Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma.

Epigenetic silencing of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation predicts successful alkylating agent therapy, such as with temozolomide, in glioblastoma patients. Stratified therapy assignment of patients in prospective clinical trials according to tumor MGMT status requires a standardized diagnostic test, suitable for high-throughput analysis of small amounts of formalin-fixed, paraffin-embedded tumor tissue. A direct, real-time methylation-specific PCR (MSP) assay was developed to determine methylation status of the MGMT gene promoter. Assay specificity was obtained by selective amplification of methylated DNA sequences of sodium bisulfite-modified DNA. The copy number of the methylated MGMT promoter, normalized to the beta-actin gene, provides a quantitative test result. We analyzed 134 clinical glioma samples, comparing the new test with the previously validated nested gel-based MSP assay, which yields a binary readout. A cut-off value for the MGMT methylation status was suggested by fitting a bimodal normal mixture model to the real-time results, supporting the hypothesis that there are two distinct populations within the test samples. Comparison of the tests showed high concordance of the results (82/91 [90%]; Cohen's kappa = 0.80; 95% confidence interval, 0.82-0.95). The direct, real-time MSP assay was highly reproducible (Pearson correlation 0.996) and showed valid test results for 93% (125/134) of samples compared with 75% (94/125) for the nested, gel-based MSP assay. This high-throughput test provides an important pharmacogenomic tool for individualized management of alkylating agent chemotherapy.

Hémorragie digestive haute: utilité des scores pronostiques [Upper gastrointestinal bleeding: usefulness of prognostic scores].

Upper gastrointestinal bleeding is a potentially serious event, usually requiring urgent endoscopic treatment. Better stratification of the risk of complication or death could optimize management and improve patient outcomes, while ensuring adequate resource allocation. Several prognostic scores have been developed, in order to identify high risk patients, who require immediate treatment, and patients at low risk for whom endoscopy may be delayed. An ideal prognostic score should be accurate, simple, reproducible, and prospectively validated in different populations. Published scores meet these requirements only partially, and thus can only be used as part of an integrative diagnostic and therapeutic process.

Expected impact of applying new 2013 AHA/ACC cholesterol guidelines criteria on the recommended lipid target achievement after acute coronary syndromes.

BACKGROUND: 2013 AHA/ACC guidelines on the treatment of cholesterol advised to tailor high-intensity statin after ACS, while previous ATP-III recommended titration of statin to reach low-density lipoprotein cholesterol (LDL-C) targets. We simulated the impact of this change of paradigm on the achievement of recommended targets. METHODS: Among a prospective cohort study of consecutive patients hospitalized for ACS from 2009 to 2012 at four Swiss university hospitals, we analyzed 1602 patients who survived one year after recruitment. Targets based on the previous guidelines approach was defined as (1) achievement of LDL-C target < 1.8 mmol/l, (2) reduction of LDL-C ≥ 50% or (3) intensification of statin in patients who did not reach LDL-C targets. Targets based on the 2013 AHA/ACC guidelines approach was defined as the maximization of statin therapy at high-intensity in patients aged ≤75 years and moderate- or high-intensity statin in patients >75 years. RESULTS: 1578 (99%) patients were prescribed statin at discharge, with 1120 (70%) at high-intensity. 1507 patients (94%) reported taking statin at one year, with 909 (57%) at high-intensity. Among 482 patients discharged with sub-maximal statin, intensification of statin was only observed in 109 patients (23%). 773 (47%) patients reached the previous LDL-C targets, while 1014 (63%) reached the 2013 AHA/ACC guidelines targetsone year after ACS (p value < 0.001). CONCLUSION: The application of the new 2013 AHA/ACC guidelines criteria would substantially increase the proportion of patients achieving recommended lipid targets one year after ACS. Clinical trial number, NCT01075868.

Global habitat suitability models of terrestrial mammals.

Detailed large-scale information on mammal distribution has often been lacking, hindering conservation efforts. We used the information from the 2009 IUCN Red List of Threatened Species as a baseline for developing habitat suitability models for 5027 out of 5330 known terrestrial mammal species, based on their habitat relationships. We focused on the following environmental variables: land cover, elevation and hydrological features. Models were developed at 300 m resolution and limited to within species' known geographical ranges. A subset of the models was validated using points of known species occurrence. We conducted a global, fine-scale analysis of patterns of species richness. The richness of mammal species estimated by the overlap of their suitable habitat is on average one-third less than that estimated by the overlap of their geographical ranges. The highest absolute difference is found in tropical and subtropical regions in South America, Africa and Southeast Asia that are not covered by dense forest. The proportion of suitable habitat within mammal geographical ranges correlates with the IUCN Red List category to which they have been assigned, decreasing monotonically from Least Concern to Endangered. These results demonstrate the importance of fine-resolution distribution data for the development of global conservation strategies for mammals.

An evolutionary analysis of the relationship between spite and altruism.

We investigate the selective pressures on a social trait when evolution occurs in a population of constant size. We show that any social trait that is spiteful simultaneously qualifies as altruistic. In other words, any trait that reduces the fitness of less related individuals necessarily increases that of related ones. Our analysis demonstrates that the distinction between "Hamiltonian spite" and "Wilsonian spite" is not justified on the basis of fitness effects. We illustrate this general result with an explicit model for the evolution of a social act that reduces the recipient's survival ("harming trait"). This model shows that the evolution of harming is favoured if local demes are of small size and migration is low (philopatry). Further, deme size and migration rate determine whether harming evolves as a selfish strategy by increasing the fitness of the actor, or as a spiteful/altruistic strategy through its positive effect on the fitness of close kin.

« Testaments de roys, princes et grands seigneurs, et homes doctes; testaments fictifs ». 1306 à 1669. Copies.

Contient : 1 « Testament de GUILLAUME LE HONGRE, chevalier de la ville de Metz... Ceste devise fust faitte devant feste S. Luc euvangeliste, quant il out a millair M.CCC.LIX ans » ; 2 « Testamentum GALESII DE BALMA, domini VALAFINI,... Actum et datum apud Montem Revellum, in castro nostro dicti loci, duodecima mensis augusti, hora meridiei, anno Domini millesimo trecentesimo sexagesimo secundo ». En latin ; 3 « Codicillus GALESII DE BALMA, domini VALAFINI ». Même date. En latin ; 4 « Testament de JEAN DE SAULZ, escuyer, seigneur DE COURTIVRON, chancelier de Bourgongne... Le mardy vint cinquiesme jour du mois de janvier, l'an de grace courant mille trois cent soixante et dix neuf » ; 5 « Testament de CATHERINE D'ESTRABONE, dame D'AUMONT ». Après 1456 ; 6 « Testament de Jean d'Arsonvalle, evesque de Chaalon. Tiré des registres du parlement de Paris ». 23 et 24 août 1416. En latin ; 7 « Testament de messire JEHAN DE CHALLON, prince D'ORENGE et seigneur D'ARLAY,... Faict et donné en mon chastel de Lyons le Saulnyer... le 21 d'octobre 1417... Extraict des registres de l'officialité de l'arcevesché de Bezançon » ; 8 Testament de « CLAUDE DE MONTAGU, chevalier, Sr DE COULCHES, DE LONGVY et D'ESPOISSE,... Le cinquiesme jour de... l'an mil IIII.C. cinquante et trois » ; 9 Extrait du testament de Pierre Berland, archevêque de Bordeaux. Samedi 5 février 1457. En latin ; 10 « Testamentum illustris comitis Troyae, Joannis Cossa, domini de Grimaldo et de Marignana, magni Provinciae senescalli ». Dimanche 15 septembre 1476. En latin ; 11 « Testament d'Olivier, seigneur de La Marche, conseiller et premier maistre d'hostel de Mr l'archiduc d'Austriche ». Bruxelles, 8 octobre 1501 ; 12 « Testament de PHILIPPE DE MONTAGU, comtesse DE JOIGNY » ; 13 « Testament de... Loys, Sr de Graville, admiral de France... Au chasteau de Marcoussys, l'an 1516, le jeudi 26 juing » ; 14 « Testamentum Claudii de Seyssel, archiepiscopi Taurinensis ». Turin, dimanche 27 mai 1520. En latin ; 15 Testament de « GUILLAUME BUDE, conseiller du roy, maistre des requestes ordinaire de son hostel, et maistre de sa librairie... 23 juin 1536 » ; 16 Testament de « Guillaume Du Bellay, seigneur de Langey et Glatigny,... lieutenant general en Italye... Turin, le 13 novembre 1542 » ; 17 « Testament de Michel Nostradamus,... docteur en medecine et astrophile de la ville de Salon... 17 juin 1566 » ; 18 « Testament de Caesar de Nostredame, gentilhomme ordinaire de la chambre du roy... Salon, 23 janvier 1630 » ; 19 Testament d'« ODINET GODRAN, baron D'ANTILLY, president au parlement de Bourgoigne ». 3 février 1581 ; 20 « Testament de JACQUELINE DE ROHAN, marquise DE ROTHELIN ». Décédée en 1586 ; 21 Testament de FRANÇOIS, duc D'ALENÇON, fils de Henri II, roi de France. Château-Thierry, 8 juin 1584 ; 22 Testament de « JEANNOT PATOILLET, protonotaire du S. Siege... demeurant à S. Ligier ». 22 juillet 1585 ; 23 Lettres de légitimation accordées par HENRI III, roi de France, à « Lune Patouillet, fille naturelle de Jeannot Patouillet et Jeanne Sailliot, du village d'Estrevaut, bailliage de Dijon... Donné à Dijon, au mois de febvrier, l'an 1575 » ; 24 à 26 Épitaphes d'«Odet Patoillet, d'Estrevaux », Richard Patoillet, et Jeannot Patoillet, le protonotaire. 1543, 1546, 1585. La première est en français, les deux autres sont en latin ; 27 Testament de « JAQUES DE GERMIGNY, Sr DE GERMOLLES, chevalier de l'ordre du roy, conseiller et maistre d'hostel ordinaire de sa maison, et cy devant ambassadeur pour S. M. en Levant », et de « JEHANNE BORLETTE, femme dud. Sr de Germigny,... Novembre 1585, en [la] ville de Chalon » ; 28 « Advis de conseil au proces de Mrs [Henri] de Vienne », baron de Chevreau, et François de Vienne, chevalier de Malte, « contre [Claude de La Baume], archevesque de Besançon ». Avant 1582. Commence par un extrait du testament de « dame JEHANNE DE MONBELIARD, [femme de] Loys de Chalon, prince d'Oranges et Sr d'Arlay » ; 29 Testament de « François, filz de feu Henry de Vienne, baron de Chevreaul,... Mostier, 25 octobre 1596 » ; 30 « Testamentum ROBERTI, cardinalis BELLARMINI,... Die 23 januarii, anno 1611 ». En latin ; 31 « Testament de FRANÇOIS PITHOU,... 20 novembre 1617 » ; 32 « Testament de PHILIPPE-GUILLAUME, prince D'ORANGE,... Faict à Bruxelles, le 20 de febvrier 1618 » ; 33 « Testament de messire GUILLAUME DU VAIR, evesque de Lizieux et garde des sceaux de France ». Du 10 juin au 5 juillet 1620 ; 34 « Testament de messire ANTHOINE FAVRE, baron de Peroges, de Domessin,... premier president au senat de Savoye... Faict à Chambery... ce 15 febvrier 1624 » ; 35 « Testamento di Leonor de Semeur, sigr de Tremon,... governatore per il re christianissimo di Francia della citta et paese di Macon di Bergongna... Nel... monasterio di molto reverendi padri capucini... sito sopra le fini d'Asti ». 14 juillet 1625. En italien ; 36 « Testament de Gabriel de Ste Marie, archevesque de Reims... Reims, 27 septembre 1628 » ; 37 « Exemplar testamenti cardinalis LUDOVISII ». Bologne, 10 avril 1629. En latin ; 38 « Testament de Nicolas Claude Fabri, seigneur de Peiresc, seigneur et abbé de Guistres, baron de Rians, conseiller du roy en sa cour de parlement de Provence... Aix, 22 juin 1637 » ; 39 Pièce imprimée, de 16 pages, contenant le « Testament de Mr le cardinal DE RICHELIEU ». Narbonne, 23 mai 1642 ; 40 « Testament d'ANNE DE MONTAFIE, comtesse DE SOISSONS,... Faict en mon chasteau de Creil, le 30 octobre 1642 » ; 41 « Premier testament de Gabriel de Syon,... prestre, docteur on theologie... et professeur royal... es langues orientales... Ligny le Chastel, 8 juin 1648 » ; 42 « Second Testament » du même. « Fontaine en Duesmois, 29 juin 1648 » ; 43 « Testament de CLAUDE DE SAUMAISE, chevalier de l'ordre du roy et conseiller en ses conseils d'Estat et privé... Spa, le 30 aoust 1653 » ; 44 Testament de « JEAN QUENAULT, conseiller du roy en ses conseils, et cy devant secretaire des commandemens de la feue reine Marie de Medicis,... Paris, 4 febvrier 1655 » ; 45 « Testament et codicille de Pierre Gassendi, prestre, prevost de Digne et professeur royal aux mathematiques à Paris ». 17 et 18 septembre 1655 ; 46 « Testament de Jules, cardinal Mazarin, duc de Nivernois et Donziois, pair de France ». Vincennes, 3 à 7 mars 1661 ; 47 « Testament d'Anne d'Autriche, royne de France et de Navarre... S. Germain en Laye, 13 aoust 1665 » ; 48 Pièce imprimée, de 6 pages, contenant le testament de « LOUIS DE LA RIVIERE, evesque de Langres... Petit Bourg, 22 may 1669 » ; 49 « Testamentum THEOPHILI VIAUT,... Datum in aula burgundica ». 1626. En latin ; 50 « Ejusdem epitaphium ». En latin ; 51 « Testamentum christianum cardinalis RICHELII ». En latin ; 52 « Testamentum politicum ». En latin ; 53 « Testamento della citta di Candia. Copia tratta da Pasquino, notaro publico ». En italien ; 54 « Testamento del Ruyseñor de Sa Eminencia ». En espagnol ; 55 « Epitaphio del Ruyseñor ». En espagnol

European expert opinion on the management of invasive candidiasis in adults.

This report discusses the present status of antifungal therapy and treatment options for candidaemia, considered by experts in the field in Europe. A conference of 26 experts from 13 European countries was held to discuss strategies for the treatment and prevention of invasive candidiasis, with the aim of providing a review on optimal management strategies. Published and unpublished comparative trials on antifungal therapy were analysed and discussed. Commonly asked questions about the management of candidaemia were selected, and possible responses to these questions were discussed. Panellists were then asked to respond to each question by using a touchpad answering system. After the initial conference, the viewpoint document has been reviewed and edited to include new insights and developments since the initial meeting. For many situations, consensus on treatment could not be reached, and the responses indicate that treatment is likely to be modified on a patient-to-patient basis, depending on factors such as degree of illness, prior exposure to azole antifungals, and the presence of potentially antifungal drug-resistant Candida species.

Loss of mating flight and shift in the pattern of carbohydrate storage in sexuals of ants (Hymenoptera; Formicidae)

In ants, energy for flying is derived from carbohydrates (glycogen and free sugars). The amount of these substrates was compared in sexuals participating or not participating in mating flights. Results show that in participating females (Lasius niger, L. flavus, Myrmica scabrinodis, Formica rufa, F. polyctena, F. lugubris), the amount of carbohydrates, especially glycogen, was higher than in non-participating females (Cataglyphis cursor, Iridomyrmex humilis). Similarly, male C. cursor and I. humilis which fly, exhibit a much higher carbohydrate content than do the non-flying females of these species. Furthermore, the quantity of carbohydrates stored was generally higher in males than in females for each species. These results are discussed with regard to the loss of the nuptial flight by some species of ants.

Retroviral infection of neonatal Peyer's patch lymphocytes: the mouse mammary tumor virus model.

Mouse mammary tumor virus is known to infect newborn mice via mother's milk. A proposed key step for viral spread to the mammary gland is by the infection of lymphocytes. We show here that although in suckling mice retroviral proteins are found in all epithelial cells of the gut, viral DNA is exclusively detectable in the Peyer's patches. As early as 5 d after birth the infection leads to a superantigen response in the Peyer's patches but not in other lymphoid organs draining the intestine. Viral DNA can be detected before the superantigen response and becomes first evident in the Peyer's patches followed by mesenteric lymph nodes and finally all lymphoid organs.

ML approaches to channel estimation for pilot-aided multi-rate DS/CDMA systems

This paper analyzes the asymptotic performance of maximum likelihood (ML) channel estimation algorithms in wideband code division multiple access (WCDMA) scenarios. We concentrate on systems with periodic spreading sequences (period larger than or equal to the symbol span) where the transmitted signal contains a code division multiplexed pilot for channel estimation purposes. First, the asymptotic covariances of the training-only, semi-blind conditional maximum likelihood (CML) and semi-blind Gaussian maximum likelihood (GML) channelestimators are derived. Then, these formulas are further simplified assuming randomized spreading and training sequences under the approximation of high spreading factors and high number of codes. The results provide a useful tool to describe the performance of the channel estimators as a function of basicsystem parameters such as number of codes, spreading factors, or traffic to training power ratio.

The future of terrestrial mammals in the Mediterranean basin under climate change.

The Mediterranean basin is considered a hotspot of biological diversity with a long history of modification of natural ecosystems by human activities, and is one of the regions that will face extensive changes in climate. For 181 terrestrial mammals (68% of all Mediterranean mammals), we used an ensemble forecasting approach to model the future (approx. 2100) potential distribution under climate change considering five climate change model outputs for two climate scenarios. Overall, a substantial number of Mediterranean mammals will be severely threatened by future climate change, particularly endemic species. Moreover, we found important changes in potential species richness owing to climate change, with some areas (e.g. montane region in central Italy) gaining species, while most of the region will be losing species (mainly Spain and North Africa). Existing protected areas (PAs) will probably be strongly influenced by climate change, with most PAs in Africa, the Middle East and Spain losing a substantial number of species, and those PAs gaining species (e.g. central Italy and southern France) will experience a substantial shift in species composition.