Increased expression of cystine/glutamate antiporter in multiple sclerosis

Background: Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter x(c)(-), an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system x(c)(-) in glutamate homeostasis alterations in MS pathology. -- Methods: Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release. Expression of cystine glutamate exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS patients. -- Results and discussion: We show here that human activated monocytes release glutamate through cystine/glutamate antiporter x(c)(-) and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper. In the later, high expression of xCT occurs both in the central nervous system (CNS) and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes. -- Conclusions: Together, these results reveal that increased expression of the cystine/glutamate antiporter system x(c)(-) in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.

Contribution of Resource-Based View and Entrepreneurial Orientation on Small Firm Growth

[EN] This research provides a useful framework for identifying a small firms’ propensity to engage in entrepreneurial orientation. We examine the impact of the Entrepreneurial Orientation (EO) as a main resource and capability on small firm’ growth. The growth seems to come out as an important demonstration of the entrepreneurial orientation of small firms (Davidsson, 1989; Green and Brown, 1997; Janney and Gregory, 2006). Thus, this research builds on prior conceptual research that suggests a positive integration between entrepreneurial orientation and resource-based view. In the first instance, the research will focus on reviewing literature in the emerging area of entrepreneurial orientation as it applies to growth oriented small firms and resource-based view of the firm. Secondly, an empirical study was developed based on a stratified sample of small firms of manufacturing industry. Data were submitted to a multivariate statistical analysis and a linear regression model was performed in order to predict the influence of the resources and capabilities on small firms’ growth. In this sense, we consider the construct growth as a dependent variable and the ones relates with resources and capabilities (entrepreneur resources, firm resources, networks and EO) as independent variables. The research results suggest a set of resources and capabilities that promote the growth of the small firms. Also, the EO seems to have a predictive value on growth. Explaining variables related with resources and capabilities and EO were identified as essential in growth oriented small firms. It was still possible to conclude that the entrepreneurial firms which grew seem to have resources and develop more capabilities and take advantage in the search for those competences. This attitude reflects on the EO of the firm. This study has important implication for both researchers and practitioners. It highlights the necessity of firms to develop superior EO of all their members and also to invest on better resources and consequently superior capabilities as a way of reaching higher levels of growth. While previous authors have attempted to analyse certain aspects of this process (linkage between entrepreneurial orientation and growth), this research developed a framework that combines these and others factors (resource-based view) pertinent to growth oriented small firms. The results support the necessity to identify explicative variables of multiple levels to explain the growth of small firms. The adoption of an entrepreneurial orientation as an indispensable variable to the growth oriented small firms seems pertinent.

Deportividad y violencia en el fútbol base: un programa de evaluación y de prevención de partidos de riesgo

Este trabajo ha recibido el “Primer Premio Delegación del Gobierno en Aragón a las buenas prácticas contra la delincuencia juvenil” (Convocatoria 2007).

The economic contribution of whalewatching to regional economies: Perspectives from two National Marine Sanctuaries

Whenever human beings have looked out on the sea, they have seen whales. First from the shore and later from ships when humanity entered the ocean realm as seafarers, we have responded to seeing these creatures with awe and wonder. Even when we hunted whales, a period well chronicled both in history and in literature, the sight of a whale brought an adrenaline rush that was not totally linked to potential economic gain. The first trips on boats specifically to watch, rather than hunt, whales began around 45 years ago in Southern California where the migrating gray whales, seen in the distance from land, drew vessels out for a closer look. Since that time whalewatching has boomed, currently conducted in over 40 countries around the world, including Antarctica, and estimated by economists at the Whale and Dolphin Conservation Society to have a 1999 worldwide economic value of around $800 million USD. The economic contribution to local coastal communities is particularly significant in developing countries and those where declining fish populations (and in some cases like the Japanese, international bans on whaling) have driven harvesters to look for viable alternatives. Clearly, whalewatching is now, in many places around the world, a small but thriving part of the regional economy. Like in the days of whaling, we still get the rush, but for some, money is back contributing to the physiological response. (PDF contains 90 pages.)

Primary production, chlorophyll, and zooplankton volumes in the tropical Eastern Pacific Ocean

ENGLISH: Between 1 October and 17 December 1955 investigations of the physical, chemical and biological oceanography of the Eastern Pacific Ocean in a region bounded approximately by 30° N. latitude, 9° S. latitude, 120° W. longitude and the mainland coast were conducted from the vessels Horizon and Spencer F. Baird of the Scripps Institution of Oceanography of the University of California. These were part of a cooperative operation, designated for convenience by the code name "Eastropic," in which a vessel of the U. S. Fish and Wildlife Service worked, during this same period, further west and a vessel of the Peruvian Navy worked further south, offshore from Peru. A vessel of the California State Fisheries Laboratory also conducted certain sub-surface tuna fishing operations and other studies in the same general region as the Scripps vessels. In addition to carrying out a number of special studies related to particular oceanographic features, the Scripps vessels occupied a considerable number of hydrographic stations. The locations of these stations, at each of which were made net-hauls for zooplankton, are shown in Figure 4 and Tables 2 and 3. At some of the hydrographic stations, and in Some places between stations, there were made from the Spencer F. Baird measurements of chlorophyll "a" and of primary production (by the C14 technique), both in situ and in a shipboard incubator. The purpose of this paper is to report on the results of these biological observations. SPANISH: Entre el 1° de octubre y el 17 de diciembre de 1955, a bordo de los barcos Horizon y Spencer F. Baird) de la Institución Scripps de Oceanografía de la Universidad de California, se hicieron investigaciones sobre la oceanografía física, química y biológica del Océano Pacífico Oriental, en una región limitada aproximadamente por los 30° N. de latitud, 9° S. de latitud, 120° O. de longitud y la costa continental. Estas investigaciones fueron parte de una operación que se realizó cooperativamente y a la que se convino darle el nombre codificado de "Eastropic". En ella, durante el mismo período, una embarcación del Servicio de Pesca y Vida Silvestre de los Estados Unidos (U. S. Fish and Wildlife Service) trabajó más hacia el oeste, y un barco de la armada peruana más hacia el sur, frente a la costa del Perú. También colaboró una nave del Laboratorio de Pesquerías del Estado de California (California State Fisheries Laboratory), realizando algunas operaciones de pesca de atún en aguas subsuperficiales, y otros estudios en la misma región general que recorrieron las embarcaciones de Scripps. Además de efectuar estudios especiales relacionados con las caracteristicas oceanográficas particulares de la región, las naves de Scripps establecieron un buen número de estaciones hidrográficas. La localización de estas estaciones se indica en la Figura 4 y en las Tablas 2 y 3; en cada una de ellas se hicieron rastreos con redes planctónicas para recoger muestras de zooplancton. En algunas de las estaciones hidrográficas, así como en algunos lugares entre estaciones, en el Spencer F. Baird se hicieron mediciones de la clorofila "a" y de la producción primaria (mediante la técnica del C14), tanto in situ como en una incubadora instalada a bordo. El propósito del presente trabajo es dar a conocer los resultados de estas observaciones biológicas. (PDF contains 44 pages.)

Increasing the contribution of small-scale fisheries to poverty alleviation and food security

The objectives of these Technical Guidelines are to provide a focus on small-scale fisheries and their current and potential role in contributing to poverty alleviation and food security by expanding on the guidance on small-scale fisheries offered by the Code. The Guidelines are complementary to existing Technical Guidelines for Responsible Fisheries. Most small-scale fishers are in developing countries and many live in communities characterized by poverty and food insecurity. Small-scale fishing communities are faced with an array of serious problems, including overexploitation and depletion of resources, lack of alternative sources of employment, rapid population growth, migration of populations, displacement in coastal areas due to industrial development and tourism, pollution and environmental degradation and conflicts with large commercial fishing operations. However, small-scale fisheries are critical for food security and poverty alleviation in many countries. The first part of the Guidelines discusses the current contribution, role and importance of small-scale fisheries in poverty alleviation and food security. It examines the importance of small-scale fisheries for poverty alleviation at a national, local and household level. It also notes the nutritional qualities of fish and thus the particular role of fish in nutritional aspects of food security. The fact that about half of all fish caught for human consumption comes from small-scale fisheries underlines the importance of this subsector for the world fish supply. In many countries small-scale fisheries contribute to national food security both directly – where fish is a crucial part of the daily diet, and indirectly – by generating foreign exchange earnings that enable the purchase through trade of a range of food products. The second part of the Guidelines explores ways through which the contribution of small-scale fisheries to poverty alleviation and food security could be enhanced. A vision for the future of small-scale fisheries is presented as a goal towards which the subsector should develop. Ensuring greater participation by small-scale fishers and their communities in the formulation of policies, the development of related legislation and regulations, and in management decision-making and implementation processes, is vital to the realization of this vision. The central role of effective fisheries management, the importance of considering cross sectoral uses of fisheries and related resources, the special role of women in fish marketing, processing and value addition, the significant scope for trade, the critical role that adequate financing may have in enabling transitions for effective fisheries management and the role of knowledge in making informed decisions are all discussed in these Guidelines. (PDF contains 97 pages)

Contribution of Pannexin1 to Experimental Autoimmune Encephalomyelitis

Pannexin1 (Panx1) is a plasma membrane channel permeable to relatively large molecules, such as ATP. In the central nervous system (CNS) Panx1 is found in neurons and glia and in the immune system in macrophages and T-cells. We tested the hypothesis that Panx1-mediated ATP release contributes to expression of Experimental Autoimmune Encephalomyelitis (EAE), an animal model for multiple sclerosis, using wild-type (WT) and Panx1 knockout (KO) mice. Panx1 KO mice displayed a delayed onset of clinical signs of EAE and decreased mortality compared to WT mice, but developed as severe symptoms as the surviving WT mice. Spinal cord inflammatory lesions were also reduced in Panx1 KO EAE mice during acute disease. Additionally, pharmacologic inhibition of Panx1 channels with mefloquine (MFQ) reduced severity of acute and chronic EAE when administered before or after onset of clinical signs. ATP release and YoPro uptake were significantly increased in WT mice with EAE as compared to WT non-EAE and reduced in tissues of EAE Panx1 KO mice. Interestingly, we found that the P2X7 receptor was upregulated in the chronic phase of EAE in both WT and Panx1 KO spinal cords. Such increase in receptor expression is likely to counterbalance the decrease in ATP release recorded from Panx1 KO mice and thus contribute to the development of EAE symptoms in these mice. The present study shows that a Panx1 dependent mechanism (ATP release and/or inflammasome activation) contributes to disease progression, and that inhibition of Panx1 using pharmacology or gene disruption delays and attenuates clinical signs of EAE.

Role of G protein coupled inwardly rectifier K+ channels (GIRK) on the neurobiology depression

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Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2

Background: Human melanoma frequently colonizes bone marrow (BM) since its earliest stage of systemic dissemination, prior to clinical metastasis occurrence. However, how melanoma cell adhesion and proliferation mechanisms are regulated within bone marrow stromal cell (BMSC) microenvironment remain unclear. Consistent with the prometastatic role of inflammatory and angiogenic factors, several studies have reported elevated levels of cyclooxygenase-2 (COX-2) in melanoma although its pathogenic role in bone marrow melanoma metastasis is unknown. Methods: Herein we analyzed the effect of cyclooxygenase-2 (COX-2) inhibitor celecoxib in a model of generalized BM dissemination of left cardiac ventricle-injected B16 melanoma (B16M) cells into healthy and bacterial endotoxin lipopolysaccharide (LPS)-pretreated mice to induce inflammation. In addition, B16M and human A375 melanoma (A375M) cells were exposed to conditioned media from basal and LPS-treated primary cultured murine and human BMSCs, and the contribution of COX-2 to the adhesion and proliferation of melanoma cells was also studied. Results: Mice given one single intravenous injection of LPS 6 hour prior to cancer cells significantly increased B16M metastasis in BM compared to untreated mice; however, administration of oral celecoxib reduced BM metastasis incidence and volume in healthy mice, and almost completely abrogated LPS-dependent melanoma metastases. In vitro, untreated and LPS-treated murine and human BMSC-conditioned medium (CM) increased VCAM-1-dependent BMSC adherence and proliferation of B16M and A375M cells, respectively, as compared to basal medium-treated melanoma cells. Addition of celecoxib to both B16M and A375M cells abolished adhesion and proliferation increments induced by BMSC-CM. TNF alpha and VEGF secretion increased in the supernatant of LPS-treated BMSCs; however, anti-VEGF neutralizing antibodies added to B16M and A375M cells prior to LPS-treated BMSC-CM resulted in a complete abrogation of both adhesion-and proliferation-stimulating effect of BMSC on melanoma cells. Conversely, recombinant VEGF increased adherence to BMSC and proliferation of both B16M and A375M cells, compared to basal medium-treated cells, while addition of celecoxib neutralized VEGF effects on melanoma. Recombinant TNFa induced B16M production of VEGF via COX-2-dependent mechanism. Moreover, exogenous PGE2 also increased B16M cell adhesion to immobilized recombinant VCAM-1. Conclusions: We demonstrate the contribution of VEGF-induced tumor COX-2 to the regulation of adhesion-and proliferation-stimulating effects of TNFa, from endotoxin-activated bone marrow stromal cells, on VLA-4-expressing

Somatisation in primary care: experiences of primary care physicians involved in a training program and in a randomised controlled trial

Background: A new intervention aimed at managing patients with medically unexplained symptoms (MUS) based on a specific set of communication techniques was developed, and tested in a cluster randomised clinical trial. Due to the modest results obtained and in order to improve our intervention we need to know the GPs' attitudes towards patients with MUS, their experience, expectations and the utility of the communication techniques we proposed and the feasibility of implementing them. Physicians who took part in 2 different training programs and in a randomised controlled trial (RCT) for patients with MUS were questioned to ascertain the reasons for the doctors' participation in the trial and the attitudes, experiences and expectations of GPs about the intervention. Methods: A qualitative study based on four focus groups with GPs who took part in a RCT. A content analysis was carried out. Results: Following the RCT patients are perceived as true suffering persons, and the relationship with them has improved in GPs of both groups. GPs mostly valued the fact that it is highly structured, that it made possible a more comfortable relationship and that it could be applied to a broad spectrum of patients with psychosocial problems. Nevertheless, all participants consider that change in patients is necessary; GPs in the intervention group remarked that that is extremely difficult to achieve. Conclusion: GPs positively evaluate the communication techniques and the interventions that help in understanding patient suffering, and express the enormous difficulties in handling change in patients. These findings provide information on the direction in which efforts for improving intervention should be directed.

Three-dimensional growth as multicellular spheroid activates the proangiogenic phenotype of colorectal carcinoma cells via LFA-1-dependent VEGF: implications on hepatic micrometastasis

Background: The recruitment of vascular stromal and endothelial cells is an early event occurring during cancer cell growth at premetastatic niches, but how the microenvironment created by the initial three-dimensional (3D) growth of cancer cells affects their angiogenesis-stimulating potential is unclear. Methods: The proangiogenic profile of CT26 murine colorectal carcinoma cells was studied in seven-day cultured 3D-spheroids of <300 mu m in diameter, produced by the hanging-drop method to mimic the microenvironment of avascular micrometastases prior to hypoxia occurrence. Results: Spheroid-derived CT26 cells increased vascular endothelial growth factor (VEGF) secretion by 70%, which in turn increased the in vitro migration of primary cultured hepatic sinusoidal endothelium (HSE) cells by 2-fold. More importantly, spheroid-derived CT26 cells increased lymphocyte function associated antigen (LFA)-1-expressing cell fraction by 3-fold; and soluble intercellular adhesion molecule (ICAM)-1, given to spheroid-cultured CT26 cells, further increased VEGF secretion by 90%, via cyclooxygenase (COX)-2-dependent mechanism. Consistent with these findings, CT26 cancer cells significantly increased LFA-1 expression in non-hypoxic avascular micrometastases at their earliest inception within hepatic lobules in vivo; and angiogenesis also markedly increased in both subcutaneous tumors and hepatic metastases produced by spheroid-derived CT26 cells. Conclusion: 3D-growth per se enriched the proangiogenic phenotype of cancer cells growing as multicellular spheroids or as subclinical hepatic micrometastases. The contribution of integrin LFA-1 to VEGF secretion via COX-2 was a micro environmental-related mechanism leading to the pro-angiogenic activation of soluble ICAM-1-activated colorectal carcinoma cells. This mechanism may represent a new target for specific therapeutic strategies designed to block colorectal cancer cell growth at a subclinical micrometastatic stage within the liver.

The contribution of fish intake, aquaculture, and small-scale fisheries to improving nutrition security: a literature review

Much of fish consumed by the poor are caught by household members and traded in local markets. These fish are rarely or poorly included in national statistics, and it is therefore difficult to estimate precisely the real contribution of fish to the rural poor households. This report is the first global overview of the role played by fish in improving nutrition. Fish consumption patterns of the poor, the nutritional value of fish, and small-scale fisheries and aquaculture activities are considered. It also highlights the gap in knowledge where more research is needed.