Feasibility of a knowledge translation CME program: courriels Cochrane.

INTRODUCTION: Systematic literature reviews provide best evidence, but are underused by clinicians. Thus, integrating Cochrane reviews into continuing medical education (CME) is challenging. We designed a pilot CME program where summaries of Cochrane reviews (Courriels Cochrane) were disseminated by e-mail. Program participants automatically received CME credit for each Courriel Cochrane they rated. The feasibility of this program is reported (delivery, participation, and participant evaluation). METHOD: We recruited French-speaking physicians through the Canadian Medical Association. Program delivery and participation were documented. Participants rated the informational value of Courriels Cochrane using the Information Assessment Method (IAM), which documented their reflective learning (relevance, cognitive impact, use for a patient, expected health benefits). IAM responses were aggregated and analyzed. RESULTS: The program was delivered as planned. Thirty Courriels Cochrane were delivered to 985 physicians, and 127 (12.9%) completed at least one IAM questionnaire. Out of 1109 Courriels Cochrane ratings, 973 (87.7%) conta-ined 1 or more types of positive cognitive impact, while 835 (75.3%) were clinically relevant. Participants reported the use of information for a patient and expected health benefits in 595 (53.7%) and 569 (51.3%) ratings, respectively. DISCUSSION: Program delivery required partnering with 5 organizations. Participants valued Courriels Cochrane. IAM ratings documented their reflective learning. The aggregation of IAM ratings documented 3 levels of CME outcomes: participation, learning, and performance. This evaluation study demonstrates the feasibility of the Courriels Cochrane as an approach to further disseminate Cochrane systematic literature reviews to clinicians and document self-reported knowledge translation associated with Cochrane reviews.

Cutting edge: cyclic polypeptide and aminoglycoside antibiotics trigger IL-1β secretion by activating the NLRP3 inflammasome.

Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1β secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro-IL-1β but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL-1β, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host.

Posttranscriptional repression of GacS/GacA-controlled genes by the RNA-binding protein RsmE acting together with RsmA in the biocontrol strain Pseudomonas fluorescens CHA0.

In the plant-beneficial soil bacterium Pseudomonas fluorescens CHA0, the production of biocontrol factors (antifungal secondary metabolites and exoenzymes) is controlled at a posttranscriptional level by the GacS/GacA signal transduction pathway involving RNA-binding protein RsmA as a key regulatory element. This protein is assumed to bind to the ribosome-binding site of target mRNAs and to block their translation. RsmA-mediated repression is relieved at the end of exponential growth by two GacS/GacA-controlled regulatory RNAs RsmY and RsmZ, which bind and sequester the RsmA protein. A gene (rsmE) encoding a 64-amino-acid RsmA homolog was identified and characterized in strain CHA0. Overexpression of rsmE strongly reduced the expression of target genes (hcnA, for a hydrogen cyanide synthase subunit; aprA, for the main exoprotease; and phlA, for a component of 2,4-diacetylphloroglucinol biosynthesis). Single null mutations in either rsmA or rsmE resulted in a slight increase in the expression of hcnA, aprA, and phlA. By contrast, an rsmA rsmE double mutation led to strongly increased and advanced expression of these target genes and completely suppressed a gacS mutation. Both the RsmE and RsmA levels increased with increasing cell population densities in strain CHA0; however, the amount of RsmA showed less variability during growth. Expression of rsmE was controlled positively by GacA and negatively by RsmA and RsmE. Mobility shift assays demonstrated specific binding of RsmE to RsmY and RsmZ RNAs. The transcription and stability of both regulatory RNAs were strongly reduced in the rsmA rsmE double mutant. In conclusion, RsmA and RsmE together account for maximal repression in the GacS/GacA cascade of strain CHA0.

But Marriage itself is no Party : Angela Carter's Translation of Charles Perrault's La Belle au bois dormant.

AbstractThis article demonstrates the importance of Angela Carter's translations of Charles Perrault's contes into English and argues for their profound influence on her subsequent literary career. Against feminist critics who rejected fairy tales as conservative and informed by patriarchal structures and values, Carter reclaimed Perrault for feminism by recovering the critical edge and emancipating potential of his Histoires ou contes du temps passé, Avec des Moralités. This essay shows, through a comparative reading of "La Belle au bois dormant" and "The Sleeping Beauty in the Wood," that Carter opposed the worldly "politics of experience" that she found in Perrault to the Disneyfied imagery of the Sleeping Beauty myth and modernized the critique of early marriages already contained in Perrault's Moralités. The subversive power of Carter's work, therefore, is not directed against Perrault but rather toward cultural and commercial appropriations of the fairy tale, which promote a naïve view of marriage.Recommended CitationHennard Dutheil de la Rochère, Martine. ""But marriage itself is no party": Angela Carter's Translation of Charles Perrault's "La Belle au bois dormant"; or, Pitting the Politics of Experience against the Sleeping Beauty Myth." Marvels & Tales 24.1 (2010).

Multicopy suppression of a gacA mutation by the infC operon in Pseudomonas fluorescens CHA0: competition with the global translational regulator RsmA.

The gacA gene of the biocontrol strain Pseudomonas fluorescens CHA0 codes for a response regulator which, together with the sensor kinase GacS (=LemA), is required for the production of exoenzymes and secondary metabolites involved in biocontrol, including hydrogen cyanide (HCN). A gacA multicopy suppressor was isolated from a cosmid library of strain CHA0 and identified as the infC-rpmI-rplT operon, which encodes the translation initiation factor IF3 and the ribosomal proteins L35 and L20. The efficiency of suppression was about 30%, as determined by the use of a GacA-controlled reporter construct, i.e. a translational hcnA'-'lacZ fusion. Overexpression of the rsmA gene (coding for a global translational repressor) reversed the suppressive effect of the amplified infC operon. This finding suggests that some product(s) of the infC operon can compete with RsmA at the level of translation in P. fluorescens CHA0 and that important biocontrol traits can be regulated at this level.

Control of jasmonate biosynthesis and senescence by miR319 targets.

Considerable progress has been made in identifying the targets of plant microRNAs, many of which regulate the stability or translation of mRNAs that encode transcription factors involved in development. In most cases, it is unknown, however, which immediate transcriptional targets mediate downstream effects of the microRNA-regulated transcription factors. We identified a new process controlled by the miR319-regulated clade of TCP (TEOSINTE BRANCHED/CYCLOIDEA/PCF) transcription factor genes. In contrast to other miRNA targets, several of which modulate hormone responses, TCPs control biosynthesis of the hormone jasmonic acid. Furthermore, we demonstrate a previously unrecognized effect of TCPs on leaf senescence, a process in which jasmonic acid has been proposed to be a critical regulator. We propose that miR319-controlled TCP transcription factors coordinate two sequential processes in leaf development: leaf growth, which they negatively regulate, and leaf senescence, which they positively regulate.

Involvement of 4E-BP1 in the protection induced by HDLs on pancreatic beta cells.

High-density lipoproteins (HDLs) protect pancreatic beta cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. The mechanisms by which HDLs protect beta cells are poorly characterized however. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in beta cells subjected to apoptotic stimuli. The transcript encoding 4E-BP1 was up-regulated by serum starvation and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypo-phosphorylated state but it looses this ability when hyper-phosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL1beta and this was blunted by HDLs. While an ectopic increase of 4E-BP1 expression induced beta cell death, silencing 4E-BP1 increase with shRNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect beta cells by blocking 4E-BP1 protein expression but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by ER stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect beta cells through modulation of 4E-BP1 depending on the type of stress stimuli.

Improving telecommunication security level by integrating quantum key distribution in communication protocols

Résumé La cryptographie classique est basée sur des concepts mathématiques dont la sécurité dépend de la complexité du calcul de l'inverse des fonctions. Ce type de chiffrement est à la merci de la puissance de calcul des ordinateurs ainsi que la découverte d'algorithme permettant le calcul des inverses de certaines fonctions mathématiques en un temps «raisonnable ». L'utilisation d'un procédé dont la sécurité est scientifiquement prouvée s'avère donc indispensable surtout les échanges critiques (systèmes bancaires, gouvernements,...). La cryptographie quantique répond à ce besoin. En effet, sa sécurité est basée sur des lois de la physique quantique lui assurant un fonctionnement inconditionnellement sécurisé. Toutefois, l'application et l'intégration de la cryptographie quantique sont un souci pour les développeurs de ce type de solution. Cette thèse justifie la nécessité de l'utilisation de la cryptographie quantique. Elle montre que le coût engendré par le déploiement de cette solution est justifié. Elle propose un mécanisme simple et réalisable d'intégration de la cryptographie quantique dans des protocoles de communication largement utilisés comme les protocoles PPP, IPSec et le protocole 802.1li. Des scénarios d'application illustrent la faisabilité de ces solutions. Une méthodologie d'évaluation, selon les critères communs, des solutions basées sur la cryptographie quantique est également proposée dans ce document. Abstract Classical cryptography is based on mathematical functions. The robustness of a cryptosystem essentially depends on the difficulty of computing the inverse of its one-way function. There is no mathematical proof that establishes whether it is impossible to find the inverse of a given one-way function. Therefore, it is mandatory to use a cryptosystem whose security is scientifically proven (especially for banking, governments, etc.). On the other hand, the security of quantum cryptography can be formally demonstrated. In fact, its security is based on the laws of physics that assure the unconditional security. How is it possible to use and integrate quantum cryptography into existing solutions? This thesis proposes a method to integrate quantum cryptography into existing communication protocols like PPP, IPSec and the 802.l1i protocol. It sketches out some possible scenarios in order to prove the feasibility and to estimate the cost of such scenarios. Directives and checkpoints are given to help in certifying quantum cryptography solutions according to Common Criteria.

Videvdad 19 : édition critique, traduction et commentaires des textes avestique et moyen-perse

Notre travail porte sur le Videvdad, texte avestique nommé d'après unmot avestique Videvdad-data-, c'est-à-dire la « Un qui tient éloignés les demons ». Ce recueil comprend 22 chapitres édictant des lois religieuses, des préceptes rituels et des mesures de purification Ces prescriptions ont pour but de repousser l'impureté des elements purs de la création d'Ahura Mazda. Notre thèse est une édition du chapitre 19 de ce recueil complétée de sa traduction commentée. Ce chapitre raconte la tentation de Zarathustra par le Mauvais Esprit et sa victoire sur ce dernier Le texte a été traduit et commenté sémantiquement, phonétiquement et philologiquement afin d'en dégager les particularités linguistiques.L'édition de référence du texte avestique est celle de Geldner, qui date de la fin du 19 siècle Dans la mesure où il a été démontré durant ces dernières années quil fallait revoir ce travail, nous avons fait une édition du texte en collationnant 13 manuscits. Notre étude nous a permis à la fois de proposer pour certains termes une autre lecture que celle de Geldner et decontinuer les recherches sur la filiation des manuscrits.De plus le texte avestique a été mis en regard de la version pehlevie. L'intérêt de cette dernière traduction réside dans ses gloses : parfois un long commentaire parfois une simple énonciation de synonymes en pehlevie. le traducteur lui-même comprenant mal le sens du mot original. L'édition du texte pehlevi a également été refaite à partir des deux manuscrits lesplus anciens (L4 et Kl).Videvdad 19 :Critical Edition, Translation and Commentary of the Avestan and Pahlavi TextsWe worked on the Videvdad, an Avestan text whose title is a Middle Persian word coming from the Avestan Videvdad-data- "the law that keeps demons away" This anthology contains 22 chapters dealing with religious laws, ritual precepts and measures of purification. These prescriptions aim ft rejecting impurity from pure elements in Ahura Mazda's creation. Our dissertation is an edition and translation with commentary of chapter 19 of this anthology. lt relates the temptation of Zarathustra by the Bad Evil and how Zarathustra overcame him. The text was translated and annotated semantically, phonetically and philologically to highlight linguistic features.Until today, Geldner's edition, which dates back to the end of the 19th century has been the edition of reference. However, in recent years, scholars have shown that this edition must be revised Therefore, we prepared an edition of the Avestan text by collating 13 manuscripts. This work led us to propose new readings for several words and pursue research onmanuscripts filiation.Furthermore, we also studied the Middle Persian text. This translation is interesting in that it contains glosses that can either be long commentaries or simple synonyms. We also made the edition of the Middle Persian text on the basis of the two oldest manuscripts (L4 and Kl).

Molecular basis of messenger RNA recognition by the specific bacterial repressing clamp RsmA/CsrA.

Proteins of the RsmA/CsrA family are global translational regulators in many bacterial species. We have determined the solution structure of a complex formed between the RsmE protein, a member of this family from Pseudomonas fluorescens, and a target RNA encompassing the ribosome-binding site of the hcnA gene. The RsmE homodimer with its two RNA-binding sites makes optimal contact with an 5'-A/UCANGGANGU/A-3' sequence in the mRNA. When tightly gripped by RsmE, the ANGGAN core folds into a loop, favoring the formation of a 3-base-pair stem by flanking nucleotides. We validated these findings by in vivo and in vitro mutational analyses. The structure of the complex explains well how, by sequestering the Shine-Dalgarno sequence, the RsmA/CsrA proteins repress translation.

Small RNAs controlled by two-component systems.

Two-component systems (TCSs) allow bacteria to monitor diverse environmental cues and to adjust gene expression accordingly at the transcriptional level. It has been recently recognized that prokaryotes also regulate many genes and operons at a posttranscriptional level with the participation of small, noncoding RNAs which serve to control translation initiation and stability of target mRNAs, either directly by establishing antisense interactions or indirectly by antagonizing RNA-binding proteins. Interestingly, the expression of a subset of these small RNAs is regulated by TCSs and in this way, the small RNAs expand the scope of genetic control exerted by TCSs. Here we review the regulatory mechanisms and biological relevance ofa number of small RNAs under TCS control in Gram-negative and -positive bacteria. These regulatory systems govern, for instance, porin-dependent permeability of the outer membrane, quorum-sensing control of pathogenicity, or biocontrol activity. Most likely, this emerging and rapidly expanding field of molecular microbiology will provide more and more examples in the near future.

Insulin and IGF-1 enhance the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway.

MCT2 is the main neuronal monocarboxylate transporter essential for facilitating lactate and ketone body utilization as energy substrates. Our study reveals that treatment of cultured cortical neurons with insulin and IGF-1 led to a striking enhancement of MCT2 immunoreactivity in a time- and concentration-dependent manner. Surprisingly, neither insulin nor IGF-1 affected MCT2 mRNA expression, suggesting that regulation of MCT2 protein expression occurs at the translational rather than the transcriptional level. Investigation of the putative signalling pathways leading to translation activation revealed that insulin and IGF-1 induced p44- and p42 MAPK, Akt and mTOR phosphorylation. S6 ribosomal protein, a component of the translational machinery, was also strongly activated by insulin and IGF-1. Phosphorylation of p44- and p42 MAPK was blocked by the MEK inhibitor PD98058, while Akt phosphorylation was abolished by the PI3K inhibitor LY294002. Phosphorylation of mTOR and S6 was blocked by the mTOR inhibitor rapamycin. In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF-1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin-induced MCT2 expression and only a slight effect on IGF-1-induced MCT2 expression. At the subcellular level, a significant increase in MCT2 protein expression within an intracellular pool was observed while no change at the cell surface was apparent. As insulin and IGF-1 are involved in synaptic plasticity, their effect on MCT2 protein expression via an activation of the PI3K-Akt-mTOR-S6K pathway might contribute to the preparation of neurons for enhanced use of nonglucose energy substrates following altered synaptic efficacy.

Mesurer la stigmatisation perçue chez les personnes souffrant de troubles psychiques : traduction française, validation et adaptation de la Stigma Scale [French translation, validation and adaptation of the Stigma Scale].

AIM: People suffering from mental illness are exposed to stigma. However, only few tools are available to assess stigmatization as perceived from the patient's perspective. The aim of this study is to adapt and validate a French version of the Stigma Scale (King et al., 2007 [8]). This self-report questionnaire has a three-factor structure: discrimination, disclosure and positive aspects of mental illness. Discrimination subscale refers to perceived negative reactions of others. Disclosure subscale refers mainly to managing disclosure to avoid discrimination and finally positive aspects subscale taps into how patients are becoming more accepting, more understanding toward their illness. METHOD: In the first step, internal consistency, convergent validity and test-retest reliability of the French adaptation of the 28-item scale were assessed in a sample of 183 patients. Results of confirmatory factor analyses (CFA) did not confirm the hypothesized structure. In the light of the failed attempts to validate the original version, an alternative 9-item short-form version of the Stigma Scale, maintaining the integrity of the original model, was developed based on results of exploratory factor analyses in the first sample and cross-validated in a new sample of 234 patients. RESULTS: Results of CFA did not confirm that the data fitted well to the three-factor model of the 28-item Stigma Scale (χ(2)/df=2.02, GFI=0.77, AGFI=0.73, RMSEA=0.07, CFI=0.77 and NNFI=0.75). Cronbach's α was excellent for discrimination (0.84) and disclosure (0.83) subscales but poor for potential positive aspects (0.46). External validity was satisfactory. Overall Stigma Scale total score was negatively correlated with the score on Rosenberg's Self-Esteem Scale (r=-0.49), and each subscale was significantly correlated with a visual analogue scale that referred to the specific aspect of stigma (0.43≤|r|≤0.60). Intraclass correlation coefficients between 0.68 and 0.89 indicated good test-retest reliability. The results of the CFA demonstrated that the items chosen for the short version of the Stigma Scale have the expected fit properties (χ(2)/df=1.02, GFI=0.98, AGFI=0.98, RMSEA=0.01, CFI=1.0 and NNFI=1.0). Considering the small number (three) of items in each subscale of the short version of the Stigma Scale, α coefficients for discrimination (0.57), disclosure (0.80) and potential positive aspects subscales (0.62) are considered as good. CONCLUSION: Our results suggest that the 9-item French short version of the Stigma Scale is a useful, reliable and valid self-report questionnaire to assess perceived stigmatization in people suffering from mental illness. The time of completion is really short and questions are well understood and accepted by the patients.

Glucagon-like peptide-1 increases beta-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression.

Glucagon-like peptide-1 (GLP-1) protects beta-cells against apoptosis, increases their glucose competence, and induces their proliferation. We previously demonstrated that the anti-apoptotic effect was mediated by an increase in insulin-like growth factor-1 receptor (IGF-1R) expression and signaling, which was dependent on autocrine secretion of insulin-like growth factor 2 (IGF-2). Here, we further investigated how GLP-1 induces IGF-1R expression and whether the IGF-2/IGF-1R autocrine loop is also involved in mediating GLP-1-increase in glucose competence and proliferation. We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.

New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.

BACKGROUND: Lactate protects mice against the ischaemic damage resulting from transient middle cerebral artery occlusion (MCAO) when administered intracerebroventricularly at reperfusion, yielding smaller lesion sizes and a better neurological outcome 48 h after ischaemia. We have now tested whether the beneficial effect of lactate is long-lasting and if lactate can be administered intravenously. METHODS: Male ICR-CD1 mice were subjected to 15-min suture MCAO under xylazine + ketamine anaesthesia. Na L-lactate (2 µl of 100 mmol/l) or vehicle was administered intracerebroventricularly at reperfusion. The neurological deficit was evaluated using a composite deficit score based on the neurological score, the rotarod test and the beam walking test. Mice were sacrificed at 14 days. In a second set of experiments, Na L-lactate (1 µmol/g body weight) was administered intravenously into the tail vein at reperfusion. The neurological deficit and the lesion volume were measured at 48 h. RESULTS: Intracerebroventricularly injected lactate induced sustained neuroprotection shown by smaller neurological deficits at 7 days (median = 0, min = 0, max = 3, n = 7 vs. median = 2, min = 1, max = 4.5, n = 5, p < 0.05) and 14 days after ischaemia (median = 0, min = 0, max = 3, n = 7 vs. median = 3, min = 0.5, max = 3, n = 7, p = 0.05). Reduced tissue damage was demonstrated by attenuated hemispheric atrophy at 14 days (1.3 ± 4.0 mm(3), n = 7 vs. 12.1 ± 3.8 mm(3), n = 5, p < 0.05) in lactate-treated animals. Systemic intravenous lactate administration was also neuroprotective and attenuated the deficit (median = 1, min = 0, max = 2.5, n = 12) compared to vehicle treatment (median = 1.5, min = 1, max = 8, n = 12, p < 0.05) as well as the lesion volume at 48 h (13.7 ± 12.2 mm(3), n = 12 vs. 29.6 ± 25.4 mm(3), n = 12, p < 0.05). CONCLUSIONS: The beneficial effect of lactate is long-lasting: lactate protects the mouse brain against ischaemic damage when supplied intracerebroventricularly during reperfusion with behavioural and histological benefits persisting 2 weeks after ischaemia. Importantly, lactate also protects after systemic intravenous administration, a more suitable route of administration in a clinical emergency setting. These findings provide further steps to bring this physiological, commonly available and inexpensive neuroprotectant closer to clinical translation for stroke.