Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

Mood and cognition in healthy older European adults: the Zenith study

YesBackground: The study aim was to determine if state and trait intra-individual measures of everyday affect predict cognitive functioning in healthy older community dwelling European adults (n = 387), aged 55-87 years. Methods: Participants were recruited from centres in France, Italy and Northern Ireland. Trait level and variability in positive and negative affect (PA and NA) were assessed using self-administered PANAS scales, four times a day for four days. State mood was assessed by one PANAS scale prior to assessment of recognition memory, spatial working memory, reaction time and sustained attention using the CANTAB computerized test battery. Results: A series of hierarchical regression analyses were carried out, one for each measure of cognitive function as the dependent variable, and socio-demographic variables (age, sex and social class), state and trait mood measures as the predictors. State PA and NA were both predictive of spatial working memory prior to looking at the contribution of trait mood. Trait PA and its variability were predictive of sustained attention. In the final step of the regression analyses, trait PA variability predicted greater sustained attention, whereas state NA predicted fewer spatial working memory errors, accounting for a very small percentage of the variance (1-2%) in the respective tests. Conclusion: Moods, by and large, have a small transient effect on cognition in this older sample

Effect of a Fatty Acid Additive on the Kinetic Friction and Stiction of Confined Liquid Lubricants

Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.The paper presents part of the research productions that accompanied the construction of bodies inserted in a Psychosocial Care Center for Alcohol and Other Drugs (CAPS-AD) of a city in the northern region of Brasil, focusing more sharply on masculinities arrangements. Special attention is given to the tension between normalized bodies and attempts at resistance and (re) exist. The argument is in the field of public health, particularly mental health, and rooted in gender and sexuality studies. The data production methodology made use of observations recorded in a diary, itinerant follow-up of a collective of research, interviews, focus groups where, among other things, was discussed diary topics, conversation circles and workshops. The attempt was to produce a way of collective narrating strategy, combining up experience and body (un)learn well as ways of producing health care and doing research

Mental Health and School Functioning for Girls in the Child Welfare System : the Mediating Role of Future Orientation and School Engagement

This study investigated the association between mental health problems and academic and behavioral school functioning for adolescent girls in the child welfare system and determined whether school engagement and future orientation meditated the relationship. Participants were 231 girls aged between 12 and 19 who had been involved with the child welfare system. Results indicated that 39% of girls reported depressive symptoms in the clinical range and 54% reported posttraumatic symptoms in the clinical range. The most common school functioning problems reported were failing a class (41%) and physical fights with other students (35%). Participants reported a mean number of 1.7 school functioning problems. Higher levels of depression and PTSD were significantly associated with more school functioning problems. School engagement fully mediated the relationship between depression and school functioning and between PTSD and school functioning, both models controlling for age, race, and placement stability. Future orientation was not significantly associated with school functioning problems at the bivariate level. Findings suggest that school engagement is a potentially modifiable target for interventions aiming to ameliorate the negative influence of mental health problems on school functioning for adolescent girls with histories of abuse or neglect

Reduced Amygdala and Ventral Striatal Activity to Happy Faces in PTSD Is Associated with Emotional Numbing

There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing

Religious Tastes and Styles as Markers of Class Belonging: A Bourdieuian Perspective on Pentecostalism in South America

Studies on the relationship between social class and religion tend to highlight the demographic dimension of class, but neglect its symbolic dimension. By addressing the symbolic dimensions through a Bourdieuian approach, this article contends that religious tastes and styles can be employed as class markers within the sphere of religion. A case study on Argentinean Pentecostalism and in-depth analysis of a lower and middle class church illustrate how symbolic class differences are cultivated in the form of distinctive religious styles. While the lower class church displays a style marked by emotional expressiveness and the search for life improvement through spiritual practices, the middle class church performs a sober and calm style of Pentecostalism. The study highlights the role of styles in the reproduction of class boundaries, while shedding a critical light on the importance of tastes

Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity

Dendritic cell (DC) immunotherapy has shown a promising ability to promote anti-tumor immunity in vitro and in vivo. Many trials have tested single epitopes and single antigens to activate single T cell specificities, and often CD8+ T cells only. We previously found that determinant spreading and breadth of antitumor immunity correlates with improved clinical response. Therefore, to promote activation and expansion of polyclonal, multiple antigen-specific CD8+ T cells, as well as provide cognate help from antigen-specific CD4+ T cells, we have created an adenovirus encoding three full length melanoma tumor antigens (tyrosinase, MART-1 and MAGE-A6, “AdVTMM”). We previously showed that adenovirus (AdV)-mediated antigen engineering of human DC is superior to peptide pulsing for T cell activation, and has positive biological effects on the DC, allowing for efficient activation of not only antigen-specific CD8+ and CD4+ T cells, but also NK cells. Here we describe the cloning and testing of “AdVTMM2,” an E1/E3-deleted AdV encoding the three melanoma antigens. This novel three-antigen virus expresses mRNA and protein for all antigens, and AdVTMM-transduced DC activate both CD8+ and CD4+ T cells which recognize melanoma tumor cells more efficiently than single antigen AdV. Addition of physiological levels of interferon-α (IFNα) further amplifies melanoma antigen-specific T cell activation. NK cells are also activated, and show cytotoxic activity. Vaccination with multi-antigen engineered DC may provide for superior adaptive and innate immunity and ultimately, improved antitumor responses

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Using formative research to develop CHANGE! : a curriculum-based physical activity promoting intervention

Background : Low childhood physical activity levels are currently one of the most pressing public health concerns. Numerous school-based physical activity interventions have been conducted with varied success. Identifying effective child-based physical activity interventions are warranted. The purpose of this formative study was to elicit subjective views of children, their parents, and teachers about physical activity to inform the design of the CHANGE! (Children\u27s Health, Activity, and Nutrition: Get Educated!) intervention programme. Methods : Semi-structured mixed-gender interviews (group and individual) were conducted in 11 primary schools, stratified by socioeconomic status, with 60 children aged 9-10 years (24 boys, 36 girls), 33 parents (4 male, 29 female) and 10 teachers (4 male, 6 female). Questions for interviews were structured around the PRECEDE stage of the PRECEDE-PROCEDE model and addressed knowledge, attitudes and beliefs towards physical activity, as well as views on barriers to participation. All data were transcribed verbatim. Pen profiles were constructed from the transcripts in a deductive manner using the Youth Physical Activity Promotion Model framework. The profiles represented analysis outcomes via a diagram of key emergent themes. Results : Analyses revealed an understanding of the relationship between physical activity and health, although some children had limited understanding of what constitutes physical activity. Views elicited by children and parents were generally consistent. Fun, enjoyment and social support were important predictors of physical activity participation, though several barriers such as lack of parental support were identified across all group interviews. The perception of family invested time was positively linked to physical activity engagement. Conclusions : Families have a powerful and important role in promoting health-enhancing behaviours. Involvement of parents and the whole family is a strategy that could be significant to increase children\u27s physical activity levels. Addressing various perceived barriers to such behaviours therefore, remains imperative. <br /