluconeogenesis, pentose phosphate pathway and amino acid metabolism in liver of Sparus aurata

The effects of diet composition and ration size on the activities of key enzymes involved in intermediary metabolism were studied in the liver of gilthead sea bream (Sparus aurata). Highcarbohydrate, low-protein diets stimulated 6-phosphofructo 1-kinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40), glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) enzyme activities, while they decreased alanine aminotransferase (EC 2.6.1.2) activity. A high degree of correlation was found between food ration size and the activity of the enzymes 6-phosphofructo 1-kinase, pyruvate kinase, glucose-6-phosphate dehydrogenase (positive correlations) and fructose-1,6-bisphosphatase (EC 3.1.3.11) (negative correlation). These correlations matched well with the high correlation also found between ration size and growth rate in starved fish refed for 22 d. Limited feeding (5 g/kg body weight) for 22 d decreased the activities of the key enzymes for glycolysis and lipogenesis, and alanine aminotransferase activity. The findings presented here indicate a high level of metabolic adaptation to both diet type and ration size. In particular, adaptation of enzyme activities to the consumption of a diet with a high carbohydrate level suggests that a carnivorous fish like Sparus aurata can tolerate partial replacement of protein by carbohydrate in the commercial diets supplied in culture. The relationship between enzyme activities, ration size and fish growth indicates that the enzymes quickly respond to dietary manipulations of cultured fish.

Effect of diet composition and ration size on key enzyme activities of glycolysis-gluconeogenesis, pentose phosphate pathway and amino acid metabolism in liver of Sparus aurata

The effects of diet composition and ration size on the activities of key enzymes involved in intermediary metabolism were studied in the liver of gilthead sea bream (Sparus aurata). Highcarbohydrate, low-protein diets stimulated 6-phosphofructo 1-kinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40), glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) enzyme activities, while they decreased alanine aminotransferase (EC 2.6.1.2) activity. A high degree of correlation was found between food ration size and the activity of the enzymes 6-phosphofructo 1-kinase, pyruvate kinase, glucose-6-phosphate dehydrogenase (positive correlations) and fructose-1,6-bisphosphatase (EC 3.1.3.11) (negative correlation). These correlations matched well with the high correlation also found between ration size and growth rate in starved fish refed for 22 d. Limited feeding (5 g/kg body weight) for 22 d decreased the activities of the key enzymes for glycolysis and lipogenesis, and alanine aminotransferase activity. The findings presented here indicate a high level of metabolic adaptation to both diet type and ration size. In particular, adaptation of enzyme activities to the consumption of a diet with a high carbohydrate level suggests that a carnivorous fish like Sparus aurata can tolerate partial replacement of protein by carbohydrate in the commercial diets supplied in culture. The relationship between enzyme activities, ration size and fish growth indicates that the enzymes quickly respond to dietary manipulations of cultured fish.

Supplier relationship management capability in the firm's global integration

Organizing is a general problem for global firms. Firms are seeking a balance between responsiveness at the local level and efficiency through worldwide integration. In this, supply management is the focal point where external commercial supply market relations are connected with the firm's internal functions. Here, effective supplier relationship management (SRM) is essential. Global supply integration processes create new challenges for supply management professionals and new capabilities are required. Previous research has developed several models and tools for managers to manage and categorize different supplier relationship types, but the role of the firm's internal capability of managing supplier relationships in their global integration has been a clearly neglected issue. Hence, the main objective of this dissertation is to clarify how the capability of SRM may influence the firm's global competitiveness. This objective is divided into four research questions aiming to identify the elements of SRM capability, the internal factors of integration, the effect of SRM capability on strategy and how SRM capability is linked with global integration. The dissertation has two parts. The first part presents the theoretical approaches and practical implications from previous research and draws a synthesis on them. The second part comprises four empirical research papers addressing the research questions. Both qualitative and quantitative methods are utilized in this dissertation. The main contribution of this dissertation is that it aggregates the theoretical and conceptual perspectives applied to SRM research. Furthermore, given the lack of valid scales to measure capability, this study aimed to provide a foundation for an SRM capability scale by showing that the construct of SRM capability is formed of five separate elements. Moreover, SRM capability was found to be the enabler in efforts toward value chain integration. Finally, it was found that the effect of capability on global competitiveness is twofold: it reduces conflicts between responsiveness and integration, and it creates efficiency. Thus, by identifying and developing the firm's capabilities it is possible to improve performance, and hence, global competitiveness.

Effect of the radiolitic sterilization in polyethylene/starch blends

Samples of LDPE/modified starch blends 80/20 m/m before and after exposure to gamma rays were examined by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction. The effect of gamma radiation is clearly seen in the samples irradiated at a dose of 25 kGy. The main alteration in the polymeric material after exposure at the radiation range was a decrease in the mechanical properties, alterations in the chemical structure of the blend with an increase in the carbonyl and vinyl indices and the appearance of new crystalline symmetry generating a crystalline domain not existing before in the blend.