Genetic dissection of the host response to Salmonella Typhimurium infection in Toll-like receptor 4 transgenic mice and recombinant congenic strains

Different individuals react differently to infection with similar pathogens and weakly pathogenic organisms can cause life-threatening infections in some, while highly virulent microbes may go undetected in others. The basis of these differences lies within the genetic makeup of each individual, which determine their response to infection. Unraveling the genetic determinants of susceptibility to infection brings a much clearer understanding of the pathogenesis of diseases and paves the way to potential prophylactic and therapeutic interventions urgently needed in the context of increasing antimicrobial resistance, globalization of infectious diseases, and emerging or re-emerging pathogens.Salmonella spp are highly successful pathogens that have co-evolved with countless host species. Even today, they continue to threaten public health throughout the world. Their zoonotic nature, their propensity to establish long-term carrier states and the emergence of antimicrobial resistant, highly virulent strains greatly complicate the fight against this pathogen. As for other infectious diseases, the host response to Salmonella is genetically controlled. In order to genetically dissect this response, a mouse model was developed and allowed identification of a few genes having a strong impact on the outcome of Salmonella infection. The mouse response to Salmonella is, however, complex and several additional genetic variants influencing the response to infection remain to be identified.Here, we present a series of experiments, which contribute to our understanding of the host response to acute Salmonella Typhimurium infection in mice. First, we investigated the impact of Tlr4 expression during Salmonella infection by comparing host responses in mice carrying 1, 2 and 3 copies of Tlr4 on the same genetic background. We show for the first time, in this narrow range of Tlr4 expression, an incremental protective effect against Salmonella due to improved control of bacterial growth and increased expression of important downstream immune genes. Second, using a set of reciprocal A/J and C57BL/6J recombinant congenic strains, we identified five novels QTL influencing the outcome of Salmonella Typhimurium infection in mice. Finally, we present evidence for the genetic basis for one of the newly identified QTL and describe a role for anemia and iron balance in the mouse response to Salmonella

Améliorer la détection et le traitement des psychoses débutantes au Québec : L’Association québécoise des programmes pour premiers épisodes psychotiques (AQPPEP) y voit

Juin 2004 : l’AQPPEP (Association québécoise des programmes pour premiers épisodes psychotiques) (http://www.aqppep.com/) voit le jour. Son rôle est de favoriser les échanges cliniques et scientifiques entre les professionnels et les chercheurs qui s’intéressent aux personnes atteintes de psychose débutante, et de permettre une détection plus précoce de la psychose. Elle vise également une prise de conscience de cette problématique par la population et les instances gouvernementales. À cette fin, l’AQPPEP a organisé la première journée québécoise de sensibilisation à la psychose, et développé un des rares sites internet francophones dans ce domaine. Dans un esprit de concertation, l’Association constitue un outil pour affronter les problèmes que plusieurs cliniques pour premiers épisodes psychotiques rencontrent, pour partager et développer des solutions communes entre elles.June 2004: the Quebec association of early psychosis programs, AQPPEP (Association québécoise des programmes pour premiers épisodes psychotiques), was created. The Association’s objectives is to promote clinical and scientific discussions between health care professionals and researchers sharing an interest for people suffering from an early psychosis, and to improve earlier detection of psychosis. It also aims at increasing awareness of the problem in the general population and governments. To reach these goals, AQPPEP has organized the first early psychosis awareness day in Quebec and developed one of the rare French language web sites in this area. Finally, the Association is a tool to better face, in a concerted approach, some difficulties that many first episode clinics have to deal with, in order to share or develop common solutions.Junio de 2004: se crea la AQPPEP (Asociación Quebequense de Programas Para los Primeros Episodios Psicóticos) (http://www.aqppep. com/). Su papel consiste en favorecer los intercambios clínicos y científicos entre los profesionales y los investigadores que se interesan en las personas que sufren de psicosis inicial, y permitir una detección más temprana de la psicosis. También busca la toma de conciencia de este problema por parte de la población y las instancias gubernamentales. Para ello, la AQPPEP organizó el primer día quebequense de sensibilización a la psicosis y desarrolló uno de los pocos sitios Internet francófonos en este campo. Con un espíritu de concertación, la Asociación constituye una herramienta para afrontar los problemas que encuentran varias clínicas para los primeros episodios psicóticos, además de compartir y desarrollar soluciones comunes entre ellas.Junho de 2004: Criação da AQPPEP, Associação Quebequense dos Programas para os Primeiros Episódios Psicóticos (Association québécoise des programmes pour premiers épisodes psychotiques -http://www.aqppep.com/). Seu papel é favorecer os intercâmbios clínicos e científicos entre os profissionais e os pesquisadores que se interessam pelas pessoas que sofrem de psicose inicial, e permitir uma detecção mais precoce da psicose. Ela visa, igualmente, uma tomada de consciência desta problemática pela população e pelas instâncias governamentais. Para este fim, a AQPPEP organizou a primeira jornada quebequense de sensibilização à psicose, e desenvolveu um dos raros sites francófonos na Internet nesta área. Com um espírito de comum acordo, a Associação constitui uma ferramenta para enfrentar os problemas que várias clínicas encontram com respeito aos primeiros episódios psicóticos, compartilhar e desenvolver soluções comuns entre elas

Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice

The mouse response to acute Salmonella typhimurium infection is complex, and it is under the influence of several genes, as well as environmental factors. In a previous study, we identified two novel Salmonella susceptibility loci, Ity4 and Ity5, in a (AcB61 × 129S6)F2 cross. The peak logarithm of odds score associated with Ity4 maps to the region of the liver and red blood cell (RBC)–specific pyruvate kinase (Pklr) gene, which was previously shown to be mutated in AcB61. During Plasmodium chabaudi infection, the Pklr mutation protects the mice against this parasite, as indicated by improved survival and lower peak parasitemia. Given that RBC defects have previously been associated with resistance to malaria and susceptibility to Salmonella, we hypothesized that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice. Using a fine mapping approach combined with complementation studies, comparative studies, and functional analysis, we show that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice through its effect on the RBC turnover and iron metabolism

Integrated obesity care management system -implementation and research protocol

<p>Abstract</p> <p>Background</p> <p>Nearly 50% of Canadians are overweight and their number is increasing rapidly. The majority of obese subjects are treated by primary care physicians (PCPs) who often feel uncomfortable with the management of obesity. The current research proposal is aimed at the development and implementation of an innovative, integrated, interdisciplinary obesity care management system involving both primary and secondary care professionals.</p> <p>Methods</p> <p>We will use both action and evaluative research in order to achieve the following specific objectives. The first one is to develop and implement a preceptorship-based continuing medical education (CME) program complemented by a web site for physicians and nurses working in Family Medicine Groups (FMGs). This CME will be based on needs assessment and will be validated by one FMG using questionnaires and semi structured interviews. Also, references and teaching tools will be available for participants on the web site. Our second objective is to establish a collaborative intra and inter-regional interdisciplinary network to enable on-going expertise update and networking for FMG teams. This tool consists of a discussion forum and monthly virtual meetings of all participants. Our third objective is to evaluate the implementation of our program for its ability to train 8 FMGs per year, the access and utilization of electronic tools and the participants' satisfaction. This will be measured with questionnaires, web logging tools and group interviews. Our fourth objective is to determine the impact for the participants regarding knowledge and expertise, attitudes and perceptions, self-efficacy for the management of obesity, and changes in FMG organization for obesity management. Questionnaires and interviews will be used for this purpose. Our fifth objective is to deliver transferable knowledge for health professionals and decision-makers. Strategies and pitfalls of setting up this program will also be identified.</p> <p>Conclusion</p> <p>This project is relevant to health system's decision-makers who are confronted with an important increase in the prevalence of obesity. It is therefore critical to develop strategies allowing the management of obesity in the 1^stline setting. Results of this research project could therefore influence health care organization in the field of obesity but also eventually for other chronic diseases.</p

Authenticated DNA from Ancient Wood Remains

• Background The reconstruction of biological processes and human activities during the last glacial cycle relies mainly on data from biological remains. Highly abundant tissues, such as wood, are candidates for a genetic analysis of past populations. While well-authenticated DNA has now been recovered from various fossil remains, the final ‘proof' is still missing for wood, despite some promising studies. • Scope The goal of this study was to determine if ancient wood can be analysed routinely in studies of archaeology and palaeogenetics. An experiment was designed which included blind testing, independent replicates, extensive contamination controls and rigorous statistical tests. Ten samples of ancient wood from major European forest tree genera were analysed with plastid DNA markers. • Conclusions Authentic DNA was retrieved from wood samples up to 1000 years of age. A new tool for real-time vegetation history and archaeology is ready to us

Deconvolution of Images from BLAST 2005: Insight into the K3-50 and IC 5146 Star-Forming Regions

We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available highresolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 4.'5 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the Spectral Energy Distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21-cm radio continuum and 12CO molecular line emission. The restored extended large scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting SEDs to multi-wavelength data. All of these compact sources are still quite cold (typical temperature below ~ 16 K) and are above the critical Bonner-Ebert mass. They have associated low-power Young Stellar Objects (YSOs). Further evidence for starless clumps has also been found in the IC 5146 region.Comment: 13 pages, 12 Figures, 3 Table

Le défi de la non-reconnaissance de la maladie en troubles psychotiques : implications pour les pharmaciens

Objectif : Présenter la littérature sur la définition, les causes, les conséquences et les traitements de la non-reconnaissance de la maladie par la personne souffrant de troubles psychotiques. Méthode : Cette revue narrative a pour objet le concept de la non-reconnaissance de la maladie. La définition du concept, les types de mesures, les causes, les conséquences et les traitements ont été cherchés dans MEDLINE. Résultats : La reconnaissance de la maladie est un concept multidimensionnel qui se distingue de l’autocritique (cognitive insight) et de l’insight narratif. Les causes de la non-reconnaissance de la maladie peuvent être psychopathologiques, neurobiologiques ou neurocognitives. La conséquence la mieux établie d’une non-reconnaissance de la maladie est l’effet sur l’adhésion au traitement. Pour le moment, il n’existe pas de traitement durable et efficace pour améliorer la non-reconnaissance de la maladie, mais les interventions métacognitives et de neurostimulation non invasive seraient les plus prometteuses. Conclusion : Dans une perspective de rétablissement, une approche multimodale et individualisée à la personne selon les causes possibles de ses symptômes semble à préconiser afin d’obtenir les meilleurs résultats. Abstract Objective: To present the literature on the definition, causes and consequences, and treatments for lack of awareness of illness in patients with psychotic disorders. Method: This narrative review focuses on the concept of lack of awareness of illness. Searches were conducted in MEDLINE for the definition of the concept, types of measures, causes, consequences, and treatments. Results: Awareness of illness is a multidimensional concept that is distinct from cognitive insight and narrative insight. The causes of a lack of awareness of illness can be psychopathological, neurobiological, or neurocognitive. The most well-established consequence of lack of awareness of illness is the impact on treatment adherence. There is currently no lasting, effective treatment to support patients in recognizing their illness, but metacognitive and non-invasive neurostimulation interventions appear to be the most promising. Conclusion: From a recovery perspective, an individualized, multimodal approach adapted to the possible causes of the patient’s symptoms appears to be a promising strategy to obtain the best possible outcomes

How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains

Background Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies. Methods The present work was designed in an attempt to determine guidelines in the field of saltinduced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry). Results In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges. Conclusions Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites

The Balloon-Borne Large Aperture Submillimeter Telescope (BLAST) 2005: A 10 deg^2 Survey of Star Formation in Cygnus X

We present Cygnus X in a new multi-wavelength perspective based on an unbiased BLAST survey at 250, 350, and 500 micron, combined with rich datasets for this well-studied region. Our primary goal is to investigate the early stages of high mass star formation. We have detected 184 compact sources in various stages of evolution across all three BLAST bands. From their well-constrained spectral energy distributions, we obtain the physical properties mass, surface density, bolometric luminosity, and dust temperature. Some of the bright sources reaching 40 K contain well-known compact H II regions. We relate these to other sources at earlier stages of evolution via the energetics as deduced from their position in the luminosity-mass (L-M) diagram. The BLAST spectral coverage, near the peak of the spectral energy distribution of the dust, reveals fainter sources too cool (~ 10 K) to be seen by earlier shorter-wavelength surveys like IRAS. We detect thermal emission from infrared dark clouds and investigate the phenomenon of cold ``starless cores" more generally. Spitzer images of these cold sources often show stellar nurseries, but these potential sites for massive star formation are ``starless" in the sense that to date there is no massive protostar in a vigorous accretion phase. We discuss evolution in the context of the L-M diagram. Theory raises some interesting possibilities: some cold massive compact sources might never form a cluster containing massive stars; and clusters with massive stars might not have an identifiable compact cold massive precursor.Comment: 42 pages, 31 Figures, 6 table