Improving community ambulation after stroke: the AMBULATE trial

<p>Abstract</p> <p>Background</p> <p>It has been reported that following rehabilitation, only 7% of stroke survivors are able to walk at a level commensurate with community participation. Previous research indicates that treadmill and overground walking training can improve walking capacity in people living in the community after stroke. The main objectives of the AMBULATE trial are to determine (i) whether a 4-month treadmill walking program is more effective than a 2-month program, compared to control, in improving walking capacity, health and community participation and (ii) the "threshold" walking speed that results in sufficient walking capacity that makes walking self-sustaining.</p> <p>Methods/Design</p> <p>A prospective randomised controlled trial of unsupported treadmill training with a 12 month follow-up with concealed allocation and blinded assessment will be conducted. 210 community-dwelling people after stroke who are able to walk independently but slowly will be recruited and randomly allocated to either a 4 month training group, 2 month training group or the control (no intervention) group. Intervention for the two training groups will occur 3 days per week for 30 minutes each session. Measurements of walking, health and community participation will be taken at baseline, 2 months, 4 months, 6 months and 12 months. This study has obtained ethical approval from the relevant Human Research Ethics Committees.</p> <p>Discussion</p> <p>By improving stroke survivors' walking ability, it is likely also to improve their general wellbeing by promoting better health and greater community participation. Furthermore, if stroke survivors can reach a point where their walking and community participation is self-sustaining, this will reduce the burden of care on family and friends as well as the economic burden on the health system. Given the major demographic shift in developed nations involving significant growth in the aged population, this research will make an important evidence-based contribution to the promotion of healthy ageing.</p> <p>Trial registration</p> <p>This trial is registered with the Australian New Zealand Clinical Trials Registry, (ACTRN012607000227493)</p

Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection

Interstitial pneumonia linked with reactivation of latent human cytomegalovirus due to iatrogenic immunosuppression can be a serious complication of bone marrow transplantation therapy of aplastic anaemia and acute leukaemia1. Cellular immunity plays a critical role in the immune surveillance of inapparent cytomegalovirus infections in man and the mouse1−7. The molecular basis of latency, however, and the interaction between latently or recurrently infected cells and the immune system of the host are poorfy understood. We have detected a so far unknown antigen in the mouse model. This antigen is found in infected cells in association with the expression of the herpesvirus 'immediate early' genes and is recognized by cytolytic T lymphocytes (CTL)8. We now demonstrate that an unexpectedly high proportion of the CTL precursors generated in vivo during acute murine cytomegalovirus infection are specific for cells that selectively synthesize immediate early proteins, indicating an immunodominant role of viral non-structural proteins

Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations

Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity

Although oligomeric β-amyloid (Aβ) has been suggested to have an important role in Alzheimer disease (AD), the mechanism(s) of how Aβ induces neuronal cell death has not been fully identified. The balance of pro- and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-w versus Bad, Bim and Bax) has been known to have a role in neuronal cell death and, importantly, expression levels of these proteins are reportedly altered in the vulnerable neurons in AD. However, the roles of apoptotic proteins in oligomeric Aβ-induced cell death remain unclear in vivo or in more physiologically relevant models. In addition, no study to date has examined whether Bax is required for the toxicity of oligomeric Aβ. Here, we found that treatment with oligomeric Aβ increased Bim levels but decreased Bcl-2 levels, leading to the activation of Bax and neuronal cell death in hippocampal slice culture and in vivo. Furthermore, the inhibition of Bax activity either by Bax-inhibiting peptide or bax gene knockout significantly prevented oligomeric Aβ-induced neuronal cell death. These findings are first to demonstrate that Bax has an essential role in oligomeric Aβ-induced neuronal cell death, and that the targeting of Bax may be a therapeutic approach for AD

Role of Germination in Murine Airway CD8+ T-Cell Responses to Aspergillus Conidia

Pulmonary exposure to Aspergillus fumigatus has been associated with morbidity and mortality, particularly in immunocompromised individuals. A. fumigatus conidia produce β-glucan, proteases, and other immunostimulatory factors upon germination. Murine models have shown that the ability of A. fumigatus to germinate at physiological temperature may be an important factor that facilitates invasive disease. We observed a significant increase in IFN-γ-producing CD8+ T cells in bronchoalveolar lavage fluid (BALF) of immunocompetent mice that repeatedly aspirated A. fumigatus conidia in contrast to mice challenged with A. versicolor, a species that is not typically associated with invasive, disseminated disease. Analysis of tissue sections indicated the presence of germinating spores in the lungs of mice challenged with A. fumigatus, but not A. versicolor. Airway IFN-γ+CD8+ T-cells were decreased and lung germination was eliminated in mice that aspirated A. fumigatus conidia that were formaldehyde-fixed or heat-inactivated. Furthermore, A. fumigatus particles exhibited greater persistence in the lungs of recipient mice when compared to non-viable A. fumigatus or A. versicolor, and this correlated with increased maintenance of airway memory-phenotype CD8+ T cells. Therefore, murine airway CD8+ T cell-responses to aspiration of Aspergillus conidia may be mediated in part by the ability of conidia to germinate in the host lung tissue. These results provide further evidence of induction of immune responses to fungi based on their ability to invade host tissue

Attitudes of Mexican anesthesiologists to indicate preoperative fasting periods: A cross-sectional survey

BACKGROUND: In Mexico, guidelines for fasting periods, or any audits on this topic are unavailable, and therefore the attitudes of anesthesiologists for recommending preoperative fasting periods are unknown. MATERIAL AND METHODS: The study was a cross-sectional survey of anesthesiologists subscribed to the Annual Updated Course, organized by the Sociedad Mexicana de Anestesiologia in 2000. The response rate was 31.4%. RESULTS: Most respondents were general anesthesiologists, with 5 or more years experience in a clinical post, were working in both public and private hospitals, and were performing anesthetic procedures on both pediatric and adult patients and in both ambulatory and hospitalized patients. Approximately 23% of the respondents considered natural fruit juices to be clear liquids. For a pediatric patient ingesting breast milk 1 h before undergoing a surgical procedure, 45% thought that surgery should be delayed for 3h, followed by those delaying the surgical procedure for 6 to 8 h. Our results show that more than 50% of the anesthesiologists had better defined attitudes for fasting milk and clear liquids in patients of 6 month or under than for older children and adults. However, due to the poor definition or pre-operative fasting, using clear liquids, in all other patient groups, several patients are allowed to go without oral clear liquids administration for prolonged periods. CONCLUSION: Preoperative fasting periods recommended by Mexican anesthesiologists differ from international guidelines

Management of environmental health issues for the 2004 Athens Olympic Games: is enhanced integrated environmental health surveillance needed in every day routine operation?

BACKGROUND: Management of environmental health issues is an integral part of public health systems. An active integrated environmental health surveillance and response system was developed for the Athens Olympics to monitor and prevent exposure to environmental hazards. The potential for permanent implementation of the program was examined. METHODS: The environmental health surveillance and response system included standardization, computerization and electronic transmission of data concerning environmental inspections of 17 site categories (restaurants, swimming pools etc) of public health interest, drinking and recreational water examinations and suggested corrective actions. The Olympic Planning Unit integrated and centrally managed data from 13 public health agencies, recommended, supervised and coordinated prompt corrective actions. Methods used to test the effectiveness of the program were the assessment of water quality test and inspection results trends over time using linear regression and epidemiological surveillance findings. RESULTS: Between January 2003 and September the 30th, 2004, 196 inspectors conducted 8562 inspections, collected 5024 water samples and recommended 17 027 corrective actions. In 10 cruise ships used as floating hotels inspectors conducted 10 full inspections, 2 re-inspections, and 27 follow-up inspections. Unsatisfactory inspection results (r = 0.44, p < 0.0001) and positive water quality tests (r = 0.39, p < 0.001) presented an overall decrease trend over time. In August, 2003, an outbreak of salmonellosis was linked to a hotel restaurant which accommodated athletes during a test event. CONCLUSION: Lessons learned for future events include timely implementation and installation of communication processes, and rapid and coordinated response to unsatisfactory inspection results. Routine national programs need to adopt enhanced environmental health surveillance aimed at public health decision-making, but with a different perspective