Extreme Precipitation Modelling Using Geostatistics and Machine Learning Algorithms

The paper presents an approach for mapping of precipitation data. The main goal is to perform spatial predictions and simulations of precipitation fields using geostatistical methods (ordinary kriging, kriging with external drift) as well as machine learning algorithms (neural networks). More practically, the objective is to reproduce simultaneously both the spatial patterns and the extreme values. This objective is best reached by models integrating geostatistics and machine learning algorithms. To demonstrate how such models work, two case studies have been considered: first, a 2-day accumulation of heavy precipitation and second, a 6-day accumulation of extreme orographic precipitation. The first example is used to compare the performance of two optimization algorithms (conjugate gradients and Levenberg-Marquardt) of a neural network for the reproduction of extreme values. Hybrid models, which combine geostatistical and machine learning algorithms, are also treated in this context. The second dataset is used to analyze the contribution of radar Doppler imagery when used as external drift or as input in the models (kriging with external drift and neural networks). Model assessment is carried out by comparing independent validation errors as well as analyzing data patterns.

Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet.

OBJECTIVE-Obesity and associated pathologies are major global health problems. Transforming growth factor-beta/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic beta-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.RESEARCH DESIGN AND METHODS-We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.RESULTS-Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein beta-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor beta/delta and proliferator-activated receptor gamma expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid beta-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.CONCLUSIONS-Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders.

Leishmania cysteine proteinases: from gene to subunit vaccine.

Whole genome sequences of microbial pathogens present new opportunities for clinical application. Presently, genome sequencing of the human protozoan parasite Leishmania major is in progress. The driving forces behind the genome project are to identify genes with key cellular functions and new drug targets, to increase knowledge on mechanisms of drug resistance and to favor technology transfer to scientists from endemic countries. Sequencing of the genome is also aimed at the identification of genes that are expressed in the infectious stages of the parasite and in particular in the intracellular form of the parasite. Several protective antigens of Leishmania have been identified. In addition to these antigens, lysosomal cysteine proteinases (CPs) have been characterized in different strains of Leishmania and Trypanosoma, as new target molecules. Recently, we have isolated and characterized Type I (CPB) and Type II (CPA) cysteine proteinase encoding genes from L. major. The exact function of cysteine proteinases of Leishmania is not completely understood, although there are a few reports describing their role as virulence factors. One specific feature of CPB in Leishmania and other trypanosomatids, is the presence of a Cterminal extension (CTE) which is possibly indicative of conserved structure and function. Recently, we demonstrated that DNA immunization of genetically susceptible BALB / c mice, using a cocktail of CPB and CPA genes, induced long lasting protection against L. major infection. This review intends to give an overview of the current knowledge on genetic vaccination used against leishmaniasis and the importance of CP genes for such an approach.

Maps as risk mitigation tools. Adaptation of the Swiss hazard assessment and mapping methodology to a Moroccan site: Beni Mellal

Dans le contexte climatique actuel, les régions méditerranéennes connaissent une intensification des phénomènes hydrométéorologiques extrêmes. Au Maroc, le risque lié aux inondations est devenu problématique, les communautés étant vulnérables aux événements extrêmes. En effet, le développement économique et urbain rapide et mal maîtrisé augmente l'exposition aux phénomènes extrêmes. La Direction du Développement et de la Coopération suisse (DDC) s'implique activement dans la réduction des risques naturels au Maroc. La cartographie des dangers et son intégration dans l'aménagement du territoire représentent une méthode efficace afin de réduire la vulnérabilité spatiale. Ainsi, la DDC a mandaté ce projet d'adaptation de la méthode suisse de cartographie des dangers à un cas d'étude marocain (la ville de Beni Mellal, région de Tadla-Azilal, Maroc). La méthode suisse a été adaptée aux contraintes spécifiques du terrain (environnement semi-aride, morphologie de piémont) et au contexte de transfert de connaissances (caractéristiques socio-économiques et pratiques). Une carte des phénomènes d'inondations a été produite. Elle contient les témoins morphologiques et les éléments anthropiques pertinents pour le développement et l'aggravation des inondations. La modélisation de la relation pluie-débit pour des événements de référence, et le routage des hydrogrammes de crue ainsi obtenus ont permis d'estimer quantitativement l'aléa inondation. Des données obtenues sur le terrain (estimations de débit, extension de crues connues) ont permis de vérifier les résultats des modèles. Des cartes d'intensité et de probabilité ont été obtenues. Enfin, une carte indicative du danger d'inondation a été produite sur la base de la matrice suisse du danger qui croise l'intensité et la probabilité d'occurrence d'un événement pour obtenir des degrés de danger assignables au territoire étudié. En vue de l'implémentation des cartes de danger dans les documents de l'aménagement du territoire, nous nous intéressons au fonctionnement actuel de la gestion institutionnelle du risque à Beni Mellal, en étudiant le degré d'intégration de la gestion et la manière dont les connaissances sur les risques influencent le processus de gestion. L'analyse montre que la gestion est marquée par une logique de gestion hiérarchique et la priorité des mesures de protection par rapport aux mesures passives d'aménagement du territoire. Les connaissances sur le risque restent sectorielles, souvent déconnectées. L'innovation dans le domaine de la gestion du risque résulte de collaborations horizontales entre les acteurs ou avec des sources de connaissances externes (par exemple les universités). Des recommandations méthodologiques et institutionnelles issues de cette étude ont été adressées aux gestionnaires en vue de l'implémentation des cartes de danger. Plus que des outils de réduction du risque, les cartes de danger aident à transmettre des connaissances vers le public et contribuent ainsi à établir une culture du risque. - Severe rainfall events are thought to be occurring more frequently in semi-arid areas. In Morocco, flood hazard has become an important topic, notably as rapid economic development and high urbanization rates have increased the exposure of people and assets in hazard-prone areas. The Swiss Agency for Development and Cooperation (SADC) is active in natural hazard mitigation in Morocco. As hazard mapping for urban planning is thought to be a sound tool for vulnerability reduction, the SADC has financed a project aimed at adapting the Swiss approach for hazard assessment and mapping to the case of Morocco. In a knowledge transfer context, the Swiss method was adapted to the semi-arid environment, the specific piedmont morphology and to socio-economic constraints particular to the study site. Following the Swiss guidelines, a hydro-geomorphological map was established, containing all geomorphic elements related to known past floods. Next, rainfall / runoff modeling for reference events and hydraulic routing of the obtained hydrographs were carried out in order to assess hazard quantitatively. Field-collected discharge estimations and flood extent for known floods were used to verify the model results. Flood hazard intensity and probability maps were obtained. Finally, an indicative danger map as defined within the Swiss hazard assessment terminology was calculated using the Swiss hazard matrix that convolves flood intensity with its recurrence probability in order to assign flood danger degrees to the concerned territory. Danger maps become effective, as risk mitigation tools, when implemented in urban planning. We focus on how local authorities are involved in the risk management process and how knowledge about risk impacts the management. An institutional vulnerability "map" was established based on individual interviews held with the main institutional actors in flood management. Results show that flood hazard management is defined by uneven actions and relationships, it is based on top-down decision-making patterns, and focus is maintained on active mitigation measures. The institutional actors embody sectorial, often disconnected risk knowledge pools, whose relationships are dictated by the institutional hierarchy. Results show that innovation in the risk management process emerges when actors collaborate despite the established hierarchy or when they open to outer knowledge pools (e.g. the academia). Several methodological and institutional recommendations were addressed to risk management stakeholders in view of potential map implementation to planning. Hazard assessment and mapping is essential to an integrated risk management approach: more than a mitigation tool, danger maps represent tools that allow communicating on hazards and establishing a risk culture.

Cadmium distribution in soils covering Jurassic oolitic limestone with high Cd contents in the Swiss Jura

Oolitic carbonates belonging to the Hauptrogenstein Formation of Bajocian (Middle Jurassic) age have been shown to be anomalously enriched in cadmium (Cd) throughout the Jura Mountains. Soils associated with this type of rock substratum may be naturally polluted with regards to Cd. At Schleifenberg (Canton Basel Land, Switzerland) the Hauptrogenstein Formation is almost entirely exposed along a trail on its SW flank. Cadmium concentrations were systematically measured throughout this formation and Cd enrichments in rocks are shown to occur to a maximum content of 4.9 mg kg(-1). We investigated associated soils, which cover the entire outcrop, and show that they have been formed through the weathering of the underlying bedrock and through the uptake of colluvial limestone fragments from the same and older formations. Cadmium contents in the soils reach a maximum value of 2.0 mg kg(-1), thereby exceeding the official Swiss indicative guideline value for soils fixed at 0.8 mg.kg(-1). Mineralogical analyses on the soils and associated bedrock suggest that no allochthonous component related to aeolian transport is present. Sequential extractions applied to selected soil samples show that about half of the Cd resides in the carbonate fraction coming from the fractured parent-rock, while the Cd released from the weathered carbonates is associated either with organic matter (over 10%) or with Fe and Mn-oxihydroxides (approximately 30%). No exchangeable Cd phase was found and this, together with the buffer capacity of this calcareous soil, suggests that the amount of mobile Cd is quite negligible in this soil, which also greatly reduces the amount of bioavailable

Palaeoenvironment and palaeoclimate of the Middle Miocene lake in the Steinheim basin, SW Germany: A reconstruction from C, O, and Sr isotopes of fossil remains

A differentiated reconstruction of palaeolimnologic, -environmental, and -climatic conditions is presented for the Middle Miocene long-term freshwater lake (14.3 to 13.5 Ma) of the Steinheim basin, on the basis of a combined C, 0, and Sr isotope study of sympatric skeletal fossils of aquatic and terrestrial organisms from the lake sediments. The oxygen isotope composition for lake water of the Steinheim basin (delta O-18(H2O) = +2.0 +/- 0.4 parts per thousand VSMOW, n = 6) was reconstructed from measurements of delta O-18(PO4) of aquatic turtle bones. The drinking water calculated from the enamel of large mammals (proboscideans, rhinocerotids, equids, cervids, suids) has delta O-18(H2O) values (delta(OH2O)-O-18 = -5.9 +/- 1.7 parts per thousand VSMOW, n = 31) typical for Middle Miocene meteoric water of the area. This delta O-18(H2O) value corresponds to a mean annual air temperature (MAT) of 18.8 +/- 3.8 degrees C, calculated using a modem-day delta(OH2O)-O-18-MAT relation. Hence, large mammals did not use the lake water as principal drinking water. In contrast, small mammals, especially the then abundant pika Prolagus oeningensis drank from O-18-enriched water sources (delta O-18(H2O) = +2.7 +/- 2.3 parts per thousand VSMOW, n = 7), such as the lake water. Differences in Sr and 0 isotopic compositions between large and small mammal teeth indicate different home ranges and drinking behaviour and support migration of some large mammals between the Swabian Alb plateau and the nearby Molasse basin, while small mammals ingested their food and water locally. Changes in the lake level, water chemistry, and temperature were inferred using isotopic compositions of ostracod and gastropod shells from a composite lake sediment profile. Calcitic ostracod valves (Ilyocypris binocularis; delta O-18 = +1.7 +/- 1.2 parts per thousand VPDB, delta C-18 = -0.5 +/- 0.9 parts per thousand, VPDB, n = 68) and aragonitic, gastropod shells (Gyraulus spp.; delta O-18 = +2.0 +/- 13 parts per thousand VPDB, delta C-13 = -1.1 +/- 1.3 parts per thousand VPDB, n = 89) have delta O-18 and delta C-13 values similar to or even higher than those of marine, carbonates. delta C-13 values:of the biogenic carbonates parallel lake level fluctuations while delta O-18 values scatter around +2 +/- 2 parts per thousand and reflect the short term variability of meteoric water inflow vs. longer term evaporation. Sr-87/Sr-86 ratios of aragonitic Gyraulus spp. gastropod shells parallel the lake level fluctuations, reflecting variable inputs of groundwater and surface waters. Using a water delta O-18(H2O) value of +2.0 parts per thousand VSMOW, water temperatures calculated from skeletal tissue delta O-18 values of ostracods are 16.7 +/- 5.0 degrees C, gastropods 20.6 +/- 5.6 degrees C, otoliths 21.8 +/- 1.4 degrees C, and fish teeth 17.0 +/- 2.7 degrees C. The calculated MAT (similar to 19 degrees C), lake water temperatures (similar to 17 to 22 degrees C) and the O-18-enriched water compositions are indicative of warm-temperate climatic conditions, possibly with a high humidity during this period. Vegetation in the area surrounding the basin was largely of the C-3-type, as indicated by carbon isotopic compositions of tooth enamel from large mammals (delta C-13 = -11.1 +/- 1.1 parts per thousand VPDB, n = 40). (c) 2006 Elsevier B.V. All rights reserved.

Flow-R, a model for susceptibility mapping of debris flows and other gravitational hazards at a regional scale: some case studies

Every year, debris flows cause huge damage in mountainous areas. Due to population pressure in hazardous zones, the socio-economic impact is much higher than in the past. Therefore, the development of indicative susceptibility hazard maps is of primary importance, particularly in developing countries. However, the complexity of the phenomenon and the variability of local controlling factors limit the use of processbased models for a first assessment. A debris flow model has been developed for regional susceptibility assessments using digital elevation model (DEM) with a GIS-based approach.. The automatic identification of source areas and the estimation of debris flow spreading, based on GIS tools, provide a substantial basis for a preliminary susceptibility assessment at a regional scale. One of the main advantages of this model is its workability. In fact, everything is open to the user, from the data choice to the selection of the algorithms and their parameters. The Flow-R model was tested in three different contexts: two in Switzerland and one in Pakistan, for indicative susceptibility hazard mapping. It was shown that the quality of the DEM is the most important parameter to obtain reliable results for propagation, but also to identify the potential debris flows sources.

Morphological scoring of human pronuclear zygotes for prediction of pregnancy outcome.

BACKGROUND: As embryo selection is not allowed by law in Switzerland, we need a single early scoring system to identify zygotes with high implantation potential and to select zygotes for fresh transfer or cryopreservation. The underlying aim is to maximize the cumulated pregnancy rate while limiting the number of multiple pregnancies. METHODS: In all, 613 fresh and 617 frozen-thawed zygotes were scored for proximity, orientation and centring of the pronuclei, cytoplasmic halo, and number and polarization of the nucleolar precursor bodies. From these individual scores, a cumulated pronuclear score (CPNS) was calculated. Correlation between CPNS and implantation was examined and compared between fresh and frozen-thawed zygotes. The effect of freezing on CPNS was also investigated. RESULTS: CPNS was positively associated with embryo implantation in both fresh and frozen zygotes. With similar CPNS, frozen zygotes presented implantation rates as high as those of fresh zygotes. Nucleolar precursor bodies pattern and cytoplasmic halo appeared as the most important factors predictive of implantation for both types of zygotes, while pronuclei position was specifically relevant for frozen-thawed zygotes. Freezing induced an alteration of most zygote parameters, resulting in a significantly lower CPNS and a lower pregnancy rate. CONCLUSIONS: CPNS may be used as a single prognostic tool for implantation of both fresh and frozen-thawed zygotes. Lower CPNS values of frozen-thawed zygotes may also be indicative of freezing damage to zygotes. Successful implantation of frozen zygotes despite lower CPNS suggests that they may recover after thawing and in vitro culture.

Sexueller Missbrauch bei Kindern und Jugendlichen- Aufdeckung, Untersuchung und Erstbetreuung [Sexual abuse of female children and adolescents--detection, examination and primary care].

Epidemiological studies show a prevalence of sexual abuse experience among girls from 14-33%. Although indicators of abuse are unspecific, the combination of several findings may be indicative: Somatic signs may be sexually transmitted diseases, vulvovaginal complaints. Psychosocial nonsexual indicators are abrupt behavioural changes, running away from home, eating disorders. Psychosexual signs are hypersexualisation of the language and behaviour, disturbed body image and gender identity. Indirect evidence of abuse is given not only in cases of old vaginal and anal lesions but also in situations, where deep tears of the hymen in the typical localization at the posterior part can be found. The workup and care for children in whom there is suspicion of abuse but no clear evidence asks for highly competent professionals in a multidisciplinary cooperation including pediatric gynecologists, child psychiatrists, children-protection groups and other specialists to avoid on one hand unjustified destabilisation or even destruction of familial structures but to assure on the other hand, that the child victims are treated and followed after in a short and long term comprehensive medical and psychosocial care.

Magma generation at the easternmost section of the Hellenic arc: Hf, Nd, Pb and Sr isotope geochemistry of Nisyros and Yali volcanoes (Greece)

Geochemical and petrographical studies of lavas and ignimbrites from the Quaternary Nisyros-Yali volcanic system in the easternmost part of the Hellenic arc (Greece) reveal insight into magma generating processes. A compositional gap between 61 and 68 wt.% SiO2 is recognized that coincides with the stratigraphic distinction between pre-caldera and postcaldera volcanic units. Trace element systematics support the subdivision of Nisyros and Yali volcanic units into two distinct suites of rocks. The variation of Nd and Hf present day isotope data and the fact that they are distinct from the isotope compositions of MORB rule out an origin by pure differentiation and require assimilation of a crustal component. Lead isotope ratios of Nisyros and Yali volcanic rocks support mixing of mantle material with a lower crust equivalent. However, Sr-87/Sr-86 ratios of 0.7036-0.7048 are incompatible with a simple binary mixing scenario and give low depleted mantle extraction ages (< 0.1 Ga), in contrast with Pb model ages of 0.3 Ga and Hf and Nd model ages of ca. 0.8 Ga. The budget of fluid-mobile elements Sr and Pb is likely to be dominated by abundant hydrous fluids characterised by mantle-like Sr isotope ratios. Late stage fluids probably were enriched in CO2, needed to explain the high Th concentrations. The occurrence of hydrated minerals (e.g., amphibole) in the first post-caldera unit with the lowermost Sr-87/Sr-86 ratio of 0.7036 +/- 2 can be interpreted as the result of the increased water activity in the source. The presence of two different plagioclase phenocryst generations in the first lava subsequent to the caldera-causing event is indicative for a longer storage time of this magma at a shallower level. A model capable of explaining these observations involves three evolutionary stages. First stage, assimilation of lower crustal material by a primitive magma of mantle origin (as modelled by Nd-Hf isotope systematics). This stage ended by an interruption in replenishment that led to an increase of crystallization and, hence, an increase in viscosity, suppressing eruption. During this time gap, differentiation by fractional crystallization led to enrichment of incompatible species, especially aqueous fluids, to silica depolymerisation and to a decrease in viscosity, finally enabling eruption again in the third stage. (c) 2005 Elsevier B.V. All rights reserved.

Assessment of recent HIV-1 infection by a line immunoassay for HIV-1/2 confirmation.

BACKGROUND: Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this "recency" information can also be gained from an HIV confirmatory assay. METHODS AND FINDINGS: The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (< or = 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%-46%). CONCLUSIONS: Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.

Immunological and clinical consequences of treating a patient with natalizumab.

BACKGROUND: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). METHODS: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. RESULTS: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. CONCLUSION: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

Prevalence of symptomatic and silent stress-induced perfusion defects in diabetic patients with suspected coronary artery disease referred for myocardial perfusion scintigraphy.

PURPOSE: Silent myocardial ischaemia--as evaluated by stress-induced perfusion defects on myocardial perfusion scintigraphy (MPS) in patients without a history of chest pain--is frequent in diabetes and is associated with increased rates of cardiovascular events. Its prevalence has been determined in asymptomatic diabetic patients, but remains largely unknown in diabetic patients with suspected coronary artery disease (CAD) in the clinical setting. In this study we therefore sought (a) to determine the prevalence of symptomatic and silent perfusion defects in diabetic patients with suspected CAD and (b) to characterise the eventual predictors of abnormal perfusion. METHODS: The patient population comprised 133 consecutive diabetic patients with suspected CAD who had been referred for MPS. Studies were performed with exercise (41%) or pharmacological stress testing (1-day protocol, (99m)Tc-sestamibi, 201Tl or both). We used semi-quantitative analysis (20-segment polar maps) to derive the summed stress score (SSS) and the summed difference score (SDS). RESULTS: Abnormal MPS (SSS> or =4) was observed in 49 (37%) patients (SSS=4.9+/-8.4, SDS=2.4+/-4.7), reversible perfusion defects (SDS> or =2) in 40 (30%) patients [SSS=13.3+/-10.9; SDS=8.0+/-5.6; 20% moderate to severe (SDS>4), 7% multivessel] and fixed defects in 21 (16%) patients. Results were comparable between patients with and patients without a history of chest pain. Of 75 patients without a history of chest pain, 23 (31%, 95% CI=21-42%) presented reversible defects (SSS=13.9+/-11.3; SDS=7.4+/-1.2), indicative of silent ischaemia. Reversible defects were associated with inducible ST segment depression during MPS stress [odds ratio (OR)=3.2, p<0.01). Fixed defects were associated with erectile dysfunction in males (OR=3.7, p=0.02) and lower aspirin use (OR=0.25, p=0.02). CONCLUSION: Silent stress-induced perfusion defects occurred in 31% of the patients, a rate similar to that in patients with a history of chest pain. MPS could identify these patients with a potentially increased risk of cardiovascular events.

Analysis of c-Myc function in mouse epidermis

Abstract The c-myc gene is one of the most frequently mutated oncogenes found in human tumors. c-Myc has been implicated in the regulation of various biological processes including cell cycle progression, cellular growth, differentiation, angiogenesis, immortalization and apoptosis. To assess the normal role of c-Myc in epithelial cell types in vitro and in vivo we have deleted the c-myc gene in keratinocytes and in the adult skin epidermis by conditional Cre/loxP mediated recombination. Similar to what we have previously shown in mouse embryonic fibroblasts acute elimination of c-Myc activity in cultured keratinocytes causes cells to cease proliferation and adapt a flat cell morphology. Mutant cells accumulate in a diploid Ki67neg stage, indicative of a quiescent Go stage. This demonstrates that c-Myc activity is essential to maintain keratinocytes in a productive cell cycle. In addition, mutant keratinocytes showed a defect in Ca2+ induced induction of the differentiation marker Keratin 1 suggesting a role for c-Myc during differentiation. To assess the in vivo role of c-Myc we used a tamoxifen inducible K5::CreERT transgene to delete the c-myc gene in the adult skin epidermis. Unexpectedly, despite strong c-Myc expression in the basal compartment it is not required for maintenance of the skin epidermis in the adult mouse. The epidermis appeared normal with respect to both proliferation and differentiation. In addition, no selection against c-Myc deficient epidermal cells occurred over many months, further confirming that c-Myc is dispensable for normal skin homeostasis. Even more surprising, TPA induced hyperproliferation also occurred in a c-Myc independent manner. Treatment of the skin with the mutagen DMBA prior to TPA is a classical way to induce papillomas by selecting for mutations that lead to dominant activation of the oncogene Ha-Ras. Most interestingly tumor formation was severely inhibited suggesting that tumor progression requires endogenous c-Myc. Further studies are required to address whether the role of c-Myc in the activation of telomerase or the Werner protein, or its role to induce angiogenesis is required for skin tumor progression, In conclusion, this work shows that while c-Myc is not required for maintenance or hyperplasia of mouse epidermis, it is essential for skin tumor progression in collaboration with Ras. Résumé Le gène c-myc est un des oncogènes les plus fréquemment mutés dans les tumeurs humaines. c-Myc est impliqué dans la régulation de processus biologiques variés, comme la progression du cycle cellulaire, la croissance cellulaire, la différenciation, l'angiogenèse, l'immortalisation et l'apoptose. Pour caractériser le rôle physiologique de c-Myc dans les cellules de type épithélial in vitro et in vivo, le gène c-myc a été délété dans des kératinocytes primaires et dans l'épiderme de peau de souris adultes par des recombinaisons conditionnelles (système Cre/loxP). De la même façon que dans les fibroblastes d'embryon de souris, l'élimination aiguë de l'activité de c-Myc dans les kératinocytes en culture primaire provoque l'arrêt de la prolifération des cellules et leur applatissement morphologique. Les cellules mutantes restent dans un stade diploïde Ki67neg, indiquant un stade quiescent Go. Cela démontre que l'activité de c-Myc est essentielle pour maintenir les kératinocytes dans le cycle cellulaire. De plus, les kératinocytes mutants montrent une déficience pour le marqueur de différenciation Kératine 1 au cours de la différenciation induite par le calcium, suggérant un rôle de c-Myc dans la différenciation cellulaire. Pour comprendre le rôle de c-Myc in vivo, le transgène K5::CreERT inductible par le tamoxifen a été utilisé pour déléter le gène c-inyc dans l'épiderme de souris adultes. Etonnemment, malgré une forte expression de c-Myc dans le compartiment basal de l'épiderme, ce gène n'est pas nécessaire pour la maintenance de l'épiderme de la peau chez la souris adulte. L'épiderme apparait normal avec une prolifération et une différenciation physiologique des cellules. De plus, il n'y a pas de sélection contre les cellules épidennales c-Myc déficientes après plusieurs mois, ce qui confirme que c-Myc n'est pas nécessaire pour l'homéostasie normale de la peau. Encore plus surprenant, une hyperprolifération est également induite par du TPA chez les souris mutantes, impliquant une voie de prolifération indépendante de c-Myc. Le traitement de la peau par le mutagène DMBA avant le traitement au TPA est une voie classique d'induction de papillomes, par sélection de mutations conduisant à l'activation de l'oncogène Ha-Ras. La formation des tumeurs est fortement inhibée chez les souris mutantes, suggérant que la progression des tumeurs nécessite la présence endogène de c-Myc. De nouvelles études sont nécessaires pour savoir si c-Myc a un rôle dans l'activation de la télomérase ou de la protéine de Werner, ou encore dans l'angiogénèse, qui sont nécessaires pour la progression tumorale. En conclusion, ce travail montre que même si c-Myc n'est pas nécessaire pour la maintenance ou l'hyperplasie de la peau de souris, il est essentiel pour la progression des tumeurs de la peau en collaboration avec Ras.

Progression of auditory discrimination based on neural decoding predicts awakening from coma.

Auditory evoked potentials are informative of intact cortical functions of comatose patients. The integrity of auditory functions evaluated using mismatch negativity paradigms has been associated with their chances of survival. However, because auditory discrimination is assessed at various delays after coma onset, it is still unclear whether this impairment depends on the time of the recording. We hypothesized that impairment in auditory discrimination capabilities is indicative of coma progression, rather than of the comatose state itself and that rudimentary auditory discrimination remains intact during acute stages of coma. We studied 30 post-anoxic comatose patients resuscitated from cardiac arrest and five healthy, age-matched controls. Using a mismatch negativity paradigm, we performed two electroencephalography recordings with a standard 19-channel clinical montage: the first within 24 h after coma onset and under mild therapeutic hypothermia, and the second after 1 day and under normothermic conditions. We analysed electroencephalography responses based on a multivariate decoding algorithm that automatically quantifies neural discrimination at the single patient level. Results showed high average decoding accuracy in discriminating sounds both for control subjects and comatose patients. Importantly, accurate decoding was largely independent of patients' chance of survival. However, the progression of auditory discrimination between the first and second recordings was informative of a patient's chance of survival. A deterioration of auditory discrimination was observed in all non-survivors (equivalent to 100% positive predictive value for survivors). We show, for the first time, evidence of intact auditory processing even in comatose patients who do not survive and that progression of sound discrimination over time is informative of a patient's chance of survival. Tracking auditory discrimination in comatose patients could provide new insight to the chance of awakening in a quantitative and automatic fashion during early stages of coma.