Methicillin-resistant Staphylococcus aureus: phylogenetic relatedness between European epidemic clones and Swiss sporadic strains.

We have compared the phylogenetic diversity of methicillin-resistant Staphylococcus aureus (MRSA) strains from Switzerland and their phylogenetic relationships with European epidemic clones, using multiprimer random amplification polymorphic DNA (RAPD). Strains included 24 European epidemic clones (59 strains), 66 sporadic strains isolated in Switzerland in 1996-1997, and 15 reference strains of five other Staphylococcus species. Similarity and clustering analysis with the Jaccard's coefficient showed that the maximum genetic distance between MRSA strains was 0.43, whereas the minimum genetic distance between the six Staphylococcus species was 0.97, indicating that the method permits phylogenetic hierarchization. The 24 MRSA clones reported to be epidemic in European countries during the 1990s were distributed into seven different genetic clusters with a maximum distance of 0.29 among them. This clustering pattern was confirmed by the analysis of a subset of MRSA strains by multilocus enzyme electrophoresis at 12 loci. Most of the sporadic Swiss strains were distributed into these seven different genetic clusters, together with the epidemic MRSA clones. This suggests that there is no phylogenetic cluster specific to epidemic clones of MRSA.

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.

Genes outside The Hla Region affecting Susceptibility to Type 1 Diabetes - The Role of Iddm2 and Iddm9 in the Finnish Population

Tyypin 1 diabeteksen perinnöllinen alttius Suomessa - HLA-alueen ulkopuolisten alttiuslokusten IDDM2 ja IDDM9 rooli taudin periytymisessä HLA-alue, joka sijaitsee kromosomissa 6p21.3, vastaa noin puolesta perinnöllisestä alttiudesta sairastua tyypin 1 diabetekseen. Myös HLA-alueen ulkopuolisten lokusten on todettu liittyvän sairausalttiuteen. Näistä kolmen lokuksen on varmistettu olevan todellisia alttiuslokuksia ja lisäksi useiden muiden, vielä varmistamattomien lokusten, on todettu liittyvän sairausalttiuteen. Tässä tutkimuksessa 12:n HLA-alueen ulkopuolisen alttiuslokuksen kytkentä tyypin 1 diabetekseen tutkittiin käyttäen 107:aa suomalaista multiplex-perhettä. Jatkotutkimuksessa analysoitiin IDDM9-alueen kytkentä ja assosiaatio sairauteen laajennetuissa perhemateriaaleissa sekä IDDM2-alueen mahdollinen interaktio HLA-alueen kanssa sairauden muodostumisessa. Lisäksi suoritettiin IDDM2-alueen suojaavien haplotyyppien alatyypitys tarkoituksena tutkia eri haplotyyppien käyttökelpoisuutta sairastumisriskin tarkempaa ennustamista varten. Ensimmäisessä kytkentätutkimuksessa ei löytynyt koko genomin tasolla merkitsevää tai viitteellistä kytkentää tutkituista HLA-alueen ulkopuolisista lokuksista. Voimakkain havaittu nimellisen merkitsevyyden tavoittava kytkentä nähtiin IDDM9-alueen markkerilla D3S3576 (MLS=1.05). Tutkimuksessa ei kyetty varmistamaan tai sulkemaan pois aiempia kytkentähavaintoja tutkituilla lokuksilla, mutta IDDM9-alueen jatkotutkimuksessa havaittu voimakas kytkentä (MLS=3.4) ja merkitsevä assosiaatio (TDT p=0.0002) viittaa vahvasti siihen, että 3q21-alueella sijaitsee todellinen tyypin 1 diabeteksen alttiusgeeni, jolloin alueen kattava assosiaatiotutkimus olisi perusteltu jatkotoimenpide. Sairauteen altistava IDDM2-alueen MspI-2221 genotyyppi CC oli nimellisesti yleisempi matalan tai kohtalaisen HLA-sairastumisriskin diabeetikoilla, verrattuna korkean HLA-riskin potilaisiin (p=0.05). Myös genotyyppijakauman vertailu osoitti merkitsevää eroa ryhmien välillä (p=0.01). VNTR-haplotyyppitutkimus osoitti, että IIIA/IIIA-homotsygootin sairaudelta suojaava vaikutus on merkitsevästi voimakkaampi kuin muiden luokka III:n genotyypeillä. Nämä tulokset viittaavat IDDM2-HLA -vuorovaikutukseen sekä siihen että IDDM2-alueen haplotyyppien välillä esiintyy etiologista heterogeniaa. Tämän johdosta IDDM2-alueen haplotyyppien tarkempi määrittäminen voisi tehostaa tyypin 1 diabeteksen riskiarviointia.

Blood culture-based diagnosis of bacteraemia: state of the art.

Blood culture remains the best approach to identify the incriminating microorganisms when a bloodstream infection is suspected, and to guarantee that the antimicrobial treatment is adequate. Major improvements have been made in the last years to increase the sensitivity and specificity and to reduce the time to identification of microorganisms recovered from blood cultures. Among other factors, the introduction in clinical microbiology laboratories of the matrix-assisted laser desorption ionization time-of-flight mass spectrometry technology revolutionized the identification of microorganisms whereas the introduction of nucleic-acid-based methods, such as DNA hybridization or rapid PCR-based test, significantly reduce the time to results. Together with traditional antimicrobial susceptibility testing, new rapid methods for the detection of resistance mechanisms respond to major epidemiological concerns such as methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase or carbapenemases. This review presents and discusses the recent developments in microbial diagnosis of bloodstream infections based on blood cultures.

Antibiotic susceptibility and molecular epidemiology of Panton-Valentine leukocidin-positive meticillin-resistant Staphylococcus aureus: An international survey

The antibiotic susceptibility and molecular epidemiology of Panton-Valentine leukocidin (PVL)-positive meticillin-resistant Staphylococcus aureus (MRSA) isolates reported from 17 countries in the Americas, Europe and, Australia-Asia were analysed. Among a total of 3236 non-duplicate isolates, the lowest susceptibility was observed to erythromycin in all regions. Susceptibility to ciprofloxacin showed large variation (25%, 75% and 84% in the Americas, Europe and Australia-Asia, respectively). Two vancomycin-intermediate PVL-positive MRSA isolates were reported, one from Hong Kong and the other from The Netherlands. Resistance to trimethoprim/sulfamethoxazole and linezolid was <1%. Among 1798 MRSA isolates from 13 countries that were tested for the requested 10 non-β-lactam antibiotics, 49.4% were multisusceptible. However, multiresistant isolates (resistant to at least three classes of non-β-lactam antibiotics) were reported from all regions. Sequence type 30 (ST30) was reported worldwide, whereas ST80 and ST93 were exclusive to Europe and Australia, respectively. USA300 and related clones (ST8) are progressively replacing the ST80 clone in several European countries. Eight major clusters were discriminated by multilocus variable-number tandem repeat assay (MLVA), showing a certain geographic specificity. PVL-positive MRSA isolates frequently remain multisusceptible to non-β-lactam agents, but multiresistance is already prevalent in all regions. Surveillance of MRSA susceptibility patterns should be monitored to provide clinicians with the most current information regarding changes in resistance patterns.

A mouse peritonitis model for the study of glycopeptide efficacy in GISA infections

In recent years, the emergence of Staphylococcus aureus strains with reduced susceptibility to glycopeptides has raised considerable concern. We studied the efficacy of vancomycin and teicoplanin, as well as cloxacillin and cefotaxime, against the infection caused by four S. aureus strains with different glycopeptide and β-lactam susceptibilities (strains A, B, C, and D; MICs for vancomycin of 1, 2, 4, and 8 µg/ml respectively), using a modified model of mouse peritonitis. This optimized model appeared to be straightforward and reproducible, and was able to detect low differences in bacterial killing between antibiotics and also between different S. aureus strains. Bactericidal activities in peritoneal fluid for vancomycin, teicoplanin, cloxacillin, and cefotaxime decreased from -2.98, -2.36, -3.22, and -3.57 log10 cfu/ml, respectively, in infection by strain A (MICs for vancomycin and cloxacillin of 1 and 0.38 µg/ml, respectively) to -1.22, -0.65, -1.04, and +0.24 in peritonitis due to strain D (MICs for vancomycin and cloxacillin of 8 and 1,024 µg/ml). Our data confirm the superiority of β-lactams against methicillin-susceptible S. aureus and show that bactericidal activity of glycopeptides decreases significantly with slight increases in MICs; this finding suggests a reduced efficacy of glycopeptides in the treatment of serious glycopeptide-intermediate S. aureus infections

Gut physiology mediates a trade-off between adaptation to malnutrition and susceptibility to food-borne pathogens.

The animal gut plays a central role in tackling two common ecological challenges, nutrient shortage and food-borne parasites, the former by efficient digestion and nutrient absorption, the latter by acting as an immune organ and a barrier. It remains unknown whether these functions can be independently optimised by evolution, or whether they interfere with each other. We report that Drosophila melanogaster populations adapted during 160 generations of experimental evolution to chronic larval malnutrition became more susceptible to intestinal infection with the opportunistic bacterial pathogen Pseudomonas entomophila. However, they do not show suppressed immune response or higher bacterial loads. Rather, their increased susceptibility to P. entomophila is largely mediated by an elevated predisposition to loss of intestinal barrier integrity upon infection. These results may reflect a trade-off between the efficiency of nutrient extraction from poor food and the protective function of the gut, in particular its tolerance to pathogen-induced damage.

A mouse peritonitis model for the study of glycopeptide efficacy in GISA infections

In recent years, the emergence of Staphylococcus aureus strains with reduced susceptibility to glycopeptides has raised considerable concern. We studied the efficacy of vancomycin and teicoplanin, as well as cloxacillin and cefotaxime, against the infection caused by four S. aureus strains with different glycopeptide and β-lactam susceptibilities (strains A, B, C, and D; MICs for vancomycin of 1, 2, 4, and 8 µg/ml respectively), using a modified model of mouse peritonitis. This optimized model appeared to be straightforward and reproducible, and was able to detect low differences in bacterial killing between antibiotics and also between different S. aureus strains. Bactericidal activities in peritoneal fluid for vancomycin, teicoplanin, cloxacillin, and cefotaxime decreased from -2.98, -2.36, -3.22, and -3.57 log10 cfu/ml, respectively, in infection by strain A (MICs for vancomycin and cloxacillin of 1 and 0.38 µg/ml, respectively) to -1.22, -0.65, -1.04, and +0.24 in peritonitis due to strain D (MICs for vancomycin and cloxacillin of 8 and 1,024 µg/ml). Our data confirm the superiority of β-lactams against methicillin-susceptible S. aureus and show that bactericidal activity of glycopeptides decreases significantly with slight increases in MICs; this finding suggests a reduced efficacy of glycopeptides in the treatment of serious glycopeptide-intermediate S. aureus infections

Rockfall susceptibility assessment and remote geological mapping with LiDAR point clouds

Characterizing the geological features and structures in three dimensions over inaccessible rock cliffs is needed to assess natural hazards such as rockfalls and rockslides and also to perform investigations aimed at mapping geological contacts and building stratigraphy and fold models. Indeed, the detailed 3D data, such as LiDAR point clouds, allow to study accurately the hazard processes and the structure of geologic features, in particular in vertical and overhanging rock slopes. Thus, 3D geological models have a great potential of being applied to a wide range of geological investigations both in research and applied geology projects, such as mines, tunnels and reservoirs. Recent development of ground-based remote sensing techniques (LiDAR, photogrammetry and multispectral / hyperspectral images) are revolutionizing the acquisition of morphological and geological information. As a consequence, there is a great potential for improving the modeling of geological bodies as well as failure mechanisms and stability conditions by integrating detailed remote data. During the past ten years several large rockfall events occurred along important transportation corridors where millions of people travel every year (Switzerland: Gotthard motorway and railway; Canada: Sea to sky highway between Vancouver and Whistler). These events show that there is still a lack of knowledge concerning the detection of potential rockfalls, making mountain residential settlements and roads highly risky. It is necessary to understand the main factors that destabilize rocky outcrops even if inventories are lacking and if no clear morphological evidences of rockfall activity are observed. In order to increase the possibilities of forecasting potential future landslides, it is crucial to understand the evolution of rock slope stability. Defining the areas theoretically most prone to rockfalls can be particularly useful to simulate trajectory profiles and to generate hazard maps, which are the basis for land use planning in mountainous regions. The most important questions to address in order to assess rockfall hazard are: Where are the most probable sources for future rockfalls located? What are the frequencies of occurrence of these rockfalls? I characterized the fracturing patterns in the field and with LiDAR point clouds. Afterwards, I developed a model to compute the failure mechanisms on terrestrial point clouds in order to assess the susceptibility to rockfalls at the cliff scale. Similar procedures were already available to evaluate the susceptibility to rockfalls based on aerial digital elevation models. This new model gives the possibility to detect the most susceptible rockfall sources with unprecented detail in the vertical and overhanging areas. The results of the computation of the most probable rockfall source areas in granitic cliffs of Yosemite Valley and Mont-Blanc massif were then compared to the inventoried rockfall events to validate the calculation methods. Yosemite Valley was chosen as a test area because it has a particularly strong rockfall activity (about one rockfall every week) which leads to a high rockfall hazard. The west face of the Dru was also chosen for the relevant rockfall activity and especially because it was affected by some of the largest rockfalls that occurred in the Alps during the last 10 years. Moreover, both areas were suitable because of their huge vertical and overhanging cliffs that are difficult to study with classical methods. Limit equilibrium models have been applied to several case studies to evaluate the effects of different parameters on the stability of rockslope areas. The impact of the degradation of rockbridges on the stability of large compartments in the west face of the Dru was assessed using finite element modeling. In particular I conducted a back-analysis of the large rockfall event of 2005 (265'000 m3) by integrating field observations of joint conditions, characteristics of fracturing pattern and results of geomechanical tests on the intact rock. These analyses improved our understanding of the factors that influence the stability of rock compartments and were used to define the most probable future rockfall volumes at the Dru. Terrestrial laser scanning point clouds were also successfully employed to perform geological mapping in 3D, using the intensity of the backscattered signal. Another technique to obtain vertical geological maps is combining triangulated TLS mesh with 2D geological maps. At El Capitan (Yosemite Valley) we built a georeferenced vertical map of the main plutonio rocks that was used to investigate the reasons for preferential rockwall retreat rate. Additional efforts to characterize the erosion rate were made at Monte Generoso (Ticino, southern Switzerland) where I attempted to improve the estimation of long term erosion by taking into account also the volumes of the unstable rock compartments. Eventually, the following points summarize the main out puts of my research: The new model to compute the failure mechanisms and the rockfall susceptibility with 3D point clouds allows to define accurately the most probable rockfall source areas at the cliff scale. The analysis of the rockbridges at the Dru shows the potential of integrating detailed measurements of the fractures in geomechanical models of rockmass stability. The correction of the LiDAR intensity signal gives the possibility to classify a point cloud according to the rock type and then use this information to model complex geologic structures. The integration of these results, on rockmass fracturing and composition, with existing methods can improve rockfall hazard assessments and enhance the interpretation of the evolution of steep rockslopes. -- La caractérisation de la géologie en 3D pour des parois rocheuses inaccessibles est une étape nécessaire pour évaluer les dangers naturels tels que chutes de blocs et glissements rocheux, mais aussi pour réaliser des modèles stratigraphiques ou de structures plissées. Les modèles géologiques 3D ont un grand potentiel pour être appliqués dans une vaste gamme de travaux géologiques dans le domaine de la recherche, mais aussi dans des projets appliqués comme les mines, les tunnels ou les réservoirs. Les développements récents des outils de télédétection terrestre (LiDAR, photogrammétrie et imagerie multispectrale / hyperspectrale) sont en train de révolutionner l'acquisition d'informations géomorphologiques et géologiques. Par conséquence, il y a un grand potentiel d'amélioration pour la modélisation d'objets géologiques, ainsi que des mécanismes de rupture et des conditions de stabilité, en intégrant des données détaillées acquises à distance. Pour augmenter les possibilités de prévoir les éboulements futurs, il est fondamental de comprendre l'évolution actuelle de la stabilité des parois rocheuses. Définir les zones qui sont théoriquement plus propices aux chutes de blocs peut être très utile pour simuler les trajectoires de propagation des blocs et pour réaliser des cartes de danger, qui constituent la base de l'aménagement du territoire dans les régions de montagne. Les questions plus importantes à résoudre pour estimer le danger de chutes de blocs sont : Où se situent les sources plus probables pour les chutes de blocs et éboulement futurs ? Avec quelle fréquence vont se produire ces événements ? Donc, j'ai caractérisé les réseaux de fractures sur le terrain et avec des nuages de points LiDAR. Ensuite, j'ai développé un modèle pour calculer les mécanismes de rupture directement sur les nuages de points pour pouvoir évaluer la susceptibilité au déclenchement de chutes de blocs à l'échelle de la paroi. Les zones sources de chutes de blocs les plus probables dans les parois granitiques de la vallée de Yosemite et du massif du Mont-Blanc ont été calculées et ensuite comparés aux inventaires des événements pour vérifier les méthodes. Des modèles d'équilibre limite ont été appliqués à plusieurs cas d'études pour évaluer les effets de différents paramètres sur la stabilité des parois. L'impact de la dégradation des ponts rocheux sur la stabilité de grands compartiments de roche dans la paroi ouest du Petit Dru a été évalué en utilisant la modélisation par éléments finis. En particulier j'ai analysé le grand éboulement de 2005 (265'000 m3), qui a emporté l'entier du pilier sud-ouest. Dans le modèle j'ai intégré des observations des conditions des joints, les caractéristiques du réseau de fractures et les résultats de tests géoméchaniques sur la roche intacte. Ces analyses ont amélioré l'estimation des paramètres qui influencent la stabilité des compartiments rocheux et ont servi pour définir des volumes probables pour des éboulements futurs. Les nuages de points obtenus avec le scanner laser terrestre ont été utilisés avec succès aussi pour produire des cartes géologiques en 3D, en utilisant l'intensité du signal réfléchi. Une autre technique pour obtenir des cartes géologiques des zones verticales consiste à combiner un maillage LiDAR avec une carte géologique en 2D. A El Capitan (Yosemite Valley) nous avons pu géoréferencer une carte verticale des principales roches plutoniques que j'ai utilisé ensuite pour étudier les raisons d'une érosion préférentielle de certaines zones de la paroi. D'autres efforts pour quantifier le taux d'érosion ont été effectués au Monte Generoso (Ticino, Suisse) où j'ai essayé d'améliorer l'estimation de l'érosion au long terme en prenant en compte les volumes des compartiments rocheux instables. L'intégration de ces résultats, sur la fracturation et la composition de l'amas rocheux, avec les méthodes existantes permet d'améliorer la prise en compte de l'aléa chute de pierres et éboulements et augmente les possibilités d'interprétation de l'évolution des parois rocheuses.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

The Influence of Chronic and Situational Social Status on Stereotype Susceptibility

We tested whether stereotypical situations would affect low-status group members' performance more strongly than high-status group members'. Experiment 1 and 2 tested this hypothesis using gender as a proxy of chronic social status and a gender-neutral task thathas been randomly presented to favor boys (men superiority condition), favor girls (women superiority condition), or show no gender preference (control condition). Both experiments found that women's (Experiment 1) and girls' performance (Experiment 2) suffered more from the evoked stereotypes than did men's and boys' ones. This result was replicated in Experiment 3, indicating that short men (low-status group) were more affected compared to tallmen (high-status group). Additionally, men were more affected compared to women when they perceived height as a threat. Hence, individuals are more or less vulnerable to identity threats as a function of the chronic social status at play; enjoying a high status provides protection and endorsing a low one weakens individual performance in stereotypical situations.