Mineralogical and Sedimentological Characterization of the Clay-Rich Sediments from Ases Cave (Cova Dets Ases, Mallorca, Spain): Origin and Classification

The Mallorca coastal caves present large amounts of speleothems that have been studied for decades. However, the sedimentary deposits also present in these cases have not been given the same attention. This work is the first study entirely focused on these deposits, specifically the ones found in the Ases cave. These deposits are formed by clay minerals (illitic phases, kaolinite, smectite, and chlorite), calcite and quartz, and minor proportions of dolomite, albite, orthoclase, hematite, and goethite. The grain size and the electron microscopy studies suggested the presence of different sedimentation processes (bedrock degradation, creep or saltation, and suspension) and different origins (authigenic and detrital origins) for the different sediments. Based on these differences, two types of deposits were characterized: autochthonous and allochthonous deposits. The first ones are located on the floor of chambers and corridors in subaqueous zones, indicating the stability of the mixing zone (and therefore the sea level) over time. The second ones appear filling voids on the walls and the ceiling in the terrestrial zone, evidencing the filling of the cavity in the presence of water (during a wet period). These results are very important to complete the understanding of the caves and their evolution and support the relevance of these materials in paleoenvironmental studies

Defects of splicing in antithrombin deficiency

Background: There is increasing evidence supporting the relevance of aberrant splicing in multiple disorders. In antithrombin deficiency only 22 intronic mutations affecting splicing sites (7% of SERPINC1 mutations) are considered as splicing mutations. Methods: SERPINC1 was analyzed by Sanger sequencing and MLPA in 141 unrelated cases with antithrombin deficiency. Plasma antithrombin was studied by functional and western blot assays, purified by FPLC and characterized by proteomic analysis. In silico predictions on splicing was done with the Human Splicing Finder software. Results: We detected 89 different SERPINC1 defects, 13 with potential effect on splicing. Ten cases presented 9 mutations disturbing splicing sites, 5 new. Three gross or small gene defects also disturbed a correct splicing. Interestingly, the first duplication of a single exon ever described (c.1154-13_1218+115dup), caused mild deficiency (75%). A deeper intronic mutation (c.1154-14G>A), identified in three unrelated patients with traces of disulphide dimers of antithrombin in plasma, created a cryptic splicing site that might generate a variant with 4 additional in frame residues according to in silico predictions. This aberrant splicing was confirmed by proteomic analysis of the dimer purified from plasma. Conclusions: A high proportion of cases with antithrombin deficiency (up to 13%) may be explained by an aberrant splicing. Up to 15% of mutations in SERPINC1: splicing site variations, gross gene defects and deep intronic mutations, may affect a correct splicing with three potential consequences type I, type II, and even moderate antithrombin deficiency

Los nuevos retos de la industria farmacéutica

Diverse challenges of the modern pharmaceutical industry are analysed in this papero High competitiveness in the pharmaceutical sector and new regulations dictated by the different governments or organizations in charge of watching over public health have generated the need to devise new ways in the discovery of new drugs. On one hand, the rational drug design has acquired a leading role and on the other, the development of robotics has prompted the development of combinatorial chemistry and high production screening. The pharmaceutical industry of the future must be more dynamic and innovating. One of the observed phenomena has been the merging of a number of pharmaceutical fusions faced to the necessity of reducing production costs.En este trabajo se analizan los distintos retos de la industria farmacéutica moderna. La elevada competitividad del sector farmacéutico y las nuevas regulaciones dictadas por los diferentes gobiernos u organismos encargados de velar por la salud pública han generado la necesidad de idear nuevas vías en el descubrimiento de nuevos medicamentos. Por una parte, el diseño racional de fármacos ha adquirido un enorme protagonismo y, por otra, el desarrollo de la robótica han potenciado el desarrollo de la química combinatoria y del tamizado de alta producción. La futura industria farmacéutica debe ser más dinámica e innovadora. Uno de sus fenómenos observados ha sido el elevado número de fusiones de empresas farmacéuticas, ante la necesidad de reducir los costes de los productos

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

NEWRUR: pression urbaine et zone rurale un programme de recherche européen 2001-2004

[Departement_IRSTEA]GT [TR1_IRSTEA]RURAMEN / AMANDEAutresThis CD-ROM presents the main results of the NEWRUR research programme on interaction between urban expansion and surrounding rural areas. It is one product of this research led by five European research centres and universities during four years. This CD ROM has been produced and displays some scientific results for the benefit of local actors in charge of European territories and their future. It offers a cross-reading of these results, in form of four gradual pathways. The progression is thought out to help taking in the project results. Each pathway follows the thread of an idea or of a demonstration, about main topics of investigation, namely integration of rural zones into city-regions, mutations in periurban areas and space management policies or land uses regulation.Ce CD-ROM présente quelques résultats du programme de recherche NEWRUR sur les interactions entre l`expansion urbaine et le développement des zones rurales voisines. Cinq universités ou instituts de recherche européens ont été associés à ce projet qui s`est déroulé de 2001 à 2004. Ce CD-ROM a été conçu non comme un produit de type scientifique, mais comme un support de communication des principaux résultats de cette recherche, destiné à les rendre plus accessibles aux décideurs locaux et aux organismes en charge des territoires de l`Union Européenne et de leur devenir. Il offre une lecture transversale de la périurbanisation et de ses effets sur les territoires ruraux sous la forme de quatre parcours progressifs, permettant de situer les résultats obtenus. Chaque parcours développe une idée ou une argumentation sur les principaux aspects abordés dans le cadre de la recherche, à savoir l`intégration des zones rurales dans les régions urbaines, les mutations à l`oeuvre dans les zones périurbaines, et enfin les politiques de gestion de l`espace et la régulation des usages du sol