Cutting edge: thymic NK cells develop independently from T cell precursors.

Although NK cells in the mouse are thought to develop in the bone marrow, a small population of NK cells in the thymus has been shown to derive from a GATA3-dependent pathway. Characteristically, thymic NK cells express CD127 and few Ly49 molecules and lack CD11b. Because these NK cells develop in the thymus, the question of their relationship to the T cell lineage has been raised. Using several different mouse models, we find that unlike T cells, thymic NK cells are not the progeny of Rorc-expressing progenitors and do not express Rag2 or rearrange the TCRγ locus. We further demonstrate that thymic NK cells develop independently of the Notch signaling pathway, supporting the idea that thymic NK cells represent bona fide NK cells that can develop independently of all T cell precursors.

T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching.

The respective production of specific immunoglobulin (Ig)G2a or IgG1 within 5 d of primary immunization with Swiss type mouse mammary tumor virus [MMTV(SW)] or haptenated protein provides a model for the development of T helper 1 (Th1) and Th2 responses. The antibody-producing cells arise from cognate T cell B cell interaction, revealed by the respective induction of Cgamma2a and Cgamma1 switch transcript production, on the third day after immunization. T cell proliferation and upregulation of mRNA for interferon gamma in response to MMTV(SW) and interleukin 4 in response to haptenated protein also starts during this day. It follows that there is minimal delay in these responses between T cell priming and the onset of cognate interaction between T and B cells leading to class switching and exponential growth. The Th1 or Th2 profile is at least partially established at the time of the first cognate T cell interaction with B cells in the T zone. The addition of killed Bordetella pertussis to the hapten-protein induces nonhapten-specific IgG2a and IgG1 plasma cells, whereas the anti-hapten response continues to be IgG1 dominated. This indicates that a Th2 response to hapten-protein can proceed in a node where there is substantial Th1 activity.

LEVERAGING SANDBOX IMMERSIVE 3D VIRTUAL WORLDS TO DEVELOP DO-IT- YOURSELF TEACHING GAMES: IMPLEMENTATION TO MARKETING CASE STUDY TEACHING IN SECOND LIFE

Games are powerful and engaging. On average, one billion people spend at least 1 hour a day playing computer and videogames. This is even more true with the younger generations. Our students have become the < digital natives >, the < gamers >, the < virtual generation >. Research shows that those who are most at risk for failure in the traditional classroom setting, also spend more time than their counterparts, using video games. They might strive, given a different learning environment. Educators have the responsibility to align their teaching style to these younger generation learning styles. However, many academics resist the use of computer-assisted learning that has been "created elsewhere". This can be extrapolated to game-based teaching: even if educational games were more widely authored, their adoption would still be limited to the educators who feel a match between the authored games and their own beliefs and practices. Consequently, game-based teaching would be much more widespread if teachers could develop their own games, or at least customize them. Yet, the development and customization of teaching games are complex and costly. This research uses a design science methodology, leveraging gamification techniques, active and cooperative learning theories, as well as immersive sandbox 3D virtual worlds, to develop a method which allows management instructors to transform any off-the-shelf case study into an engaging collaborative gamified experience. This method is applied to marketing case studies, and uses the sandbox virtual world of Second Life. -- Les jeux sont puissants et motivants, En moyenne, un milliard de personnes passent au moins 1 heure par jour jouer à des jeux vidéo sur ordinateur. Ceci se vérifie encore plus avec les jeunes générations, Nos étudiants sont nés à l'ère du numérique, certains les appellent des < gamers >, d'autres la < génération virtuelle >. Les études montrent que les élèves qui se trouvent en échec scolaire dans les salles de classes traditionnelles, passent aussi plus de temps que leurs homologues à jouer à des jeux vidéo. lls pourraient potentiellement briller, si on leur proposait un autre environnement d'apprentissage. Les enseignants ont la responsabilité d'adapter leur style d'enseignement aux styles d'apprentissage de ces jeunes générations. Toutefois, de nombreux professeurs résistent lorsqu'il s'agit d'utiliser des contenus d'apprentissage assisté par ordinateur, développés par d'autres. Ceci peut être extrapolé à l'enseignement par les jeux : même si un plus grand nombre de jeux éducatifs était créé, leur adoption se limiterait tout de même aux éducateurs qui perçoivent une bonne adéquation entre ces jeux et leurs propres convictions et pratiques. Par conséquent, I'enseignement par les jeux serait bien plus répandu si les enseignants pouvaient développer leurs propres jeux, ou au moins les customiser. Mais le développement de jeux pédagogiques est complexe et coûteux. Cette recherche utilise une méthodologie Design Science pour développer, en s'appuyant sur des techniques de ludification, sur les théories de pédagogie active et d'apprentissage coopératif, ainsi que sur les mondes virtuels immersifs < bac à sable > en 3D, une méthode qui permet aux enseignants et formateurs de management, de transformer n'importe quelle étude de cas, provenant par exemple d'une centrale de cas, en une expérience ludique, collaborative et motivante. Cette méthode est appliquée aux études de cas Marketing dans le monde virtuel de Second Life.

La cohorte sepsis lausannoise: une opportunité de développer la recherche dans le Réseau latin de médecine intensive [Lausanne Cohort of septic patients as an opportunity to develop multidisciplinary research within the Swiss Latin Network of Intensive Care Medicine]

Despite recent medical progresses in patient support, the mortality of sepsis remains high. Recently, new supporting strategies were proposed to improve outcome. Whereas such strategies are currently considered as standard of care, their real impact on mortality, morbidity, length of stay, and hence, health care resources utilization has been only weakly evaluated so far. Obviously, there is a critical need for epidemiologic surveys of sepsis to better address these major issues. The Lausanne Cohort of septic patients aims at building a large clinical, biological and microbiological database that will be used as a multidisciplinary research platform to study the various pathogenic mechanisms of sepsis in collaboration with the various specialists. This could be an opportunity to strengthen the collaboration within the Swiss Latin network of Intensive Care Medicine.

Evidence for an overestimated vulnerability of adolescent rats to develop signs of drug addiction

Drug addiction is a multi-etiological disorder to which some individuals are more vulnerable an others. Whereas converging clinical and epidemiological studies report a peak of drug use ring adolescence, many behavioral traits characterizing teenagers have been proposed to contribute to this vulnerability, including a heightened sensation-seeking, an enhanced impulsivity d a larger influence exerted by peers. By many aspects, juvenile rodents display behavioral traits at resemble those of teenagers. However, the concept of increased vulnerability to drug addiction juvenile rats remains in debate. Indeed, only a few studies directly compared juvenile and adult fdents regarding behavioral predictors of drug abuse. Moreover, some key features of drug diction have never been investigated in juvenile rats yet. For this very reason, we conducted a arge-scale behavioral comparison of adult and adolescent rats with the aim of dissecting their espective behavioral traits and vulnerabilities to drug addiction. We first have shown that juvenile rats exhibited an enhanced motor impulsivity, and a loss of control over reward seeking assessed by a persistent reward taking despite adverse consequences mild electric footshocks]. We also report that juvenile rats displayed a higher anxiety profile, ind we discuss why these behaviors might represent key underpinning mechanisms leading to an enhanced vulnerability to drug abuse. Meanwhile, we collected clear cut observations that do not support such an interpretation. In Articular, juvenile and adult rats displayed identical novelty-induced habituation and preference at are considered to represent two potent predictors of cocaine initiation and compulsive intake, "pre strikingly, juvenile rats were less attracted by cues predicting reward in a Pavlovian utoshaping task, suggesting a lower propensity for cues or context to trigger the reinstatement of a^previously extinguished reward seeking behavior. Finally, using a paradigm assessing schedule- ciuced polydipsia, juvenile and adult rats exhibited similar compulsive drinking, under control conditions and following a chronic cocaine treatment as well. Hence, these observations call for a cautious interpretation of adolescent vulnerability to drug use. In particular, we underlined that even the most compulsive young rats did not consume ärger amounts of cocaine than adults, nor exhibited larger efforts in a cue-induced relapse aradigm, despite a transient increased motivation for lever-pressing. And further, despite a higher ensitivity to the behavioral effects of cocaine, juvenile rats did not differ from adults in their ropensity to constantly prefer saccharin over cocaine in a discrete-choice procedure, even after a ?'Id chronic stress procedure. Altogether, our results shape an objective overview of the juvenile rats' behavior in relation to oth drug and non-drug rewards, suggesting a heterogeneous and task-specific profile. Despite elements potentially underlying a real risk for substance use, adolescent rats do not exhibit a ehavioral repertoire suggesting increased vulnerability for compulsive drug abuse. Our conclusions strongly encourage deeper neurobiological investigations of the developing brain, and also open a debate on a possible overestimation of juvenile rats' and teenager's risk to develop aladaptive behaviors and drug addiction. - L'addiction aux drogues est une pathologie d'origine multifactorielle, à laquelle certains individus sont plus vulnérables que d'autres. De nombreuses études cliniques et épidémiologiques suggèrent une consommation excessive de drogues pendant l'adolescence, et plusieurs explications ont été avancées pour justifier cette tendance, parmi lesquelles on note une augmentation de la recherche de sensation, une impulsivité plus marquée et une plus forte influence de l'entourage. Le rat juvénile présente de nombreuses caractéristiques développementales similaires à l'adolescence humaine. En revanche, la vulnérabilité des rats juvéniles à l'abus de drogue est encore sujette à caution. En effet, peu d'études ont directement comparé des traits de comportements pouvant refléter un accroissement du risque d'abus chez les rats juvéniles par comparaison aux rats adultes. En outre, certaines caractéristiques fondamentales de l'addiction chez l'homme n'ont pas encore été étudiées chez le rat adolescent. Ce travail de thèse s'est donc donné pour objectif de comparer le comportement de rats adultes vis-à-vis de celui de rats adolescents, afin d'évaluer dans quelle mesure ces derniers seraient plus vulnérables à l'abus de drogues. Nos résultats indiquent que les rats juvéniles présentent une augmentation des comportements impulsifs, ainsi qu'une plus grande persistance à rechercher de manière compulsive une récompense en dépit de légers chocs électriques. Les rats juvéniles présentent également un profil anxieux plus élevé, ce qui peut constituer une autre source de vulnérabilité. Cependant, certaines caractéristiques comportementales ne suggèrent pas de vulnérabilité chez les rats juvéniles. Aucune différence entre rats adultes et adolescents n'a été trouvée pour l'habituation et la préférence pour la nouveauté, deux traits prédisant l'initiation et la prise compulsive de drogue. De plus, nous avons montré que les rats adolescents attribuent moins d'intérêt à des stimuli prédisant la disponibilité d'une récompense, suggérant une vulnérabilité plus faible à la rechute induite par les stimuli associés à la prise de drogue. Une étude complémentaire des comportements compulsifs indique une absence de différence entre rats adultes et adolescents, à la fois en condition basale ou après un traitement chronique à la cocaïne. L'étude des comportements de prise de drogue ne va pas non plus dans le sens d'une vulnérabilité des rats adolescents. Bien que les rats compulsifs sélectionnés pendant la période juvénile présentent une plus grande motivation à prendre de la cocaïne, ils ne diffèrent ni dans la quantité de cocaïne consommée, ni dans la rechute induite par les stimuli environnementaux. En dépit d'une sensibilisation comportementale plus importante, les rats adolescents présentent la même préférence que les adultes face à un choix entre une drogue et une récompense alternative, suggérant une résilience à la cocaïne comparable à celle des adultes. Enfin, cette résilience pour la cocaïne n'est pas affectée par un stress chronique lors de l'adolescence. En résumé, cette étude dresse un regard objectif sur les comportements en lien avec une vulnérabilité à l'abus de drogues chez le rat juvénile, suggérant que celle-ci est hétérogène et spécifique au protocole utilisé. En dépit de certains éléments de vulnérabilité, les rats adolescents ne présentent pas d'attirance excessive pour la cocaïne, ni de prédisposition à la consommation compulsive de cette drogue. L'ensemble de ces éléments pourra constituer une base solide pour l'investigation neurobiologique du cerveau en développement, et ouvre un débat sur une possible surestimation de la vulnérabilité des rats juvéniles et de leurs homologues humains aux pathologies psychiatriques telles que l'addiction aux drogues.

How do the different components of episodic memory develop? Role of executive functions and short-term feature-binding abilities.

This study investigated the development of all 3 components of episodic memory (EM), as defined by Tulving, namely, core factual content, spatial context, and temporal context. To this end, a novel, ecologically valid test was administered to 109 participants aged 4-16 years. Results showed that each EM component develops at a different rate. Ability to memorize factual content emerges early, whereas context retrieval abilities continue to improve until adolescence, due to persistent encoding difficulties (isolated by comparing results on free recall and recognition tasks). Exploration of links with other cognitive functions revealed that short-term feature-binding abilities contribute to all EM components, and executive functions to temporal and spatial context, although ability to memorize temporal context is predicted mainly by age.

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC. METHODS: Analysis of the database of the Swiss Hepatitis C Cohort Study, a multicentre study that is being carried out in eight major Swiss hospitals since the year 2000. Patients with chronic hepatitis C and HCC were regrouped and compared to the patients without HCC. RESULTS: Among the 3,390 patients of the cohort, 130 developed an HCC. Age was one of the determining factors. Cirrhosis and its complications ascites and porto-systemic encephalopathy were associated with HCC. Males presented a higher risk for HCC than females. Alcohol consumption was associated with HCC. Diabetes mellitus was an important risk factor, especially in patients with low fibrosis. Patients with Hepatitis C genotype 2 had significantly less HCC than patients with other genotypes. A low socioeconomic status (income, education, profession) was associated with HCC. CONCLUSIONS: Beside the expected characteristics (age, gender, cirrhosis, alcohol), these data stress the role of diabetes mellitus and reveal the importance of low socioeconomic status as a risk factor for HCC in Swiss patients infected with hepatitis C virus. This vulnerable population should be closely monitored.

Concrete Pavement Mixture Design and Analysis (MDA): Evaluation of the Fresh and Hardened Properties of Concrete Mixtures Containing Permeability-Reducing Admixtures to Develop Standard Test Protocol, 2014

Concrete durability may be considered as the ability to maintain serviceability over the design life without significant deterioration, and is generally a direct function of the mixture permeability. Therefore, reducing permeability will improve the potential durability of a given mixture and, in turn, improve the serviceability and longevity of the structure. Given the importance of this property, engineers often look for methods that can decrease permeability. One approach is to add chemical compounds known as integral waterproofing admixtures or permeability-reducing admixtures, which help fill and block capillary pores in the paste. Currently, there are no standard approaches to evaluate the effectiveness of permeability-reducing admixtures or to compare different products in the US. A review of manufacturers’ data sheets shows that a wide range of test methods have been used, and rarely are the same tests used on more than one product. This study investigated the fresh and hardened properties of mixtures containing commercially available hydrophilic and hydrophobic types of permeability-reducing admixtures. The aim was to develop a standard test protocol that would help owners, engineers, and specifiers compare different products and to evaluate their effects on concrete mixtures that may be exposed to hydrostatic or non-hydrostatic pressure. In this experimental program, 11 concrete mixtures were prepared with a fixed water-to-cement ratio and cement content. One plain mixture was prepared as a reference, 5 mixtures were prepared using the recommended dosage of the different permeability-reducing admixtures, and 5 mixtures were prepared using double the recommended dosage. Slump, air content, setting time, compressive and flexural strength, shrinkage, and durability indicating tests including electrical resistivity, rapid chloride penetration, air permeability, permeable voids, and sorptivity tests were conducted at various ages. The data are presented and recommendations for a testing protocol are provided.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

Outcomes in neurosurgical patients who develop venous thromboembolism: a review of the RIETE registry.

OBJECTIVES: Registro Informatizado de Enfermedad TromboEmbólica (RIETE) database was used to investigate whether neurosurgical patients with venous thromboembolism (VTE) were more likely to die of bleeding or VTE and the influence of anticoagulation on these outcomes. METHODS: Clinical characteristics, treatment details, and 3-month outcomes were assessed in those who developed VTE after neurosurgery. RESULTS: Of 40 663 patients enrolled, 392 (0.96%) had VTE in less than 60 days after neurosurgery. Most patients in the cohort (89%) received initial therapy with low-molecular-weight heparin, (33% received subtherapeutic doses). In the first week, 10 (2.6%) patients died (8 with pulmonary embolism [PE], no bleeding deaths; P = .005). After the first week, 20 (5.1%) patients died (2 with fatal bleeding, none from PE). Overall, this cohort was more likely to develop a fatal PE than a fatal bleed (8 vs 2 deaths, P = .058). CONCLUSIONS: Neurosurgical patients developing VTE were more likely to die from PE than from bleeding in the first week, despite anticoagulation.

Undressing of Waddlia chondrophila to enrich its outer membrane proteins to develop a new species-specific ELISA.

Waddlia chondrophila, an obligate intracellular bacterium of the Chlamydiales order, is considered as an agent of bovine abortion and a likely cause of miscarriage in humans. Its role in respiratory diseases was questioned after the detection of its DNA in clinical samples taken from patients suffering from pneumonia or bronchiolitis. To better define the role of Waddlia in both miscarriage and pneumonia, a tool allowing large-scale serological investigations of Waddlia seropositivity is needed. Therefore, enriched outer membrane proteins of W. chondrophila were used as antigens to develop a specific ELISA. After thorough analytical optimization, the ELISA was validated by comparison with micro-immunofluorescence and it showed a sensitivity above 85% with 100% specificity. The ELISA was subsequently applied to human sera to specify the role of W. chondrophila in pneumonia. Overall, 3.6% of children showed antibody reactivity against W. chondrophila but no significant difference was observed between children with and without pneumonia. Proteomic analyses were then performed using mass spectrometry, highlighting members of the outer membrane protein family as the dominant proteins. The major Waddlia putative immunogenic proteins were identified by immunoblot using positive and negative human sera. The new ELISA represents an efficient tool with high throughput applications. Although no association with pneumonia and Waddlia seropositivity was observed, this ELISA could be used to specify the role of W. chondrophila in miscarriage and in other diseases.

Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake

Different levels of insulin sensitivity have been described in several animal models of obesity as well as in humans. Monosodium glutamate (MSG)-obese mice were considered not to be insulin resistant from data obtained in oral glucose tolerance tests. To reevaluate insulin resistance by the intravenous glucose tolerance test (IVGTT) and by the clamp technique, newborn male Wistar rats (N = 20) were injected 5 times, every other day, with 4 g/kg MSG (N = 10) or saline (control; N = 10) during the first 10 days of age. At 3 months, the IVGTT was performed by injecting glucose (0.75 g/kg) through the jugular vein into freely moving rats. During euglycemic clamping plasma insulin levels were increased by infusing 3 mU . kg-1 . min-1 of regular insulin until a steady-state plateau was achieved. The basal blood glucose concentration did not differ between the two experimental groups. After the glucose load, increased values of glycemia (P<0.001) in MSG-obese rats occurred at minute 4 and from minute 16 to minute 32. These results indicate impaired glucose tolerance. Basal plasma insulin levels were 39.9 ± 4 µU/ml in control and 66.4 ± 5.3 µU/ml in MSG-obese rats. The mean post-glucose area increase of insulin was 111% higher in MSG-obese than in control rats. When insulinemia was clamped at 102 or 133 µU/ml in control and MSG rats, respectively, the corresponding glucose infusion rate necessary to maintain euglycemia was 17.3 ± 0.8 mg . kg-1 . min-1 for control rats while 2.1 ± 0.3 mg . kg-1 . min-1 was sufficient for MSG-obese rats. The 2-h integrated area for total glucose metabolized, in mg . min . dl-1, was 13.7 ± 2.3 vs 3.3 ± 0.5 for control and MSG rats, respectively. These data demonstrate that MSG-obese rats develop insulin resistance to peripheral glucose uptake

Impact of initial exposure to calcineurin inhibitors on kidney graft function of patients at high risk to develop delayed graft function

We conducted a retrospective analysis of the influence of full doses of calcineurin inhibitors [8-10 mg kg-1 day-1 cyclosporine (N = 80), or 0.2-0.3 mg kg-1 day-1 tacrolimus (N = 68)] administered from day 1 after transplantation on the transplant outcomes of a high-risk population. Induction therapy was used in 13% of the patients. Patients also received azathioprine (2 mg kg-1 day-1, N = 58) or mycophenolate mofetil (2 g/day, N = 90), and prednisone (0.5 mg kg-1 day-1, N = 148). Mean time on dialysis was 79 ± 41 months, 12% of the cases were re-transplants, and 21% had panel reactive antibodies >10%. In 43% of donors the cause of death was cerebrovascular disease and 27% showed creatinine above 1.5 mg/dL. The incidence of slow graft function (SGF) and delayed graft function (DGF) was 15 and 60%, respectively. Mean time to last dialysis and to nadir creatinine were 18 ± 15 and 34 ± 20 days, respectively. Mean creatinine at 1 year after transplantation was 1.48 ± 0.50 mg/dL (DGF 1.68 ± 0.65 vs SGF 1.67 ± 0.66 vs immediate graft function (IGF) 1.41 ± 0.40 mg/dL, P = 0.089). The incidence of biopsy-confirmed acute rejection was 22% (DGF 31%, SGF 10%, IGF 8%). One-year patient and graft survival was 92.6 and 78.4%, respectively. The incidence of cytomegalovirus disease, post-transplant diabetes mellitus and malignancies was 28, 8.1, and 0%, respectively. Compared to previous studies, the use of initial full doses of calcineurin inhibitors without antibody induction in patients with SGF or DGF had no negative impact on patient and graft survival.

Almond and peanut flours suppelmented with iron as potential ingredients to develop gluten-free cookies

Brazil is the second biggest worldwide producer of cookies and there are many varieties in the market; however, only a few are gluten-free. The objectives of this work were to formulate two gluten-free cookies added with iron, peanut or almond, and analyze their physicochemical, chromatic and sensory properties. Moisture, instrumental color (L*, a*, b* and C*), ash, proteins, lipids, iron, carbohydrates (estimated by difference), and water activity were determined. The acceptance of the products was assessed by 115 untrained taste panelists using a five-point hedonic scale. The data collected from the physicochemical analyses were submitted to Levene's, ANOVA, and Tukey's tests, which showed statistical difference (p < 0.05) in all the attributes for centesimal composition, water activity, and color of the cookies. Peanut and almond cookies could be considered sources of iron once they presented at least 15% of the daily recommended value of intake. They also garnered acceptance indexes of 80 and 85%, respectively, concluding that both formulations developed in this study were source of iron and contained high concentration of lipids and proteins with great sensory acceptance, suggesting their potential consumption by gluten-intolerants.