The Rac activator Tiam1 is required for α3β1-mediated laminin-5 deposition, cell spreading, and cell migration

The Rho-like guanosine triphosphatase Rac1 regulates various signaling pathways, including integrin-mediated adhesion and migration of cells. However, the mechanisms by which integrins signal toward Rac are poorly understood. We show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis 1) is required for the integrin-mediated laminin (LN)-5 deposition, spreading, and migration of keratinocytes. In contrast to wild-type keratinocytes, Tiam1-deficient (Tiam1−/−) keratinocytes are unable to adhere to and spread on a glass substrate because they are unable to deposit their own LN5 substrate. Both Tiam1 and V12Rac1 can rescue the defects of Tiam1−/− keratinocytes, indicating that these deficiencies are caused by impaired Tiam1-mediated Rac activation. Tiam1−/− cells are unable to activate Rac upon α3β1-mediated adhesion to an exogenous LN5 substrate. Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin. Our studies indicate that Tiam1 is a key molecule in α3β1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes

Evaluation of patients on sertindole treatment after failure of other antipsychotics: A retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Use of the atypical antipsychotic sertindole was suspended for four years due to safety concerns. During the suspension, the regulatory authorities required further studies, including this one, to be conducted. The purpose of this study was to determine if a subset of patients with psychotic illness exists which particularly benefits from sertindole treatment after failure of other antipsychotic drugs, including atypical antipsychotics.</p> <p>Methods</p> <p>This was a retrospective single-arm observational crossover study of 344 patients, who served as their own controls. Patients mainly from the Sertindole Safety Study who had shown good response to sertindole, and who had followed up to four alternating six month periods of treatment with sertindole and other antipsychotics, were included. (In Period 1 patients took non-sertindole treatment, in Period 2, sertindole was taken, in Period 3, patients reverted to non-sertindole treatment, and in Period 4, sertindole was taken again.) Patient records for each period of treatment were assessed for objective data: number and duration of hospitalizations due to worsening of psychotic symptoms; the amount of self-harming behaviour; indicators of social status. Retrospective evaluation of changes in clinical symptoms from the patients' records was also conducted. Dates and reasons for stopping and/or switching medication were also recorded.</p> <p>Results</p> <p>There was improvement in all objective measured parameters during the periods of sertindole treatment. In particular, the average number of hospitalizations per year due to worsening of psychotic symptoms was reduced in the following way in the group studied over four treatment periods: Period 1 (non-sertindole treatment) 3.4; Period 2 (sertindole treatment) 1.0; Period 3 (non-sertindole treatment) 2.0; Period 4 (sertindole treatment) 1.8. The duration of hospitalizations also decreased significantly during the periods of sertindole treatment. Results showed that patients improved in objective social parameters when switched to sertindole treatment; assessment of the patients' affective lives showed a significant increase in the number of patients having a stable relationship during sertindole treatment; and assessment of the number of patients employed showed an increase after the first and second switch to sertindole treatment (from Period 1 to Period 2 and from Period 3 to Period 4, respectively).</p> <p>Adverse events and lack of efficacy were the main reasons for switching to sertindole.</p> <p>Conclusion</p> <p>A group of patients benefited from sertindole after other antipsychotic treatments, including that with atypical antipsychotics, had failed. Further studies are needed to investigate if there is a specific patient profile that corresponds to these responders.</p

Using knowledge brokers to facilitate the uptake of pediatric measurement tools into clinical practice: a before-after intervention study

<p>Abstract</p> <p>Background</p> <p>The use of measurement tools is an essential part of good evidence-based practice; however, physiotherapists (PTs) are not always confident when selecting, administering, and interpreting these tools. The purpose of this study was to evaluate the impact of a multifaceted knowledge translation intervention, using PTs as knowledge brokers (KBs) to facilitate the use in clinical practice of four evidence-based measurement tools designed to evaluate and understand motor function in children with cerebral palsy (CP). The KB model evaluated in this study was designed to overcome many of the barriers to research transfer identified in the literature.</p> <p>Methods</p> <p>A mixed methods before-after study design was used to evaluate the impact of a six-month KB intervention by 25 KBs on 122 practicing PTs' self-reported knowledge and use of the measurement tools in 28 children's rehabilitation organizations in two regions of Canada. The model was that of PT KBs situated in clinical sites supported by a network of KBs and the research team through a broker to the KBs. Modest financial remuneration to the organizations for the KB time (two hours/week for six months), ongoing resource materials, and personal and intranet support was provided to the KBs. Survey data were collected by questionnaire prior to, immediately following the intervention (six months), and at 12 and 18 months. A mixed effects multinomial logistic regression was used to examine the impact of the intervention over time and by region. The impact of organizational factors was also explored.</p> <p>Results</p> <p>PTs' self-reported knowledge of all four measurement tools increased significantly over the six-month intervention, and reported use of three of the four measurement tools also increased. Changes were sustained 12 months later. Organizational culture for research and supervisor expectations were significantly associated with uptake of only one of the four measurement tools.</p> <p>Conclusions</p> <p>KBs positively influenced PTs' self-reported knowledge and self-reported use of the targeted measurement tools. Further research is warranted to investigate whether this is a feasible, cost-effective model that could be used more broadly in a rehabilitation setting to facilitate the uptake of other measurement tools or evidence-based intervention approaches.</p

Safe vs. Fair: A formidable trade-off in tackling climate change

Global warming requires a response characterized by forward-looking management of atmospheric carbon and respect for ethical principles. Both safety and fairness must be pursued, and there are severe trade-offs as these are intertwined by the limited headroom for additional atmospheric CO2 emissions. This paper provides a simple numerical mapping at the aggregated level of developed vs. developing countries in which safety and fairness are formulated in terms of cumulative emissions and cumulative per capita emissions respectively. It becomes evident that safety and fairness cannot be achieved simultaneously for strict definitions of both. The paper further posits potential global trading in future cumulative emissions budgets in a world where financial transactions compensate for physical emissions: the safe vs. fair tradeoff is less severe but remains formidable. Finally, we explore very large deployment of engineered carbon sinks and show that roughly 1,000 Gt CO2 of cumulative negative emissions over the century are required to have a significant effect, a remarkable scale of deployment. We also identify the unexplored issue of how such sinks might be treated in sub-global carbon accounting

A description of a knowledge broker role implemented as part of a randomized controlled trial evaluating three knowledge translation strategies

<p>Abstract</p> <p>Background</p> <p>A knowledge broker (KB) is a popular knowledge translation and exchange (KTE) strategy emerging in Canada to promote interaction between researchers and end users, as well as to develop capacity for evidence-informed decision making. A KB provides a link between research producers and end users by developing a mutual understanding of goals and cultures, collaborates with end users to identify issues and problems for which solutions are required, and facilitates the identification, access, assessment, interpretation, and translation of research evidence into local policy and practice. Knowledge-brokering can be carried out by individuals, groups and/or organizations, as well as entire countries. In each case, the KB is linked with a group of end users and focuses on promoting the integration of the best available evidence into policy and practice-related decisions.</p> <p>Methods</p> <p>A KB intervention comprised one of three KTE interventions evaluated in a randomized controlled trial.</p> <p>Results</p> <p>KB activities were classified into the following categories: initial and ongoing needs assessments; scanning the horizon; knowledge management; KTE; network development, maintenance, and facilitation; facilitation of individual capacity development in evidence informed decision making; and g) facilitation of and support for organizational change.</p> <p>Conclusion</p> <p>As the KB role developed during this study, central themes that emerged as particularly important included relationship development, ongoing support, customized approaches, and opportunities for individual and organizational capacity development. The novelty of the KB role in public health provides a unique opportunity to assess the need for and reaction to the role and its associated activities. Future research should include studies to evaluate the effectiveness of KBs in different settings and among different health care professionals, and to explore the optimal preparation and training of KBs, as well as the identification of the personality characteristics most closely associated with KB effectiveness. Studies should also seek to better understand which combination of KB activities are associated with optimal evidence-informed decision making outcomes, and whether the combination changes in different settings and among different health care decision makers.</p