Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.

Deconstructing antiobesity compound action : requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects

The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5-HT(2B) receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT(2B) receptors (5-HT(2B)(-/-)). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22 ± 0.24). Using microdialysis, we observed that in 5-HT(2B)(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) receptors is a limiting step in the serotonin transporter dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.

Systems-based approach to investigate unsafe pedestrian behaviour at level crossings

Crashes at level crossings are a major issue worldwide. In Australia, as well as in other countries, the number of crashes with vehicles has declined in the past years, while the number of crashes involving pedestrians seems to have remained unchanged. A systematic review of research related to pedestrian behaviour highlighted a number of important scientific gaps in current knowledge. The complexity of such intersections imposes particular constraints to the understanding of pedestrians’ crossing behaviour. A new systems-based framework, called Pedestrian Unsafe Level Crossing framework (PULC) was developed. The PULC organises contributing factors to crossing behaviour on different system levels as per the hierarchical classification of Jens Rasmussen’s Framework for Risk Management. In addition, the framework adapts James Reason’s classification to distinguish between different types of unsafe behaviour. The framework was developed as a tool for collection of generalizable data that could be used to predict current or future system failures or to identify aspects of the system that require further safety improvement. To give it an initial support, the PULC was applied to the analysis of qualitative data from focus groups discussions. A total number of 12 pedestrians who regularly crossed the same level crossing were asked about their daily experience and their observations of others’ behaviour which allowed the extraction and classification of factors associated with errors and violations. Two case studies using Rasmussen’s AcciMap technique are presented as an example of potential application of the framework. A discussion on the identified multiple risk contributing factors and their interactions is provided, in light of the benefits of applying a systems approach to the understanding of the origins of individual’s behaviour. Potential actions towards safety improvement are discussed.

Direct observations of pedestrian unsafe crossing at urban Australian level crossings

The number of pedestrian victims at Australian and foreign level crossings has remained stable over the past decade and it continues to be a significant problem. To examine the factors contributing to pedestrians’ unsafe crossing behaviours, direct observations were conducted at three black spot urban level crossings in Brisbane for a total of 45 h during morning and afternoon peak. In total, 129 pedestrians transgressed the active controls. More transgressions were observed at the crossings located in more populated suburbs in close proximity to large shopping centres and school zones, whereas the smallest number of transgressions were observed at the least populated locations. In addition to characteristics associated with the larger socio-economic area, the patterns of transgression could be associated with the properties of the existing safety equipment and the design of each level crossing (i.e. location of the platforms, number of rail tracks). Indeed, the largest number of crossed unoccupied but “at risk” rail tracks (where a train could have passed), was observed at the crossing with the least transgressions. Contrary to previous findings, younger adults were the most frequent transgressors. School children and elderly were most likely to transgress in groups. Potential directions for future research and more effective measures are discussed.

Non-invasive MR imaging of inflammation in a patient with both asymptomatic carotid atheroma and an abdominal aortic aneurysm: A case report

Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. USPIO-enhanced MRI imaging is a promising non-i nvasive method to identify high-risk atheromatous plaque inflammation in vivo in humans, in which areas of focal signal loss on MR images have been shown to correspond to the location of activated macrophages, typically at the shoulder regions of the plaque. This is the first report in humans describing simultaneous USPIO uptake within atheroma in two different arterial territories and again emphasises that atherosclerosis is a truly systemic disease. With further work, USPIO-enhanced MR imaging may be useful in identifying inflamed vulnerable atheromatous plaques in vivo, so refining patient selection for intervention and allowing appropriate early aggressive pharmacotherapy to prevent plaque rupture.

Diel variation in fig volatiles across syconium development: making sense of scents

Plants produce volatile organic compounds (VOCs) in a variety of contexts that include response to abiotic and biotic stresses, attraction of pollinators and parasitoids, and repulsion of herbivores. Some of these VOCs may also exhibit diel variation in emission. In Ficus racemosa, we examined variation in VOCs released by fig syconia throughout syconium development and between day and night. Syconia are globular enclosed inflorescences that serve as developing nurseries for pollinating and parasitic fig wasps. Syconia are attacked by gallers early in their development, serviced by pollinators in mid phase, and are attractive to parasitoids in response to the development of gallers at later stages. VOC bouquets of the different development phases of the syconium were distinctive, as were their day and night VOC profiles. VOCs such as alpha-muurolene were characteristic of the pollen-receptive diurnal phase, and may serve to attract the diurnally-active pollinating wasps. Diel patterns of release of volatiles could not be correlated with their predicted volatility as determined by Henry's law constants at ambient temperatures. Therefore, factors other than Henry's law constant such as stomatal conductance or VOC synthesis must explain diel variation in VOC emission. A novel use of weighted gene co-expression network analysis (WGCNA) on the volatilome resulted in seven distinct modules of co-emitted VOCs that could be interpreted on the basis of syconium ecology. Some modules were characterized by the response of fig syconia to early galling by parasitic wasps and consisted largely of green leaf volatiles (GLVs). Other modules, that could be characterized by a combination of syconia response to oviposition and tissue feeding by larvae of herbivorous galler pollinators as well as of parasitized wasps, consisted largely of putative herbivore-induced plant volatiles (HIPVs). We demonstrated the usefulness of WGCNA analysis of the volatilome in making sense of the scents produced by the syconia at different stages and diel phases of their development.

A coat of many scents: Cuticular hydrocarbons in multitrophic interactions of fig wasps with ants

The fig fig wasp system of Ficus racemosa constitutes an assemblage of galler and parasitoid wasps in which tritrophic interactions occur. Since predatory ants (Oecophylla smaragdina and Technomyrmex albipes) or mostly trophobiont-tending ants (Myrmicaria brunnea) were previously shown to differentially use volatile organic compounds (VOCs) from figs as proximal cues for predation on fig wasps, we examined the response of these ants to the cuticular hydrocarbons (CHCs) of the wasps. CHC signatures of gallers were distinguished from those of parasitoids by the methyl-branched alkanes 5-methylpentacosane and 13-methylnonacosane which characterised trophic group membership. CHC profiles of wasp predator and wasp prey were congruent suggesting that parasitoids acquire CHCs from their prey; the CHC composition of the parasitoid Apocrypta sp 2 clustered with that of its galler host Apocryptophagus fusca, while the CHC profile of the parasitoid Apocryptophagus agraensis clustered with its galler prey, the fig pollinator Ceratosolen fusciceps. In behavioural assays with ants, parasitoid CHC extracts evoked greater response in all ant species compared to galler extracts, suggesting that parasitoid CHC extracts contain more elicitors of ant behaviour than those of plant feeders. CHCs of some wasp species did not elicit significant responses even in predatory ants, suggesting chemical camouflage. Contrary to earlier studies which demonstrated that predatory ants learned to associate wasp prey with specific fig VOCs, prior exposure to fig wasp CHCs did not affect the reaction of any ant species to these CHCs. (C) 2015 Elsevier Masson SAS. All rights reserved.

Da contemplação à imersão e subjetividade: estéticas dos museus de arte contemporânea e centros culturais

O estudo desenvolvido nesta Tese de Doutorado trata da análise crítica da estética dos conceitos: forma, tectônica, funcionalidade, semiótica e afetuosidade, no âmbito da arquitetura, no programa de museus de arte contemporânea e centros culturais. Os museus de arte contemporânea e centros culturais, estudos de caso, selecionados para nossa Tese de Doutorado foram inaugurados na década de 1990. Como segue: Centro Cultural Jean-Marie Tijibaou (Nova Caledônia, França), de Renzo Piano; Museu de Arte Contemporânea de Naoshima (Japão), de Tadao Ando; Museu Guggenheim Bilbao (Espanha), de Frank O. Gehry; Museu de Arte Contemporânea Fundação Serralves (Portugal), de Álvaro Siza Vieira; Museu de Arte Contemporânea de Niterói (Brasil), de Oscar Niemeyer; Fundació Museu d'Art Contemporani de Barcelona (Espanha), de Richard Meier; Museu de Arte Contemporânea Carré d'Art de Nimes (França), de Norman Foster; Museu de Arte Contemporânea de Lyon (França), de Renzo Piano; Centro Cultural Consonni (Espanha), ausência de um arquiteto autor do projeto. Tanto os estudos de caso como os arquitetos, autores dos projetos, são considerados de destaque no panorama da arquitetura internacional erudita contemporânea. Os teóricos que forneceram a fundamentação conceitual deste estudo multidisciplinar são, em primeiro lugar, o Professor Catedrático Luiz Felipe Baêta Neves Flores (Transdisciplinaridade) além da Professora Catedrática Maria Luisa Amigo Fernández de Arroyabe (Ócio Estético) e ainda, os também importantes, Manuel Cuenca Cabeza (Ócio Humanista), Charles Jencks e Gonçalo Miguel Furtado Cardoso Lopes (Crítica de Arquitetura), Jesús Pedro Lorente, Chris van Uffelen e Roberto Segre (Museus de Arte Contemporânea).

Uso de web services e softwares livres na disseminação de informações georreferenciadas sobre produtos da floresta amazônica.

Georreferenced information has been increasingly required for the planning and decision-making in different sectors of society. New ways of dissemination of data, such as the Open Geospatial Consortium (OGC) web services, have contributed to the ease of access to this information. Even with all the technological advances in the area of data distribution, there is still low availability of georreferenced data about the Amazon. The goal of the present work is the development of a spatial data infrastructure (SDI), that is, an environment of sharing and use of georreferenced data based on the technology of web services, metadata and interfaces that allow the user easy access to these data. The present work discussess the OGC patterns, the most relevant georeferrenced data servers, the main web clients, and the revolution in the dissemination of georeferrenced data which geobrowsers and web clients offered to regular users. Data to be released for the case study come from the project Exploitation of Non-wooden Forest Products-PFNM-in progress at the National Institute of Research in the Amazon-INPA-as well as from inventories of NGOs and other government bodies. Besides contributing to the enhancement of PFNM, this project aims at encouraging the use of GIS in the state of Amazonas offering tech support for the deployment of geographic databases and sharing between agencies, optimizing the resources applied in this area through the use of free software and integration of diffuse information currently available.

Molybdenum containing surface complex for olefin epoxidation

Silica-supported molybdenum surface complexes were prepared by the reaction between (N=) Mo(OtBu)(3) and silica via displacement of the tert-butoxy ligands for siloxyls from the silica surface. The structure of the surface molybdenum complexes was well defined by in-situ FT-IR, elemental analysis, H-1 NMR and C-13 CP/MAS NMR techniques. The surface complexes could undergo alcoholysis reaction with CD3OD and CH3OH in the same way as free (N =) Mo(OtBu)(3) and they show high catalytic activity and selectivity in olefin epoxidation. Initial rates up to 24.9 mmol epoxide (mmol Mo)(-1) min(-1) were achieved in the epoxidation of cyclohexene using TBHP as oxidant.

Relation de la Mission Abnaquise de St. Franðcois de Sales L'Annâee 1702 / par le Páere Jacques Bigot, de la Compagnie de Jâesus.

http://www.archive.org/details/missionabnaquise00bigorich

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

Sensitivity of HER-2/neu antibodies in archival tissue samples of invasive breast carcinomas. Correlation with oncogene amplification in 160 cases.

Overexpression and amplification of the HER-2 oncogene in patients with breast cancer has correlated with early onset of metastasis, resistance to hormonal therapy and some forms of chemotherapy, and shortened survival. Therefore, evaluation of this putative prognostic or predictive factor seems critical. Because different antibodies are used for the detection of the 185-kd HER-2 oncoprotein, we studied the sensitivity of 3 frequently used antibodies. Immunohistochemistry results were correlated with gene amplification level as assessed by fluorescence in situ hybridization. Protein overexpression was found in 17.2% and 12.5% of cases using antibodies against the external (TAB250) and internal (CB11) domains of the protein, respectively, and in 38.0% of cases using a rabbit polyclonal antibody. Fluorescence in situ hybridization was successful in all 160 tumors, and amplification was found in 37 tumors (23.1%). The monoclonal antibody TAB250 had the lowest misclassification rate, 9.6% (sensitivity, 67%; specificity, 97.5%).

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.