Termination of major ductile strike-slip shear and differential cooling along the Insubric line (Central Alps): U-Pb, Rb-Sr and 40Ar/39Ar ages of cross-cutting pegmatites

To constrain the age of strike-slip shear, related granitic magmatism, and cooling along the Insubric line, 29 size fractions of monazite and xenotime were dated by the U-Pb method, and a series of 25 Rb-Sr and Ar-40/Ar-39 ages were measured on different size fractions of muscovite and biotite. The three pegmatitic intrusions analyzed truncate high-grade metamorphic mylonite gneisses of the Simplon shear zone, a major Alpine structure produced in association with dextral strike-slip movements along the southern edge of the European plate, after collision with its Adriatic indenter. Pegmatites and aplites were produced between 29 and 25 Ma in direct relation to right-lateral shear along the Insubric line, by melting of continental crust having Sr-87/Sr-86 between 0.7199 and 0.7244 at the time of melting. High-temperature dextral strike-slip shear was active at 29.2 +/- 0.2 (2 sigma) Ma, and it terminated before 26.4 +/- 0.1 Ma. During dike injection, temperatures in the country rocks of the Isorno-Orselina and Monte Rosa structural units did not exceed approximate to 500 degrees C, leading to fast initial cooling, followed by slower cooling to approximate to 350 degrees C within several million years. In one case, initial cooling to approximate to 500 degrees C was significantly delayed by about 4 m.y., with final cooling to approximate to 300 degrees C at 20-19 Ma in all units. For the period between 29 and 19 Ma, cooling of the three sample localities was non-uniform in space and time, with significant variations on the kilometre scale. These differences are most likely due to strongly varying heat flow, and/or heterogeneous distribution of unroofing rates within the continuously deforming Insubric line. If entirely ascribed to differences in unroofing, corresponding rates would vary between 0.5 and 2.5 mm/y, for a thermal gradient of 30 degrees/km.

Cutting edge: cell autonomous rather than environmental factors control bacterial superantigen-induced T cell anergy in vivo.

Anergic T cells display a marked decrease in their ability to produce IL-2 and to proliferate in the presence of an appropriate antigenic signal. Two nonmutually exclusive classes of models have been proposed to explain the persistence of T cell anergy in vivo. While some reports indicate that anergic T cells have intrinsic defects in signaling pathways or transcriptional activities, other studies suggest that anergy is maintained by environmental "suppressor" factors such as cytokines or Abs. To distinguish between these conflicting hypotheses, we employed the well-characterized bacterial superantigen model system to evaluate in vivo the ability of a trace population of adoptively transferred naive or anergized T cells to proliferate in a naive vs anergic environment upon subsequent challenge. Our data clearly demonstrate that bacterial superantigen-induced T cell anergy is cell autonomous and independent of environmental factors.

Cutting edge: stimulation with the cognate self-antigen induces expression of the Ly49A receptor on self-reactive T cells which modulates their responsiveness.

NK cell self-tolerance is maintained by inhibitory receptors specific for MHC class I molecules. Inhibitory NK receptors are also expressed on memory CD8 T cells but their biological relevance on T cells is unclear. In this study, we describe the expression of the Ly49A receptor on a subset of autoreactive T cells which persist in mice double-transgenic for the lymphocytic choriomeningitis virus-derived peptide gp33 and a TCRalphabeta specific for the gp33. No Ly49A-expressing cells are found in TCRalphabeta single-transgenic mice, indicating that the presence of the autoantigen is required for Ly49A induction. Direct evidence for an Ag-specific initiation of Ly49A expression has been obtained in vitro after stimulation of autoreactive TCRalphabeta T cells with the cognate self-Ag. This expression of Ly49A substantially reduces Ag-specific activation of autoreactive T cells. These findings thus suggest that autoantigen-specific induction of inhibitory NK cell receptors on T cells may contribute to peripheral self-tolerance.

Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome.

Adjuvants are vaccine additives that stimulate the immune system without having any specific antigenic effect of itself. In this study we show that alum adjuvant induces the release of IL-1beta from macrophages and dendritic cells and that this is abrogated in cells lacking various NALP3 inflammasome components. The NALP3 inflammasome is also required in vivo for the innate immune response to OVA in alum. The early production of IL-1beta and the influx of inflammatory cells into the peritoneal cavity is strongly reduced in NALP3-deficient mice. The activation of adaptive cellular immunity to OVA-alum is initiated by monocytic dendritic cell precursors that induce the expansion of Ag-specific T cells in a NALP3-dependent way. We propose that, in addition to TLR stimulators, agonists of the NALP3 inflammasome should also be considered as vaccine adjuvants.

Qualitative, quantitative and temporal study of cutting agents for cocaine and heroin over 9 years

Forensic laboratories mainly focus on the qualification and the quantitation of the illicit drug under analysis as both aspects are used for judiciary purposes. Therefore, information related to cutting agents (adulterants and diluents) detected in illicit drugs is limited in the forensic literature. This article discusses the type and frequency of adulterants and diluents detected in more than 6000 cocaine specimens and 3000 heroin specimens, confiscated in western Switzerland from 2006 to 2014. The results show a homogeneous and quite unchanging adulteration for heroin, while for cocaine it could be characterised as heterogeneous and relatively dynamic. Furthermore, the results indicate that dilution affects more cocaine than heroin. Therefore, the results provided by this study tend to reveal differences between the respective structures of production or distribution of cocaine and heroin. This research seeks to promote the systematic analysis of cutting agents by forensic laboratories. Collecting and processing data related to the presence of cutting agents in illicit drug specimens produces relevant information to understand and to compare the structure of illicit drug markets.

The cutting of cocaine and heroin: a critical review

The illicit drug cutting represents a complex problem that requires the sharing of knowledge from addiction studies, toxicology, criminology and criminalistics. Therefore, cutting is not well known by the forensic community. Thus, this review aims at deciphering the different aspects of cutting, by gathering information mainly from criminology and criminalistics. It tackles essentially specificities of cocaine and heroin cutting. The article presents the detected cutting agents (adulterants and diluents), their evolution in time and space and the analytical methodology implemented by forensic laboratories. Furthermore, it discusses when, in the history of the illicit drug, cutting may take place. Moreover, researches studying how much cutting occurs in the country of destination are analysed. Lastly, the reasons for cutting are addressed. According to the literature, adulterants are added during production of the illicit drug or at a relatively high level of its distribution chain (e.g. before the product arrives in the country of destination or just after its importation in the latter). Their addition seems hardly justified by the only desire to increase profits or to harm consumers' health. Instead, adulteration would be performed to enhance or to mimic the illicit drug effects or to facilitate administration of the drug. Nowadays, caffeine, diltiazem, hydroxyzine, levamisole, lidocaïne and phenacetin are frequently detected in cocaine specimens, while paracetamol and caffeine are almost exclusively identified in heroin specimens. This may reveal differences in the respective structures of production and/or distribution of cocaine and heroin. As the relevant information about cutting is spread across different scientific fields, a close collaboration should be set up to collect essential and unified data to improve knowledge and provide information for monitoring, control and harm reduction purposes. More research, on several areas of investigation, should be carried out to gather relevant information.

Conference scene: Immune signatures in the tumor and beyond.

Led by key opinion leaders in the field, the Cancer Immunotherapy Consortium of the Cancer Research Institute 2012 Scientific Colloquium included 179 participants who exchanged cutting-edge information on basic, clinical and translational cancer immunology and immunotherapy. The meeting revealed how rapidly this field is advancing. The keynote talk was given by Wolf H Fridman and it described the microenvironment of primary and metastatic human tumors. Participants interacted through oral presentations and panel discussions on topics that included host reactions in tumors, advances in imaging, monitoring therapeutic immune modulation, the benefit and risk of immunotherapy, and immune monitoring activities. In summary, the annual meeting gathered clinicians and scientists from academia, industry and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.

"How I Do It"-Radical Right Colectomy with Side-to-Side Stapled Ileo-Colonic Anastomosis.

BACKGROUND AND OBJECTIVE: Standardization of surgical technique helps to reproduce excellent clinical outcomes, especially in teaching institutions. We aim to describe in detail our established approach for oncological right colectomy. TECHNIQUE: The right colon is mobilized in a five-step latero-inferior approach starting off with (1) the terminal ileum, visualizing the duodenum and the head of pancreas. (2) The ascending colon is dissected from the retroperitoneum, and takedown of the hepatic flexure is completed coming retrograde from the transverse colon (3). (4) Transection of the remaining retroperitoneal attachments completes exposure of the duodenum and mobilization of the right colon. (5) Ileocolic vessels are dissected out and divided close to their origin, and the mesocolon is divided. We then establish intestinal continuity by use of a side-to-side stapled technique. (1) The arms of a linear cutting stapler are inserted via transverse incisions at the anti-mesenteric sides of the terminal ileum and the transverse colon (tenia) and fired. (2) The enterotomy site is closed by removal of the specimen using a second transverse firing of the linear cutting stapler. An important final step is the (3) reinforcement of the anastomotic ends and the crossing of the staple lines; an omental patch and closure of the mesenteric window are optional. CONCLUSION: The suggested standardized five-step lateral-to-medial dissection of the right colon and the three-step side-to-side stapled technique for ileo-colonic anastomosis are easy to learn and to reproduce. Careful adherence to pivotal technical details will help to obtain an optimal oncological outcome and a consistently low leak rate around 2 %.

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Induction chemotherapy, as part of an integrated plan of management for locally advanced cancers, is being practised throughout the world in independent, isolated departments in universities, teaching hospitals, and clinical schools. Frequently, however, teams are relatively unaware of the work being undertaken in other institutions, and this situation may slow further progress. This book aims to present the full range of management techniques and practices used in induction chemotherapy within one accessible volume. It provides up-to-date information on the pioneering and cutting edge practices employed in different institutions and documents the advantages of integrated treatment schedules. Patient selection is discussed, and each of the cancer types for which induction therapy has proved important is considered in detail. All who are responsible for the treatment of patients with locally advanced cancers will find this book to be an invaluable source of information. It will be particularly interesting for specialist oncologists aiming to set up and develop fully comprehensive cancer centres and for health administrators wishing to learn about the benefits of establishing such centres in strategic locations.

Tight open knots.

The tightest open conformations of a few prime knots (3(1), 4(1), 5(1), 5(2), and 6(3)) found with the use of the SONO algorithm are presented and discussed. The conformations are obtained from the tightest closed conformations of the knots by cutting and opening them at different locations. The length of the rope engaged in each of the open conformations is calculated. The curvature and torsion profiles of the unique tightest conformations of the 3(1) and 4(1) open knots are presented and discussed. In particular, symmetry properties of the knots reflected within their curvature and torsion profiles are analysed. Connections with the physics of polymers are discussed.

Are virtual planning and guided surgery for head and neck reconstruction economically viable?

PURPOSE: Virtual planning and guided surgery with or without prebent or milled plates are becoming more and more common for mandibular reconstruction with fibular free flaps (FFFs). Although this excellent surgical option is being used more widely, the question of the additional cost of planning and cutting-guide production has to be discussed. In capped payment systems such additional costs have to be offset by other savings if there are no special provisions for extra funding. Our study was designed to determine whether using virtual planning and guided surgery resulted in time saved during surgery and whether this time gain resulted in self-funding of such planning through the time saved. MATERIALS AND METHODS: All consecutive cases of FFF surgery were evaluated during a 2-year period. Institutional data were used to determine the price of 1 minute of operative time. The time for fibula molding, plate adaptation, and insetting was recorded. RESULTS: During the defined period, we performed 20 mandibular reconstructions using FFFs, 9 with virtual planning and guided surgery and 11 freehand cases. One minute of operative time was calculated to cost US $47.50. Multiplying this number by the time saved, we found that the additional cost of virtual planning was reduced from US $5,098 to US $1,231.50 with a prebent plate and from US $6,980 to US $3,113.50 for a milled plate. CONCLUSIONS: Even in capped health care systems, virtual planning and guided surgery including prebent or milled plates are financially viable.

Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction.

BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility.

Lire, écrire : d'un désir l'autre : le "roman de Meliadus" du XIIIe au XVIIIe siècle

Continuation elleptique du Tristan en prose, qui s'inscrit dans l'interstice séparant la naissance de Tristan du remariage de Méliadus avec la fille du roi Hoël, le Roman de Meliadus (1235-1240) est une oeuvre fondamentalement ouverte, de par son inachèvement et de par le dialogue constant qu'il instaure avec les autres romans arthuriens. S'il revendique sa filiation et assume son statut de récit puîné, les réminiscences qu'il exhibe masquent aussi les gauchissements, les infléchissements qui lui permettent de faire du neuf avec du vieux. C'est ce jeu - aux deux sens du terme - que cette étude se propose de mettre en lumière et de voir fonctionner, non seulement dans le Roman de Meliadus proprement dit, mais également dans trois de ses relectures, qui actualisent et renouvellent la signification du roman en profondeur. La première est une continuation qui date de la toute fin du XIIIe ou du début du XIVe siècle et qui est aujourd'hui conservée par le seul manuscrit Ferrell 5. La deuxième actualisation retenue est celle qu'offre Meliadus de Leonnoys, l'imprimé publié en 1528 par Galliot du Pré, puis en 1532 par Denis Janot, fruit d'un minutieux travail de découpage et de remontage. La dernière enfin est l'extrait paru en 1776 dans la Bibliothèque Universelle des Romans sous le titre Méliadus de Léonnois. An ellipitic continuation of the Prose Tristan, which inscribes itself in the space separating the birth of Tristan from Meliadus' new marriage with king Hoël's daughter, the Meliadus' romance (1235-1240) is essentially an open text on account of its incompleteness and the dialogue it establishes with other arthurian romances. Even asserting filiation status, the reminiscences also show the reshaping and the inflection that allow the text to transform old into new. Analyzing this game is the central purpose of this work; to observe the operation in the Meliadus' romance, as well as in three of its recuperations that profoundly renew the significance of the novel; beginning with a continuation from the end of the 13th century or the early 14th century, preserved nowadays in only one manuscript (Ferrel 5); followed by the meticulous work of cutting and reassembling offered by the Meliadus of Leonnoys (printed by Galliot du Pré in 1528 first and again by Denis Janot in 1532) and finally an excerpt published in 1776 in the Bibliothèque Universelle des Romans with the title Méliadus of Leonnois.

The average crossing number of equilateral random polygons.

In this paper, we study the average crossing number of equilateral random walks and polygons. We show that the mean average crossing number ACN of all equilateral random walks of length n is of the form . A similar result holds for equilateral random polygons. These results are confirmed by our numerical studies. Furthermore, our numerical studies indicate that when random polygons of length n are divided into individual knot types, the for each knot type can be described by a function of the form where a, b and c are constants depending on and n0 is the minimal number of segments required to form . The profiles diverge from each other, with more complex knots showing higher than less complex knots. Moreover, the profiles intersect with the ACN profile of all closed walks. These points of intersection define the equilibrium length of , i.e., the chain length at which a statistical ensemble of configurations with given knot type -upon cutting, equilibration and reclosure to a new knot type -does not show a tendency to increase or decrease . This concept of equilibrium length seems to be universal, and applies also to other length-dependent observables for random knots, such as the mean radius of gyration Rg.

Angioplastie des stenoses juxta-anastomotiques de survenue precoce apres creation de fistules d'hemodialyse

Objectifs: Evaluer l'angioplastie au ballon pour le traitement des sténoses juxta-anastomotiques de survenue précoce après création des fistules d'hémodialyse.Matériels et méthodes: De septembre 2004 à septembre 2005, 9 patients ont été référés dans notre institution pour traitement d'une sténose juxta-anastomotique (0-2 cm post-anastomotiques) diagnostiquée 1 (n = 2) à 3 mois (n = 7) après chirurgie. La sténose était détectée par défaut de développement de la fistule (n = 9), échec de ponction ou de dialyse (n = 7). L'échographie confirmait une réduction de diamètre de plus de 50 % (n = 9). Après approche rétrograde veineuse 6F, l'angioplastie était réalisée avec un ballon de 4 mm (n = 4) ou 5 mm (n = 5) et complétée par angioplastie au cutting ballon de 4 mm en cas de sténose résiduelle. Le succès technique était l'absence de sténose résiduelle < 30 %, le succès clinique la dialyse possible à 3 mois de suivi.Résultats: Le succès technique était obtenu chez 8 patients (1 cas de thrombose suivant l'angioplastie) et le succès clinique chez 6/8 patients. Chez les 2 patients restants, la fistule ne se développait pas malgré l'absence de sténose récidivante.Conclusion: L'angioplastie au ballon devrait être proposée en première intention pour le traitement des sténoses juxta-anastomotiques de survenue précoce après création de fistule d'hémodialyse