The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice

<p>Abstract</p> <p>Background</p> <p>Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure.</p> <p>Methods</p> <p>Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy.</p> <p>Results</p> <p>Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone.</p> <p>Conclusion</p> <p>Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.</p

The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice

© 2008 Lei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Macrophage signaling in HIV-1 infection

The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection

predictive precision medicine towards the computational challenge

The emerging fields of predictive and precision medicine are changing the traditional medical approach to disease and patient. Current discoveries in medicine enable to deepen the comprehension of diseases, whereas the adoption of high-quality methods such as novel imaging techniques (e.g. MRI, PET) and computational approaches (i.e. machine learning) to analyse data allows researchers to have meaningful clinical and statistical information. Indeed, applications of radiology techniques and machine learning algorithms rose in the last years to study neurology, cardiology and oncology conditions. In this chapter, we will provide an overview on predictive precision medicine that uses artificial intelligence to analyse medical images to enhance diagnosis, prognosis and treatment of diseases. In particular, the chapter will focus on neurodegenerative disorders that are one of the main fields of application. Despite some critical issues of this new approach, adopting a patient-centred approach could bring remarkable improvement on individual, social and business level

Barriers in the access, diagnosis and treatment completion for tuberculosis patients in central and western Nepal: A qualitative study among patients, community members and health care workers

BACKGROUND:Nepal has achieved a significant reduction of TB incidence over the past decades. Nevertheless, TB patients continue to experience barriers in access, diagnosis and completion of the treatment. The main objective of this study was to explore the factors affecting the access to the health services, diagnosis and the treatment completion for TB patients in central and western Nepal. METHODS:Data were collected using in-depth interviews (IDI) with the TB patients (n = 4); Focus Group Discussions (FGDs) with TB suspected patients (n = 16); Semi Strucutred Interviews (SSIs) with health workers (n = 24) and traditional healers (n = 2); and FGDs with community members (n = 8). All data were audio recorded, transcribed and translated to English. All transcriptions underwent thematic analysis using qualitative data analysis software: Atlas.ti. RESULTS:Barriers to access to the health centre were the long distance, poor road conditions, and costs associated with travelling. In addition, lack of awareness of TB and its consequences, and the belief, prompted many respondents to visit traditional healers. Early diagnosis of TB was hindered by lack of trained health personnel to use the equipment, lack of equipment and irregular presence of health workers. Additional barriers that impeded the adherence and treatment completion were the need to visit health centre daily for DOTS treatment and associated constraints, complex treatment regimen, and the stigma. CONCLUSIONS:Barriers embedded in health services and care seekers' characteristics can be dealt by strengthening the peripheral health services. A continuous availability of (trained) human resources and equipment for diagnosis is critical. As well as increasing the awareness and collaborating with the traditional healers, health services utilization can be enhanced by compensating the costs associated with it, including the modification in current DOTS strategy by providing medicine for a longer term under the supervision of a family member, peer or a community volunteer