Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Precise U-Pb age constraints for end-Triassic mass extinction, its correlation to volcanism and Hettangian post-extinction recovery

New precise zircon U-Pb ages are proposed for the Triassic-Jurassic (Rhetian-Hettangian) and the Hettangian-Sinemurian boundaries, The ages were obtained by ID-TIMS dating of single chemical-abraded zircons from volcanic ash layers within the Pucara Group, Aramachay Formation in the Utcubamba valley, northern Peru. Ash layers situated between last and first occurrences of boundary-defining ammonites yielded Pb-206/U-238 ages of 201.58 +/- 0.17/0.28 Ma (95% c.l., uncertainties without/with decay constant errors, respectively) for the Triassic-Jurassic and of 199.53 +/- 0.19/0.29 Ma for the Hettangian-Sinemurian boundaries. The former is established on a tuff located 1 m above the last local occurrence of the topmost Triassic genus Choristoceras, and 5 m below the Hettangian genus Psiloceras. The latter sample was obtained from a tuff collected within the Badouxia canadensis beds. Our new ages document total duration of the Hettagian of no more than c. 2 m.y., which has fundamental implications for the interpretation and significance of the ammonite recovery after the topmost Triassic extinction. The U-Pb age is about 0.8 +/- 0.5% older than Ar-40-Ar-39 dates determined on flood basalts of the Central Atlantic Magmatic Province (CAMP). Given the widely accepted hypothesis that inaccuracies in the K-40 decay constants or physical constants create a similar bias between the two dating methods, our new U-Pb zircon age determination for the T/J boundary corroborates the hypothesis that the CAMP was emplaced at the same time and may be responsible for a major climatic turnover and mass extinction. The zircon Pb-206/U-238 age for the T/J boundary is marginally older than the North Mountain Basalt (Newark Supergroup, Nova Scotia, Canada), which has been dated at 201.27 +/- 0.06 Ma [Schoene et al., 2006. Geochim. Cosmochim. Acta 70, 426-445]. It will be important to look for older eruptions of the CAMP and date them precisely by U-Pb techniques while addressing all sources of systematic uncertainty to further test the hypothesis of volcanic induced climate change leading to extinction. Such high-precision, high-accuracy data will be instrumental for constraining the contemporaneity of geological events at a 100 kyr level. (C) 2007 Elsevier B.V. All rights reserved.

Pharmaceutical care in an inpatient pediatric intensive care unit: an international multicentric study

Introduction Pediatric intensive care patient represent a population athigh risk for drug-related problems. Our objective is to describe drugrelated problems and intervention of four decentralized pharmacists inpediatric and cardiac intensive care unit.Materials & Methods Multicentric, descriptive and prospectivestudy over a six-month period (August 1st 2009-January 31st 2010).Drug-related problems and clinical interventions were compiled infour pediatric centers using a tool developed by the Socie´te´ Franc¸aisede Pharmacie Clinique. Data concerning patients, drugs, intervention,documentation, approval (if needed), and estimated impact werecompiled. The four pharmacists participating were from Belgium (B),France (F), Quebec (Q) and Switzerland (S).Results A total of 996 interventions were collected: 129 (13%) in B,238 (24%) in F, 278 (28%) in Q and 351 (35%) in S. These interventionstargeted 269 patients (median 22 month-old, 52% male): 69(26%) in B, 88 (33%) in F, 56 (21%) in Q and in S. These data werecollected during 28 non consecutive days in the clinical unit in B, 59days in F, 42 days in Q and 63 days in S. The main drug-relatedproblems were inappropriate administration technique (293, 29%),untreated indication (254, 25%) and supra therapeutic dosage (106,11%). The pharmacist's interventions concerned mainly administrationmode optimization (223, 22%), dose adjustment (200, 20%) andtherapeutic monitoring (164, 16%). The three major drug classesleading to interventions were anti-infectives for systemic use (233,23%) and alimentary tract and metabolism drugs (218, 22%). Interventionsconcerned mainly residents and all clinical staff (209, 21%).Among the 879 (88%) interventions requiring a physician's approval,731 (83%) were accepted. Interventions were considered as having amoderate (51%) or major (17%) clinical impact. Among the interventionsprovided, 10% were considered to have an economicalpositive impact. Differences and similarities between countries willbe presented at the poster session.Discussion & Conclusion Decentralized pharmacist at patient bedsideis a pre-requisite for pharmaceutical care. There are limitedstudies comparing the activity of clinical pharmacists betweencountries. This descriptive study illustrates the ability of clinicalpharmacist to identify and solve drug-related problems in pediatricintensive care unit in four different francophone countries.

New vineyard cultivation practices create patchy ground vegetation, favouring Woodlarks

Intensive agriculture, in which detrimental farming practices lessen food abundance and/or reduce food accessibility for many animal species, has led to a widespread collapse of farmland biodiversity. Vineyards in central and southern Europe are intensively cultivated; though they may still harbour several rare plant and animal species, they remain little studied. Over the past decades, there has been a considerable reduction in the application of insecticides in wine production, with a progressive shift to biological control (integrated production) and, to a lesser extent, organic production. Spraying of herbicides has also diminished, which has led to more vegetation cover on the ground, although most vineyards remain bare, especially in southern Europe. The effects of these potentially positive environmental trends upon biodiversity remain mostly unknown as regards vertebrates. The Woodlark (Lullula arborea) is an endangered, short-distance migratory bird that forages and breeds on the ground. In southern Switzerland (Valais), it occurs mostly in vineyards. We used radiotracking and mixed effects logistic regression models to assess Woodlark response to modern vineyard farming practices, study factors driving foraging micro-habitat selection, and determine optimal habitat profile to inform management. The presence of ground vegetation cover was the main factor dictating the selection of foraging locations, with an optimum around 55% at the foraging patch scale. These conditions are met in integrated production vineyards, but only when grass is tolerated on part of the ground surface, which is the case on ca. 5% of the total Valais vineyard area. In contrast, conventionally managed vineyards covering a parts per thousand yen95% of the vineyard area are too bare because of systematic application of herbicides all over the ground, whilst the rare organic vineyards usually have a too-dense sward. The optimal mosaic with ca. 50% ground vegetation cover is currently achieved in integrated production vineyards where herbicide is applied every second row. In organic production, ca. 50% ground vegetation cover should be promoted, which requires regular mechanical removal of ground vegetation. These measures are likely to benefit general biodiversity in vineyards.

Stimulated-echo acquisition mode (STEAM) MRI for black-blood delayed hyperenhanced myocardial imaging.

PURPOSE: To develop a breathhold method for black-blood viability imaging of the heart that may facilitate identifying the endocardial border. MATERIALS AND METHODS: Three stimulated-echo acquisition mode (STEAM) images were obtained almost simultaneously during the same acquisition using three different demodulation values. Two of the three images were used to construct a black-blood image of the heart. The third image was a T(1)-weighted viability image that enabled detection of hyperintense infarcted myocardium after contrast agent administration. The three STEAM images were combined into one composite black-blood viability image of the heart. The composite STEAM images were compared to conventional inversion-recovery (IR) delayed hyperenhanced (DHE) images in nine human subjects studied on a 3T MRI scanner. RESULTS: STEAM images showed black-blood characteristics and a significant improvement in the blood-infarct signal-difference to noise ratio (SDNR) when compared to the IR-DHE images (34 +/- 4.1 vs. 10 +/- 2.9, mean +/- standard deviation (SD), P < 0.002). There was sufficient myocardium-infarct SDNR in the STEAM images to accurately delineate infarcted regions. The extracted infarcts demonstrated good agreement with the IR-DHE images. CONCLUSION: The STEAM black-blood property allows for better delineation of the blood-infarct border, which would enhance the fast and accurate measurement of infarct size.

[Illustrations de Au Temps des grands voiliers.] / Georges Le Poitevin, dess. ; Jean Furet, aut. du texte

Comprend : [Fig. après le titre :] Figure de proue de "France I". [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [Photographie 1 après le titre :] La magnifique voilure d'un Cap-Hornier. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [Photographie 2 après le titre :] A serrer le Grand Perroquet volant avant. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [Photographie 3 après le titre :] A serrer la Misaine. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [Photographie 4 après le titre :] A la cape. Un beau coup de roulis. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [pl. en reg. p.51. Chapitre III : un bateau Cap-Hornier, le Prométhée.] Dans le pot au noir. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [pl. en reg. p.75. Chapitre IV : sur le pont d'un navire au moment du passage du Cap-Horn.] La houle furieuse du Cap Horn déferle sur le pont d'un voilier. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [pl. en reg. p.103. Chapitre V :] Le timonier. [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [pl. en reg. p.195. Chapitre XI :] Serrer les voiles sur les vergues pendant la tempête est une manoeuvre périlleuse... [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [Pl. en reg. p.237 : schémas explicantifs des diverses parties d'une voile et d'une vergue. Rose des vents.] [Cote : 8 ° V 64722 (1,I)/microfilm R 122007] ; [pl. en double page après p.238 : Le cap-Hornier Le Prométhée.] Prométhée (...). [Cote : 8 ° V 64722 (1,I)/microfilm R 122007]

[Lettre autographe signée de Giuseppe Verdi adressée à Du Locle (sans date)]

Comprend aussi une enveloppe

Use of duplex ultrasonography in the treatment of thromboangiitis obliterans with iloprost.

We present a 34-year-old patient with digital necrosis due to thromboangiitis obliterans. He was successfully treated with iloprost, a prostaglandin analogue. Duplex ultrasonography was performed during the perfusion of iloprost to optimize the doses and the treatment duration. A complete revascularization was observed after 10 days. Iloprost perfusions were stopped, and a slow regression of the necroses was observed in the subsequent days. With the use of duplex ultrasonography, unnecessary high doses of iloprost and long periods of treatment can be avoided reducing side effects and treatment costs.

Extractants to assess zinc phytoavailability in mineral fertilizer and industrial by-products

Efficient analytical methods for the quantification of plant-available Zn contained in mineral fertilizers and industrial by-products are fundamental for the control and marketing of these inputs. In this sense, there are some doubts on the part of the scientific community as well as of the fertilizer production sector, whether the extractor requested by the government (Normative Instruction No. 28, called 2nd extractor), which is citric acid 2 % (2 % CA) (Brasil, 2007b), is effective in predicting the plant availability of Zn via mineral fertilizers and about the agronomic significance of the required minimal solubility of 60 % compared to the total content (HCl) (Brasil, 2007a). The purpose of this study was to evaluate the alternative extractors DTPA, EDTA, neutral ammonium citrate (NAC), buffer solution pH 6.0, 10 % HCl, 10 % sulfuric acid, 1 % acetic acid, water, and hot water to quantify the contents of Zn available for maize and compare them with indices of agronomic efficiency of fertilizers and industrial by-products when applied to dystrophic Clayey Red Latosol and Dystrophic Alic Red Yellow Latosol with medium texture. The rate of Zn applied to the soil was 5 mg kg-1, using the sources zinc sulfate, commercial granular zinc, ash and galvanic sludge, ash and two brass slags. Most Zn was extracted from the sources by DTPA, 10 % HCl, NAC, 1% acetic acid, and 10 % sulfuric acid. Recovery by the extractors 2 % CA, EDTA, water, and hot water was low. The agronomic efficiency index was found to be high when using galvanic sludge (238 %) and commercial granular zinc (142 %) and lower with brass slag I and II (67 and 27 %, respectively). The sources galvanizing ash and brass ash showed solubility lower than 60 % in 2 % CA, despite agronomic efficiency indices of 78 and 125 %, respectively. The low agronomic efficiency index of industrial by-products such as brass slag I and galvanizing ash can be compensated by higher doses, provided there is no restriction, as well as for all other sources, in terms of contaminant levels of arsenic, cadmium, chromium, lead, and mercury as required by law (Normative Instruction No 27/2006). The implementation of 2nd extractor 2 % CA and the requirement of minimum solubility for industrial by-products could restrict the use of alternative sources as potential Zn sources for plants.