Natural Products from Antarctic Colonial Ascidians of the Genera Aplidium and Synoicum: Variability and Defensive Role

Ascidians have developed multiple defensive strategies mostly related to physical, nutritional or chemical properties of the tunic. One of such is chemical defense based on secondary metabolites. We analyzed a series of colonial Antarctic ascidians from deep-water collections belonging to the genera Aplidium and Synoicum to evaluate the incidence of organic deterrents and their variability. The ether fractions from 15 samples including specimens of the species A. falklandicum, A. fuegiense, A. meridianum, A. millari and S. adareanum were subjected to feeding assays towards two relevant sympatric predators: the starfish Odontaster validus, and the amphipod Cheirimedon femoratus. All samples revealed repellency. Nonetheless, some colonies concentrated defensive chemicals in internal body-regions rather than in the tunic. Four ascidian-derived meroterpenoids, rossinones B and the three derivatives 2,3-epoxy-rossinone B, 3-epi-rossinone B, 5,6-epoxy-rossinone B, and the indole alkaloids meridianins AG, along with other minoritary meridianin compounds were isolated from several samples. Some purified metabolites were tested in feeding assays exhibiting potent unpalatabilities, thus revealing their role in predation avoidance. Ascidian extracts and purified compound-fractions were further assessed in antibacterial tests against a marine Antarctic bacterium. Only the meridianins showed inhibition activity, demonstrating a multifunctional defensive role. According to their occurrence in nature and within our colonial specimens, the possible origin of both types of metabolites is discussed.

A method for decision making with the OWA operator

A new method for decision making that uses the ordered weighted averaging (OWA) operator in the aggregation of the information is presented. It is used a concept that it is known in the literature as the index of maximum and minimum level (IMAM). This index is based on distance measures and other techniques that are useful for decision making. By using the OWA operator in the IMAM, we form a new aggregation operator that we call the ordered weighted averaging index of maximum and minimum level (OWAIMAM) operator. The main advantage is that it provides a parameterized family of aggregation operators between the minimum and the maximum and a wide range of special cases. Then, the decision maker may take decisions according to his degree of optimism and considering ideals in the decision process. A further extension of this approach is presented by using hybrid averages and Choquet integrals. We also develop an application of the new approach in a multi-person decision-making problem regarding the selection of strategies.

J2EE: Inter Golf

TFC de la carrera d'ETIS, que pretén mostrar els passos i pautes que es tenen que seguir per desenvolupar l'aplicació Inter Golf en l'arquitectura J2EE. Inter Golf serà una pàgina web destinada a la gestió dels tornejos realitzats en un camp de golf, fent servir J2EE, MVC, Struts2, Hibernate i Tiles.

Ink dating using thermal desorption and gas chromatography / mass spectrometry: comparison of results obtained in two laboratories

Recent ink dating methods focused mainly on changes in solvent amounts occurring over time. A promising method was developed at the Landeskriminalamt of Munich using thermal desorption (TD) followed by gas chromatography / mass spectrometry (GC/MS) analysis. Sequential extractions of the phenoxyethanol present in ballpoint pen ink entries were carried out at two different temperatures. This method is applied in forensic practice and is currently implemented in several laboratories participating to the InCID group (International Collaboration on Ink Dating). However, harmonization of the method between the laboratories proved to be a particularly sensitive and time consuming task. The main aim of this work was therefore to implement the TD-GC/MS method at the Bundeskriminalamt (Wiesbaden, Germany) in order to evaluate if results were comparable to those obtained in Munich. At first validation criteria such as limits of reliable measurements, linearity and repeatability were determined. Samples were prepared in three different laboratories using the same inks and analyzed using two TDS-GC/MS instruments (one in Munich and one in Wiesbaden). The inter- and intra-laboratory variability of the ageing parameter was determined and ageing curves were compared. While inks stored in similar conditions yielded comparable ageing curves, it was observed that significantly different storage conditions had an influence on the resulting ageing curves. Finally, interpretation models, such as thresholds and trend tests, were evaluated and discussed in view of the obtained results. Trend tests were considered more suitable than threshold models. As both approaches showed limitations, an alternative model, based on the slopes of the ageing curves, was also proposed.

The effect of workplace smoking bans on heart rate variability and pulse wave velocity of non-smoking hospitality workers

OBJECTIVES: To investigate the effect of a change in second-hand smoke (SHS) exposure on heart rate variability (HRV) and pulse wave velocity (PWV), this study utilized a quasi-experimental setting when a smoking ban was introduced. METHODS: HRV, a quantitative marker of autonomic activity of the nervous system, and PWV, a marker of arterial stiffness, were measured in 55 non-smoking hospitality workers before and 3-12 months after a smoking ban and compared to a control group that did not experience an exposure change. SHS exposure was determined with a nicotine-specific badge and expressed as inhaled cigarette equivalents per day (CE/d). RESULTS: PWV and HRV parameters significantly changed in a dose-dependent manner in the intervention group as compared to the control group. A one CE/d decrease was associated with a 2.3 % (95 % CI 0.2-4.4; p = 0.031) higher root mean square of successive differences (RMSSD), a 5.7 % (95 % CI 0.9-10.2; p = 0.02) higher high-frequency component and a 0.72 % (95 % CI 0.40-1.05; p < 0.001) lower PWV. CONCLUSIONS: PWV and HRV significantly improved after introducing smoke-free workplaces indicating a decreased cardiovascular risk.

Pharmacokinetic and pharmacodynamic assessment of valganciclovir in solid organ transplant recipients

RESUME : Valganciclovir (Valcyte®) is an orally administered ester prodrug of the standard anticytomegalovirus (CMV) drug ganciclovir. This drug enabled an important reduction of the burden of CMV morbidity and mortality in solid organ transplant recipients. Prevention of CMV infection and treatment of CMV disease requires drug administration during many weeks. Oral drug administration is therefore convenient. Valganciclovir has been developed to overcome the poor oral availability of ganciclovir, which limits its concentration exposure after oral administration and thus its efficacy. This prodrug crosses efficiently the intestinal barrier, is then hydrolyzed into ganciclovir, providing exposure similar to intravenous ganciclovir. Valganciclovir is now preferred for the prophylaxis and treatment of CMV infection in solid organ transplant recipients. Nevertheless, adequate dosage adjustment is necessary to optimize its use, avoiding either insufficient or exaggerate exposure related to differences in its pharmacokinetic profile between patients. The main goal of this thesis was to better describe the pharmacokinetic and pharmacodynamic profile of valganciclovir in solid organ transplant recipients, to assess their reproducibility and their predictability, and thus to evaluate the current recommendations for valganciclovir dosage adjustment and the potential contribution of routine therapeutic drug monitoring (TDM) to patients' management. A total of 437 ganciclovir plasma concentration data from 65 transplant patients (41 kidney, 12 lung, 10 heart and 2 liver recipients, 58 under oral valganciclovir prophylaxis, 8 under oral valganciclovir treatment and 2 under intravenous ganciclovir) were measured using a validated chromatographic method (HPLC) developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by GFR, with further differences between graft types and sex (CL/GFR = 1.7 in kidney, 0.9 in heart and 1.2 in lung and liver recipients) with interpatient variability (CV%) of 26% and interoccasion variability of 12%. Body weight and sex influenced central volume of distribution (V1 = 0.34 l/kg in males and 0.27 l/kg in females) with an interpatient variability of 20%. Residual intrapatient variability was 21 %. No significant drug interaction influenced GCV disposition. VGC prophylactic efficacy and tolerability were good, without detectable dependence on GCV profile. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of GCV profile after oral VGC in solid organ transplant recipients, routine TDM does not appear to be clinically indicated. However, GCV plasma measurement may still be helpful in specific clinical situations such as documentation of appropriate exposure in patients with potentially compromised absorption, or lack of response to CMV disease treatment, or under renal replacement therapy. RESUME : Le valganciclovir (Valcyte®) est un promédicament oral du ganciclovir qui est un anti-infectieux de référence contre les infections à cytomegalovirus (CMV). Cet antiviral a permis de réduire les effets délétères de cette infection jusqu'ici responsable d'une importante morbidité et mortalité chez les transplantés d'organe. La prévention et le traitement de l'infection à CMV sont donc nécessaires mais requièrent l'administration d'un agent antiviral sur une longue période. Un médicament administré par voie orale représente donc un avantage évident. Le valganciclovir a été développé dans le but d'améliorer la faible absorption orale du ganciclovir, et donc son efficacité. Cet ester valylique du ganciclovir traverse plus facilement la barrière gastro-intestinale, puis est hydrolysé en ganciclovir dans la circulation sanguine, produisant une exposition comparable à celle d'une perfusion intraveineuse de ganciclovir. De ce fait, le valganciclovir est devenu largement utilisé pour la prophylaxie mais aussi le traitement de l'infection à CMV. Néanmoins une utilisation optimale de ce nouveau médicament nécessite de bonnes connaissances sur son profil pharmacocinétique afin d'établir un schéma de dose adapté pour éviter tant une surexposition qu'une sous-exposition résultant des différences d'élimination entre les patients. Le but de cette thèse a été d'étudier le profil pharmacocinétique et pharmacodynamique du valganciclovir chez les transplantés d'organe ainsi que sa reproductibilité et sa prédictibilité. Il s'agissait d'apprécier de manière critique le schéma actuellement recommandé pour l'adaptation des doses de valganciclovir, mais aussi la contribution éventuelle d'un suivi des concentrations sanguines en routine. Un total de 437 taux sanguins de ganciclovir ont été mesurés, provenant de 65 patients transplantés d'organe (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques, 58 sous une prophylaxie orale de valganciclovir, 8 sous un traitement de valganciclovir et 2 sous un traitement intraveineux). Une méthode de chromatographie liquide à haute performance a été développée et validée pour cette étude. Les résultats ont été ensuite analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle à deux compartiments avec absorption de premier ordre a permis de décrire les données. La clairance systémique était principalement influencée par le débit de filtration glomérulaire (GFR), avec une différence entre les types de greffe et les sexes (CL/GFR = 1.7 chez les greffés rénaux, 0.9 pour les greffés cardiaques et 1.2 pour le groupe des greffés pulmonaires et hépatiques) avec un variabilité inter-individuelle de 26% (CV%) et une variabilité inter-occasion de 12%. Le poids corporel ainsi que le sexe avaient une influence sur le volume central de distribution (V1 = 0.34 l/kg chez les hommes et 0.27 l/kg chez les femmes) avec une variabilité inter-individuelle de 20%. La variabilité intra-individuelle résiduelle était de 21 %. Aucune interaction médicamenteuse n'a montré d'influence sur le profil du ganciclovir. La prophylaxie avec le valganciclovir s'est révélée efficace et bien tolérée. En conclusion, cette analyse souligne l'importance d'une adaptation de la dose du valganciclovir à la fonction rénale et au poids du patient. Au vu de la bonne reproductibilité et prédictibilité du profil pharmacocinétique du ganciclovir chez les patients transplantés recevant du valganciclovir, un suivi des concentrations sanguines en routine ne semble pas cliniquement indiqué. Néanmoins, la mesure des taux plasmatiques de ganciclovir peut être utile dans certaines situations particulières, comme la vérification d'une exposition appropriée chez des patients susceptibles d'absorption insuffisante, ou ne répondant pas au traitement d'une infection à CMV ou encore sous épuration extra-rénale. RESUME LARGE PUBLIC : Le valganciclovir est un précurseur capable de libérer du ganciclovir, récemment développé pour améliorer la faible absorption orale de ce dernier. Une fois le valganciclovir absorbé, le ganciclovir libéré dans la circulation sanguine devient efficace contre les infections à cytomégalovirus. Ce virus largement répandu est responsable de maladies insidieuses et parfois graves chez les personnes présentant une baisse des défenses immunitaires, comme les greffés d'organe recevant un traitement anti-rejet. Le ganciclovir est administré pendant plusieurs mois consécutifs soit pour prévenir une infection après la transplantation, soit pour traiter une infection déclarée. La facilité d'administration du valganciclovir par voie orale représente un avantage sur une administration du ganciclovir par perfusion, qui nécessite une hospitalisation. Toutefois, la voie orale peut être une source supplémentaire de variabilité chez les patients, avec un impact potentiel sur l'efficacité ou la toxicité du médicament. Le but de cette étude a été - de décrire le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline de la pharmacocinétique) - de définir les facteurs cliniques pouvant expliquer les différences de concentration sanguine observées entre les patients sous une posologie donnée - d'explorer les relations entre les concentrations du médicament dans le sang et son efficacité ou la survenue d'effets indésirables (dont l'étude relève de la discipline de la pharmacodynamie). Cette étude a nécessité le développement et la validation, d'une méthode d'analyse pour mesurer la concentration sanguine du ganciclovir, puis son application à 437 échantillons provenant de 65 patients transplantés d'organe solide (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques) recevant du valganciclovir. Les résultats des mesures effectuées ont été analysés à l'aide d'un outil mathématique afin d'élaborer un modèle du devenir du médicament dans le sang chez chaque patient et à chaque occasion. Cette étude a permis d'évaluer chez des patients recevant le valganciclovir, la vitesse à laquelle l'organisme absorbe, distribue, puis élimine le médicament. La vitesse d'élimination dépendait étroitement de la fonction rénale, du type de greffe et du sexe alors que la distribution dépendait du poids et du sexe du patient. La variabilité non expliquée par ces facteurs cliniques était modérée et vraisemblablement sans conséquence clinique évidente soit sur l'efficacité ou la tolérance, qui se révèlent très satisfaisantes chez les patients de l'étude. Les observations n'ont pas révélé de relation entre les concentrations de médicament et l'efficacité thérapeutique ou la survenue d'effets indésirables, confirmant que les doses relativement faibles utilisées dans notre collectif de patients suffisaient à produire une exposition reproductible à des concentrations adéquates. En conclusion, le profil (et par conséquent l'absorption) du valganciclovir chez les patients transplantés semble bien prédictible après une adaptation de la dose à la fonction rénale et au poids du patient. Un contrôle systématique des concentrations sanguines n'est probablement pas indiqué en routine, mais cette mesure peut présenter un intérêt dans certaines conditions particulières.

Variabilité des concentrations plasmatiques de l'angiotensinogène et risque d'hypertension artérielle chez le rat transgénique [Variability of plasma angiotensinogen levels and risk of hypertension in a transgenic rat model].

AIM: Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors. METHODS: Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction). RESULTS: At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05). CONCLUSION: Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Genetic variability of Brazilian rice landraces determined by SSR markers

The objective of this study was to evaluate the genetic variability of rice (Oryza sativa) landraces collected in Brazilian small farms. Twelve simple sequence repeat (SSR) markers characterized 417 landraces collected in 1986, 1987 and 2003, in the state of Goiás, Brazil. The number of landraces with long and thin grain type increased in the evaluated period, probably due to market demand. Based on the molecular data, the genetic variability increased during this period and, as per to the factorial correspondence analysis, most of the accessions were grouped according to the year of collection. The incorporation of modern rice cultivars in landrace cultivation areas and the selection carried out by small farmers are the most probable factors responsible for increasing landrace genetic variability, during the evaluated period. Genotype exchange between farmers, selection practice and local environmental adaptation are able to generate novel adapted allele combinations, which can be used by breeding programs, to reinitiate the process.

Diurnal and exercise-related variability of haemoglobin and reticulocytes in athletes.

Haemoglobin (Hb) and Reticulocytes (Ret) are measured as indirect markers of doping in athletes. We studied the diurnal variation, the impact of exercise, fluid intake and ambient temperature in athletes on these parameters. Hourly venous blood samples were obtained from 36 male athletes of different disciplines (endurance (END) and non-endurance (NON-END)) over 12 h during a typical training day. Seven inactive subjects served as controls (CON). Hb and Ret were determined. A mixed model procedure was used to analyse the data. At baseline, Hb was similar for all groups, END showed lower Ret than NON-END and CON. Exercise showed a significant impact on Hb (+0.46 g/dl, p<0.001), the effect disappeared approximately 2 h after exercise. Hb decreased over the day by approximately 0.55 g/dl (p<0.01). There was no relevant effect on Ret. Fluid intake and ambient temperature had no significant effect. Hb shows significant diurnal- and exercise related variations. In an anti-doping context, most of these variations are in favour of the athlete. Blood samples taken after exercise might therefore provide reliable results and thus be used for the longitudinal monitoring of athletes if a timeframe for the re-equilibration of vascular volumes is respected.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Divergence and genetic variability among superior rubber tree genotypes

The objective of this work was to estimate the genetic variability and divergence among 22 superior rubber tree (Hevea sp.) genotypes of the IAC 400 series. Univariate and multivariate analyses were performed using eight quantitative traits (descriptors), including yield. In the univariate analyses, the estimated parameters were: genetic and environmental variances; genetic and environmental coefficients of variation; and the variation index. The Mahalanobis generalized distance, the Tocher agglomerative method and canonical variables were used for the multivariate analyses. In the univariate analyses, variability was verified among the genotypes for all the variables evaluated. The Tocher method grouped the genotypes into 11 clusters of dissimilarity. The first four canonical variables explained 87.93% of the cumulative variation. The highest genetic variability was found in rubber yield-related traits, which contributed the most to the genetic divergence. The most divergent pairs of genotypes are suggested for crossbreeding. The genotypes evaluated are suitable for breeding and may be used to continue the IAC rubber tree breeding program.

Raman analysis of multilayer automotive paints in forensic science: measurement variability and depth profile?

The aim of this work is to study the influence of several analytical parameters on the variability of Raman spectra of paint samples. In the present study, microtome thin section and direct (no preparation) analysis are considered as sample preparation. In order to evaluate their influence on the measures, an experimental design such as 'fractional full factorial' with seven factors (including the sampling process) is applied, for a total of 32 experiments representing 160 measures. Once the influence of sample preparation highlighted, a depth profile of a paint sample is carried out by changing the focusing plane in order to measure the colored layer under a clearcoat. This is undertaken in order to avoid sample preparation such a microtome sectioning. Finally, chemometric treatments such as principal component analysis are applied to the resulting spectra. The findings of this study indicate the importance of sample preparation, or more specifically, the surface roughness, on the variability of the measurements on a same sample. Moreover, the depth profile experiment highlights the influence of the refractive index of the upper layer (clearcoat) when measuring through a transparent layer.

Genetic parameters and variability in physic nut accessions during early developmental stages

The objective of this work was to estimate the genetic parameters and variability among accessions (half-sib families) of physic nut (Jatropha curcas) during the early stages of development. For this study, 110 accessions in the first year of development of the physic nut germplasm bank, maintained at Embrapa Cerrados, DF, Brazil, were evaluated in situ. The experiment was established in a randomized complete block design, with two replicates and five plants per plot arranged in rows at 4x2 m spacing. Grain yield, total number of branches per plant, plant height, stem diameter, canopy projection on the row, canopy projection between rows, canopy volume, number of days until first flowering and height of the first inflorescence were evaluated. Estimates of vegetative genetic parameters showed the existence of genetic variability in the physic nut germplasm bank. Physic nut accessions of the germplasm bank were grouped into five similarity groups based on character divergence. Although preliminary, the obtained results are promising for showing potential for Jatropha improvement with selective efficiency.