Xilax, creació i llançament d'un producte nou

Treball de recerca realitzat per un alumne d’ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l’any 2008. S’ha desenvolupat el llançament d’un nou producte al mercat farmacèutic, concretament un xiclet. Per començar s’ha estudiat la composició química del xiclet i com actua de vehicle de principis actius des del punt de vista farmacològic. Simultàniament s’ha dissenyat un xiclet amb propietats terapèutiques, assegurant-se que no existeix al mercat i que és innovador. A partir de la definició del producte i de l’anàlisi dels mètodes tradicionals de fabricació, s’ha optimitzat el procés de fabricació per control de variables. Quan s’ha tingut el prototipus del producte, s’ha avaluat en relació amb els objectius marcats. Finalment s’ha estudiat la viabilitat econòmica. Després d’haver refusat diferents idees de nou producte, per no innovadores o per inviables, s’ha pogut optimitzar el procés de fabricació, s’han ajustat les variables i s’ha obtingut el producte definit com a objectiu. L’estudi de viabilitat econòmica el fa rentable, i està a punt per a la comercialització.

Role of microRNAs in the pathogenesis of Ewing's sarcoma

SummaryEwing's sarcoma family tumors (ESFT) are the second most frequent cancer of bone in adolescents and young adults. ESFT are characterized by a chromosomal translocation that involves the 5' segment of the EWSR1 gene and the 3' segment of an ets transcription factor family member gene. In 85% of cases the chromosomal translocation generates the fusion protein EWSR1-FLI-1. Recent work from our laboratory identified mesenchymal stem cells (MSC) as the putative cell of origin of ESFT and characterized a CD133+ subpopulation of ESFT cells with tumor initating and self-renewal capacity, known as cancer stem cells (CSC). MicroRNAs (miRNAs) are small non-coding RNA that regulate protein expression at the post-transcriptional level by either repressing translation or destabilizing mRNA. MiRNAs participate in several biological processes including cell proliferation and differentiation. We used miRNA expression profile comparison between MSC and ESFT cell lines and CD133+ ESFT cells and CD133" ESFT cells to investigate the role of miRNAs in ESFT pathogenesis. MiRNA expression profile comparison of MSC and ESFT cell lines identified 35 differentially expressed miRNAs. Among these was down-regulation of let-7a which results, in part, by the direct repression of let-7a-l promoter by EWSR1-FLI-1. Overexpression of let-7a in ESFT cells blocked ESFT tumorigenesis through an High-motility group AT-hook2 (HMGA2)-mediated mechanism.MiRNA profiling of CD133+ ESFT and CD 133" ESFT cells revealed a broad repression of miRNAs in CD133+ ESFT mediated by down-regulation of TARBP2, a central regulator of the miRNA maturation pathway. Down-regulation of TARBP2 in ESFT cell lines results in a miRNA expression profile reminescent of that observed in CD133+ ESFT and associated with increased tumorigenicity. Enhancement of TARBP2 activity using the antibiotic enoxacin or overexpression of miRNA-143 or miRNA-145, two targets of TARBP2, impaired ESFT CSC self-renewal and block ESFT tumorigenicity. Moreover in vivo administration of synthetic let- 7a, miRNA-143 or miRNA-145 blocks ESFT tumor growth.Thus, dysregulation of miRNA expression is a key feature in ESFT pathogenesis and restoration of their expressions might be used as a new therapeutic tool.RésuméLe sarcome d'Ewing est la deuxième tumeur osseuse la plus fréquente chez l'enfant et le jeune adolescent. Le sarcome d'Ewing est caractérisé par une translocation chromosomique qui produit une protéine de fusion EWSR1-FLI-1. Des récents travaux ont identifié les cellules mésenchymateuses souches (MSC) comme étant les cellules à l'origine du sarcome d'Ewing ainsi qu'une sous-population de cellules exprimant le marqueur CD 133, dans le sarcome d'Ewing connu comme les cellules cancéreuses souches (CSC). Ces cellules ont la capacité d'initier la croissance tumorale et possèdent des propriétés d'auto-renouvellement. Les microRNAs (miRNAs) sont de petits ARN qui ne codent pas pour des protéines et qui contrôlent l'expression des protéines en bloquant la traduction ou en dégradant l'ARNm. Les miRNAs participent à différents processus biologiques comme la prolifération et la différenciation cellulaires.Le but de ce travail est d'étudier le rôle des miRNAs dans le sarcome d'Ewing. Un profil d'expression de miRNAs entre les MSC et des lignées cellulaires de sarcome d'Ewing a mis en évidence 35 miRNAs différemment exprimés. Parmi ceux-ci, la répression de let-7a est liée à la répression directe du promoteur de let-7a-l par EWSR-FLI-1. La sur-expression de let-7a dans des lignées cellulaires de sarcome d'Ewing inhibe leur croissance tumorale. Cette inhibition de croissance tumorale est régulée par la protéine high-motility group AT-hook2 (HMGA2).Un profil d'expression de miRNAs entre les cellules du sarcome d'Ewing CD133+ et CD133" montre une sous-expression d'un grand nombre de miRNAs dans les cellules CD133+ par rapport aux cellules CD133". Cette différence d'expression de miRNAs est due à la répression du gène TARBP2 qui participe à la maturation des miRNAs. La suppression de TARBP2 dans des cellules d'Ewing induit un profil d'expression de miRNAs similaire aux cellules CD133+ du sarcome d'Ewing et augmente la tumorigenèse des lignées cellulaires. De plus l'utilisation d'enoxacin, une molécule qui augmente l'activité de TARBP2 ou la sur- expression des miRNA143 ou miRNA-145 dans les CSC du sarcome d'Ewing bloque l'auto- renouvellement des cellules et la croissance tumorale. Finalement, l'administration de let-7a, miRNA-143 ou miRNA-145, dans des souris bloque la croissance du sarcome d'Ewing. Ces résultats indiquent que la dysrégulation des miRNAs participe à la pathogenèse du sarcome d'Ewing et que les miRNAs peuvent être utilisés comme des agents thérapeutiques.

Influência da temperatura na biologia de triatomíneos: IX. Rhodnius nasutus Stal, 1859 (Hemiptera, Reduviidae)

Estudou-se a influência da temperatura na biologia de Rhodnius nasutus Stal, 1859 (Hemiptera, Reduviidae), tendo em vista a sua criação em grande escala, em laboratório, para serem utilizados no xenodiagnóstico e fornecer informações que subsidien as ações de controle. Os experimentos realizaram-se em duas câmaras climatizadas, a 25 ± 0,5ºC e 3º ± 1ºC, com umidade relativa de 70 ± 5% e fotoperíodo de 12 horas. Apresentam-se os dados relativos ao ciclo evolutivo, pré-postura, fecundidade, fertilidade, sobrevivência ao jejum e quantidade de sangue ingerido. A duração média do ciclo evolutivo foi de 145,7 dias a 25ºC e de 114,2 dias, a 30ºC. A quantidade de sangue ingerido para completar o ciclo evolutivo foi de 304,3mg e 350,3 mg, a 25º e 30ºC, respectivamente. A sobrevivência ao jejum absoluto foi significativamente maior a 25º do que a 30ºC, ao nível de 1%.

The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis.

OBJECTIVES: To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). METHODS: The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen's κ agreement. RESULTS: The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. CONCLUSION: PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.

Who Ultimately Bears the Burden of Greater Non-Wage Labour costs?

We investigate the effect of a rise in non-wage labour costs (NWLC) on real anufacturing labour costs in OECD countries, taking into account the degree of coordination in the wage bargaining process. We find that, in countries in which wage bargaining is not highly coordinated, 55% of an increase in NWLC appears to be shifted to workers in the long run, whereas in countries operating under a highly coordinated bargaining regime, full shifting occurs. Overall, our results suggest that high NWLC can be associated with a high equilibrium unemployment rate, but only in those OECD countries that do not have highly coordinated wage bargaining.

Accurate performance of a rat model of schizophrenia in the water maze depends on visual cue availability and stability: a distortion in cognitive mapping abilities?

Rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R)-sulfoximine) in an animal model of schizophrenia based on transient glutathione deficit. The BSO treated rats were impaired in patrolling a maze or a homing table when adult, yet demonstrated preserved escape learning, place discrimination and reversal in a water maze task [37]. In the present work, BSO rats' performance in the water maze was assessed in conditions controlling for the available visual cues. First, in a completely curtained environment with two salient controlled cues, BSO rats showed little accuracy compared to control rats. Secondly, pre-trained BSO rats were impaired in reaching the familiar spatial position when curtains partially occluded different portions of the room environment in successive sessions. The apparently preserved place learning in a classical water maze task thus appears to require the stability and the richness of visual landmarks from the surrounding environment. In other words, the accuracy of BSO rats in place and reversal learning is impaired in a minimal cue condition or when the visual panorama changes between trials. However, if the panorama remains rich and stable between trials, BSO rats are equally efficient in reaching a familiar position or in learning a new one. This suggests that the BSO accurate performance in the water maze does not satisfy all the criteria for a cognitive map based navigation on the integration of polymodal cues. It supports the general hypothesis of a binding deficit in BSO rats.

Older persons' perceptions of general practitioner or specialist primary care physicians : same point of view?

BACKGROUND: Identification of a Primary Care Physician (PCP) by older patients is considered as essential for the coordination of care, but the extent to which identified PCPs are general practitioners or specialists is unknown. This study described older patients' experiences with their PCP and tested the hypothesis of differences between patients who identify a specialist as their PCP (SP PCP) and those who turn to a general practitioner (GP PCP). METHODS: In 2012, a cross-sectional postal survey on care was conducted in the 68+ year old population of the canton of Vaud. Data was provided by 2,276 participants in the ongoing Lausanne cohort 65+ (Lc65+), a study of those born between 1934 and 1943, and by 998 persons from an additional sample drawn to include the population outside of Lausanne or born before 1934. RESULTS: Participants expressed favourable perceptions, at rates exceeding 75% for most items. However, only 38% to 51% responded positively for out-of-hours availability, easy access and at home visits, likelihood of prescribing expensive medication if needed, and doctors' awareness of over-the-counter drugs. 12.0% had an SP PCP, in 95.9% specialised in a discipline implying training in internal medicine. Bivariate and multivariate analyses did not result in significant differences between GP and SP PCPs regarding perceptions of accessibility/availability, doctor-patient relationship, information and continuity of care, prevention, spontaneous use of the emergency department or ambulatory care utilisation. CONCLUSIONS: Experiences of old patients were mostly positive despite some lack in reported hearing, memory testing, and colorectal cancer screening. We found no differences between GP and SP PCP groups.

Geometry and physics of knots

KNOTS are usually categorized in terms of topological properties that are invariant under changes in a knot's spatial configuration(1-4). Here we approach knot identification from a different angle, by considering the properties of particular geometrical forms which we define as 'ideal'. For a knot with a given topology and assembled from a tube of uniform diameter, the ideal form is the geometrical configuration having the highest ratio of volume to surface area. Practically, this is equivalent to determining the shortest piece of tube that can be closed to form the knot. Because the notion of an ideal form is independent of absolute spatial scale, the length-to-diameter ratio of a tube providing an ideal representation is constant, irrespective of the tube's actual dimensions. We report the results of computer simulations which show that these ideal representations of knots have surprisingly simple geometrical properties. In particular, there is a simple linear relationship between the length-to-diameter ratio and the crossing number-the number of intersections in a two-dimensional projection of the knot averaged over all directions. We have also found that the average shape of knotted polymeric chains in thermal equilibrium is closely related to the ideal representation of the corresponding knot type. Our observations provide a link between ideal geometrical objects and the behaviour of seemingly disordered systems, and allow the prediction of properties of knotted polymers such as their electrophoretic mobility(5).

Des céramiques aux hommes : étude céramique des premiers horizons fouillés sous la cathédrale Saint-Pierre de Genève (1er millénaire av. J.-C. - 40 apr. J.-C.)

Résumé Le travail présenté est basé sur l'analyse systématique des 145'157 fragments de céramique émanant de 2137 ensembles recueillis entre 1976 et 2003 lors de la fouille de la cathédrale Saint-Pierre. Datés entre le Ier millénaire av. J-C. et le XIXe siècle, ils témoignent de l'ampleur et de la richesse des activités menées au sein de ce site phare de la ville de Genève. Les particularités observées pour les six premiers horizons reconnus, qui couvrent une période comprise entre le Ier millénaire av. J.-C. et 40 apr. J.-C., liées aux structures a priori énigmatiques mises en évidence lors de la fouille, ont orienté le champ d'étude vers une compréhension fine du mobilier recueilli dans ces strates anciennes. Ainsi cadrée, l'étude s'est concentrée sur 237 complexes céramiques ayant livré 23'129 fragments. La corrélation stratigraphique menée sur les 8000 m2 de terrain fouillé a permis de porter l'analyse sur la répartition spatiale du corpus considéré. Développée également sur le plan diachronique, cette démarche a largement contribué à la définition des activités menées sur le site. Ainsi, la concentration de fragments de panses d'amphore et de vaisselle de table importée de Campanie au pied d'un tertre mis en évidence sous le choeur de la cathédrale a conduit à reconnaître l'existence d'un banquet funéraire témoignant de l'ensevelissement sous tumulus d'un aristocrate allobroge décédé entre 120 et 70 av. J.-C. Réparties sur la totalité de la surface occupée par la nef de la cathédrale et des rues la flanquant, les quelques 1024 coupes à boire de La Tène finale mises au jour ont quant à elles permis d'identifier les surfaces de gravier qu'elles scellaient comme une aire de rassemblement ayant abrité des banquets tenus périodiquement. Le maintien de ces activités rituelles et collectives jusqu'au milieu du Ier siècle de notre ère conclut l'analyse diachronique. La mise en perspective historique des données recueillies sur le terrain souligne l'importance de l'antique oppidum extremum des Allobroges, dont le sort fut en 58 av. J.-C. à l'origine de la Guerre des Gaules.

Are glutamate and lactate increases ubiquitous to physiological activation? A (1)H functional MR spectroscopy study during motor activation in human brain at 7Tesla.

Recent studies at high field (7Tesla) have reported small metabolite changes, in particular lactate and glutamate (below 0.3μmol/g) during visual stimulation. These studies have been limited to the visual cortex because of its high energy metabolism and good magnetic resonance spectroscopy (MRS) sensitivity using surface coil. The aim of this study was to extend functional MRS (fMRS) to investigate for the first time the metabolite changes during motor activation at 7T. Small but sustained increases in lactate (0.17μmol/g±0.05μmol/g, p<0.001) and glutamate (0.17μmol/g±0.09μmol/g, p<0.005) were detected during motor activation followed by a return to the baseline after the end of activation. The present study demonstrates that increases in lactate and glutamate during motor stimulation are small, but similar to those observed during visual stimulation. From the observed glutamate and lactate increase, we inferred that these metabolite changes may be a general manifestation of the increased neuronal activity. In addition, we propose that the measured metabolite concentration increases imply an increase in ΔCMRO2 that is transiently below that of ΔCMRGlc during the first 1 to 2min of the stimulation.

Quality of life: a potentially useful measure to indicate subclinical flares in Crohn disease.

Background:  While quality of life (QoL) is a well-recognised outcome measure of Crohn disease (CD) activity, its influence on other outcome measures, including exacerbation of CD is poorly understood. If QoL measures were to be associated with intestinal inflammatory activity, they might be useful for early detection of subclinical flares. Aims:  We hypothesised that low QoL might be associated with subsequent CD flares. Methods:  A cohort of 318 adult CD patients was observed for 1 year after assessment of baseline characteristics. Data were collected in Swiss university hospitals, regional hospitals and private practices. At inclusion, patients completed the Inflammatory Bowel Disease QoL Questionnaire (gastrointestinal QoL; range: 32 to 224 points) and the Short Form-36 Health Survey (general QoL; range: 35 to 145 points). During follow up, flares were recorded. Binary logistic regression was performed to estimate the relation between QoL and the odds of subsequent flares. Results:  A twofold decrease in the odds of flares (99% CI: 1.1; 4.0) per standard deviation of gastrointestinal QoL and a threefold decrease (99% CI: 1.5; 6.2) per standard deviation of general QoL were observed. Conclusions:  The close association between QoL and subsequent flares suggests that QoL measures might be useful in detecting upcoming flares before they become clinically apparent.

Le Nouveau Testament est-il anti-juif ? L'exemple de Matthieu et du livre des Actes

Le problème de l'antijudaïsme du NT est une question récente en théologie : il s'agit de savoir dans quel cas une mauvaise lecture des Ecritures a pu favoriser pareille chose et dans quel cas celle-ci est une donnée interne du NT. L'A. se propose de répondre à cette question en examinant l'Evangile de Matthieu et les Actes des Apôtres pour évaluer le jugement théologique que leurs auteurs ont porté sur le judaïsme. Dans une première partie, l'article insiste sur la violence de l'antijudaïsme de Matthieu, dans une seconde, il en donne les raisons historiques, dans la dernière partie, il examine le livre de Luc et conclut sur trois remarques