Two GacA-dependent small RNAs modulate the quorum-sensing response in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, the GacS/GacA two-component system positively controls the quorum-sensing machinery and the expression of extracellular products via two small regulatory RNAs, RsmY and RsmZ. An rsmY rsmZ double mutant and a gacA mutant were similarly impaired in the synthesis of the quorum-sensing signal N-butanoyl-homoserine lactone, the disulfide bond-forming enzyme DsbA, and the exoproducts hydrogen cyanide, pyocyanin, elastase, chitinase (ChiC), and chitin-binding protein (CbpD). Both mutants showed increased swarming ability, azurin release, and early biofilm development.

Transaortic transcatheter aortic valve replacement with the Sapien? valve and the first generations of Ascendra?.

Traditionally, the transcatheter aortic valve replacement is performed through a transapical, a transfemoral or a trans-subclavian approach. Recently, the transaortic approach for transcatheter aortic valve replacement through the distal part of the ascending aorta was successfully implemented in order to avoid peripheral vascular access-related complications and apical life-threatening haemorrhage. The Sapien? stent valve has great transaortic potential because it can be loaded 'upside down' in different generations of delivery systems. However, because of their health regulatory systems and despite the launch, in 2012, of the latest generation of the Ascendra? delivery system, the Ascendra+?, specifically designed for transapical and transaortic valve placements, several countries are still using the first generations of Ascendra? (Ascendra? 1 and 2). This device was specifically designed for transapical procedures, and retrograde stent-valve positioning through the stenotic aortic valve may be very challenging and risk the integrity of the aorta. We describe the manoeuvre required in order to pass the stenotic aortic valve safely in a retrograde direction using the Sapien? stent valve and the first generations of Ascendra?.

PPAR gamma: ally and foe in bone metabolism.

Bone homeostasis is a well-balanced process that is largely dependent on the contribution of both bone-forming osteoblasts and bone-resorbing osteoclasts. A new study (Wan et al., 2007) suggests a previously unsuspected role for the transcription factor PPARgamma in promoting bone progenitors to the osteoclastic lineage.

Cataractogenesis after total body irradiation.

PURPOSE: To evaluate the prognostic factors and the ophthalmologic follow-up on cataract formation following total body irradiation (TBI) prior to bone marrow transplantation (BMT). METHODS AND MATERIALS: Between 1980 and 1992, 494 patients were referred to our department for TBI prior to BMT. The mean age was 32 +/- 11 (median: 32, range: 2-63) years and the male to female ratio was 1.6 (304:190). The majority of patients were treated for acute leukemia (lymphoblastic, n = 177, 36%; or nonlymphoblastic , n = 139, 28%); 80 (16%) for chronic myeloid leukemia, 60 (12%) for non-Hodgkin's lymphoma, 23 (5%) for multiple myeloma, and 15 (3%) for other malignancies. Two hundred and fifty-four (51%) patients were grafted in the first complete remission (CR), 118 (24%) in second CR. Allogenic BMT was performed in 210 (43%) patients, and autologous BMT in 284 (57%). Methotrexate combined to steroids (n = 47, 22%) or to cyclosporine (n = 163, 78%) was administered for graft-versus-host disease (GvHD) prophylaxis. In 188 patients (38%), heparin was used in the prevention of veno-occlusive disease (VOD) of the liver. Furthermore, steroid administration was registered in 223 (45%). The conditioning chemotherapy consisted of cyclophosphamide (Cy) alone in 332 (67%) patients. Total-body irradiation was administered either in single dose (STBI; 10 Gy in 1 day, n = 291) or in six fractions (FTBI; 12 Gy over 3 consecutive days, n = 203) before BMT. The mean instantaneous dose rate was 0.0574 +/- 0.0289 Gy/min (0.024-0.1783). It was < 0.048 Gy/min in 157 patients (LOW group), > or = 0.048 Gy/min and <0.09 Gy/min in 301 patients (MEDIUM group), and > or = 0.09 Gy/min in 36 patients (HIGH group). RESULTS: When considering all patients, 42 (8.5%) patients developed cataracts after 13 to 72 months (median: 42 months) with a 5-year estimated cataract incidence (ECI) of 23%. Thirty-three (11.3%) out of 291 patients in the STBI group, and 9 (4.4%) out of 203 patients in the FTBI group developed cataracts with 5-year estimated incidences of 34 and 11%, respectively (p = 0.0004). Seven (19.4%) out of 36 patients in the HIGH group, 33 (10.9%) out of 301 in the MEDIUM group, and 2 (1.2%) out of 157 in the LOW group developed cataracts with respective 5-year cataract incidences of 54%, 30%, and 3.5% (HIGH vs. MEDIUM, p = 0.07; MEDIUM vs. LOW, p = 0.0001; HIGH vs. LOW, p < 0.0001). On the other hand, patients who received heparin as prophylactic treatment against VOD of the liver had less cataracts than those who did not receive (5-year ECI of 16% vs. 28%, respectively; p = 0.01). There was no statistically significant difference in terms of 5-year ECI according to age, sex, administration of steroids, GvHD prophylaxis, type of BMT, or previous cranial radiotherapy in children. Multivariate analysis revealed that the instantaneous dose rate (p = 0.001), and the administration of heparin against VOD (p = 0.05) were the two independent factors influencing the cataract incidence, while age, fractionation, and use of steroids were not. Among the 42 patients who developed cataracts, 38 had bilateral extracapsular cataract extraction and intraocular lens implantation, and only 4 (10%) developed secondary cataracts in a median follow-up period of 39 months. CONCLUSION: Among the abovementioned TBI parameters, high instantaneous dose rate seems to be the main risk factor of cataract formation, and the administration of heparin appears to have a protective role in cataractogenesis. On the other hand, ionizing radiation seems to have a protective effect on posterior capsule opacification following extracapsular cataract extraction and intraocular lens implantation.

Effect of antiviral therapy on circulating cytokeratin-18 fragments in patients with chronic hepatitis C.

Hepatocellular apoptosis plays a major role in the pathogenesis of chronic hepatitis C. It can be measured noninvasively by determining the circulating levels of cytokeratin-18 fragments. We hypothesized that the effect of antiviral therapy on this parameter will be different in patients with a sustained virological response, relapse (REL) and nonresponse (NR). We quantified cytokeratin-18 fragments in plasma of patients participating in the Swiss Hepatitis C cohort, who received antiviral therapy without stopping because of sides effects. A total of 315 patients were included, 183 with a sustained response, 64 with NR and 68 who relapsed. Mean levels ±SD of circulating cytokeratin-18 fragments before therapy were 174 ± 172 U/L for responsders, 188 ± 145 for nonresponders and 269 ± 158 U/L for patients who relapsed. The values were significantly higher in the REL group (ANOVA P < 0.006). A sustained response was associated with a significant improvement of the plasma levels (94 ± 92 U/L, paired test P < 0.000001), whereas there was no improvement in the nonresponder group (183 ± 158 U/L) and in the relapser group (158 ± 148 U/L). There was a weak correlation between alanine aminotransferase (ALT) and cytokeratin-18 fragment levels (r² = 0.35, P < 0.000001) before therapy but not after therapy and none with hepatitis C virus (HCV) viremia. Successful antiviral therapy results in a significant decrease in circulating levels of cytokeratin-18 fragments arguing for a reduction in hepatocellular apoptosis after clearance of the HCV. Baseline cytokeratin-18 fragment levels are higher in relapsers. Correlations with ALT are weak, suggesting that these two tests measure different but related processes.

Fast liver catabolism of C1q in patients with paraproteinaemia and depletion of the classical pathway of complement.

The main clinical features in four patients with IgG1k paraproteinaemia and acquired complement deficiency included xanthomatous skin lesions (in three), panniculitis (in three) and hepatitis (in two). Hypocomplementaemia concerned the early classical pathway components--in particular C1q. Metabolic studies employing 125I-C1q revealed a much faster catabolism of this protein in the four patients than in five normal controls and three patients with cryoglobulinaemia (mean fractional catabolic rates respectively: 23.35%/h; 1.44%/h; 5.84%/h). Various experiments were designed to characterize the mechanism of the hypocomplementaemia: the patients' serum, purified paraprotein, blood cells, bone marrow cells, or xanthomatous skin lesions did not produce significant complement activation or C1q binding. When three of the patients (two with panniculitis and hepatitis) were injected with 123I-C1q, sequential gamma-camera imaging demonstrated rapid accumulation of the radionuclide in the liver, suggesting that complement activation takes place in the liver where it could produce damage.

Nouveautés en médecine ambulatoire [Innovations in ambulatory care]

During 2008, we selected 8 studies of interest. It seems important to continue to treat high tension for old patients. To give a good medication against pain, to maintain activity and to reassure patient is the treatment for acute back pain; surgery for spinal stenosis has better results than other treatments at two years of evolution. Pregabalin seems to provide clinically benefit to patients with fibromyalgia. Helicobacter pylori test and treat has the same results than proton pomp inhibitor in initial management of dyspepsia; extending triple therapy beyond 7 days is unlikely to be a clinical useful strategy. Syphilis testing algorithms using treponemal tests for initial screening could be inversed. Finally, selective reporting of clinical trials results for antidepressant are relatively frequent.

Stable one-step technetium-99m labeling of His-tagged recombinant proteins with a novel Tc(I)-carbonyl complex.

We have developed a technetium labeling technology based on a new organometallic chemistry, which involves simple mixing of the novel reagent, a 99m Tc(I)-carbonyl compound, with a His-tagged recombinant protein. This method obviates the labeling of unpaired engineered cysteines, which frequently create problems in large-scale expression and storage of disulfide-containing proteins. In this study, we labeled antibody single-chain Fv fragments to high specific activities (90 mCi/mg), and the label was very stable to serum and all other challenges tested. The pharmacokinetic characteristics were indistinguishable from iodinated scFv fragments, and thus scFV fragments labeled by the new method will be suitable for biodistribution studies. This novel labeling method should be applicable not only to diagnostic imaging with 99mTc, but also to radioimmunotherapy approaches with 186/188 Re, and its use can be easily extended to almost any recombinant protein or synthetic peptide.

NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflammatory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-κB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5(Δ/Δ)). In this article we show that these animals exhibit slightly decreased CD8(+) T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5(Δ/Δ) macrophages efficiently primed CD8(+) T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5(Δ/Δ) lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines. Hence, loss of NLRC5 expression represents an advantage for evading CD8(+) T cell-mediated elimination by downmodulation of MHC I levels-a mechanism that may be exploited by transformed cells. Our data show that NLRC5 acts as a key transcriptional regulator of MHC I in lymphocytes and support an essential role for NLRs in directing not only innate but also adaptive immune responses.

The cross-cultural generalizability of Zuckerman's alternative Five-Factor Model of personality

The aim of this study was to analyze the cross-cultural generalizability of the alternative Five-Factor Model (AFFM). The total sample was made up of 9,152 subjects from six countries: China, Germany, Italy, Spain, Switzerland, and the United States. The internal consistencies for all countries were generally similar to those found for the normative American sample. Factor analyses within cultures showed that the normative American structure was replicated in all cultures, however the congruence coefficients were slightly lower in China and Italy. A similar analysis at the facet level confirmed the high cross-cultural replicability of the AFFM. Mean-level comparisons did not always show the hypothesized effects. The mean score differences across countries were very small.

Detection and measurement of paracaspase MALT1 activity.

The paracaspase MALT1 is a Cys-dependent, Arg-specific protease that plays an essential role in the activation and proliferation of lymphocytes during the immune response. Oncogenic activation of MALT1 is associated with the development of specific forms of B-cell lymphomas. Through specific cleavage of its substrates, MALT1 controls various aspects of lymphocyte activation, including the activation of transcriptional pathways, the stabilization of mRNAs, and an increase in cellular adhesion. In lymphocytes, the activity of MALT1 is tightly controlled by its inducible monoubiquitination, which promotes the dimerization of MALT1. Here, we describe both in vitro and in vivo assays that have been developed to assess MALT1 activity.

The Reliability of Pre-travel History to Decide on Appropriate Counseling and Vaccinations: A Prospective Study.

BACKGROUND: Although medical and travel plans gathered from pre-travel interviews are used to decide the provision of specific pre-travel health advice and vaccinations, there has been no evaluation of the relevance of this strategy. In a prospective study, we assessed the agreement between pre-travel plans and post-travel history and the effect on advice regarding the administration of vaccines and recommendations for malaria prevention. METHODS: We included prospectively all consenting adults who had not planned an organized tour. Pre- and post-travel information included questions on destination, itineraries, departure and return dates, access to bottled water, plan of bicycle ride, stays in a rural zone, and close contact with animals. The outcomes measured included: agreement between pre- and post-travel itineraries and activities; and the effect of these differences on pre-travel health recommendations, had the traveler gone to the actual versus intended destinations for actual versus intended duration and activities. RESULTS: Three hundred and sixty-five travelers were included in the survey, where 188 (52%) were males (median age 38 years). In 81(23%) travelers, there was no difference between pre- and post-travel history. Disagreement between pre- and post-travel history were the highest for stays in rural zones or with local people (66% of travelers), close contact with animals (33%), and bicycle riding (21%). According to post-travel history, 125 (35%) travelers would have needed rabies vaccine and 9 (3%) typhoid fever vaccine. Potential overprovision of vaccine was found in <2% of travelers. A change in the malaria prescription would have been recommended in 18 (5%) travelers. CONCLUSIONS: Pre-travel history does not adequately reflect what travelers do. However, difference between recommendations for the actual versus intended travel plans was only clinically significant for the need for rabies vaccine. Particular attention during pre-travel health counseling should focus on the risk of rabies, the need to avoid close contact with animals and to seek care for post-exposure prophylaxis following an animal bite.

Prediction markets supporting technology assessment

In this thesis, we study the use of prediction markets for technology assessment. We particularly focus on their ability to assess complex issues, the design constraints required for such applications and their efficacy compared to traditional techniques. To achieve this, we followed a design science research paradigm, iteratively developing, instantiating, evaluating and refining the design of our artifacts. This allowed us to make multiple contributions, both practical and theoretical. We first showed that prediction markets are adequate for properly assessing complex issues. We also developed a typology of design factors and design propositions for using these markets in a technology assessment context. Then, we showed that they are able to solve some issues related to the R&D portfolio management process and we proposed a roadmap for their implementation. Finally, by comparing the instantiation and the results of a multi-criteria decision method and a prediction market, we showed that the latter are more efficient, while offering similar results. We also proposed a framework for comparing forecasting methods, to identify the constraints based on contingency factors. In conclusion, our research opens a new field of application of prediction markets and should help hasten their adoption by enterprises. Résumé français: Dans cette thèse, nous étudions l'utilisation de marchés de prédictions pour l'évaluation de nouvelles technologies. Nous nous intéressons plus particulièrement aux capacités des marchés de prédictions à évaluer des problématiques complexes, aux contraintes de conception pour une telle utilisation et à leur efficacité par rapport à des techniques traditionnelles. Pour ce faire, nous avons suivi une approche Design Science, développant itérativement plusieurs prototypes, les instanciant, puis les évaluant avant d'en raffiner la conception. Ceci nous a permis de faire de multiples contributions tant pratiques que théoriques. Nous avons tout d'abord montré que les marchés de prédictions étaient adaptés pour correctement apprécier des problématiques complexes. Nous avons également développé une typologie de facteurs de conception ainsi que des propositions de conception pour l'utilisation de ces marchés dans des contextes d'évaluation technologique. Ensuite, nous avons montré que ces marchés pouvaient résoudre une partie des problèmes liés à la gestion des portes-feuille de projets de recherche et développement et proposons une feuille de route pour leur mise en oeuvre. Finalement, en comparant la mise en oeuvre et les résultats d'une méthode de décision multi-critère et d'un marché de prédiction, nous avons montré que ces derniers étaient plus efficaces, tout en offrant des résultats semblables. Nous proposons également un cadre de comparaison des méthodes d'évaluation technologiques, permettant de cerner au mieux les besoins en fonction de facteurs de contingence. En conclusion, notre recherche ouvre un nouveau champ d'application des marchés de prédiction et devrait permettre d'accélérer leur adoption par les entreprises.