Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic downregulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for <i>in vivo</i> use

A blended knowledge translation initiative to improve colorectal cancer staging [ISRCTN56824239]

BACKGROUND: A significant gap has been documented between best practice and the actual practice of surgery. Our group identified that colorectal cancer staging in Ontario was suboptimal and subsequently developed a knowledge translation strategy using the principles of social marketing and the influence of expert and local opinion leaders for colorectal cancer. METHODS/DESIGN: Opinion leaders were identified using the Hiss methodology. Hospitals in Ontario were cluster-randomized to one of two intervention arms. Both groups were exposed to a formal continuing medical education session given by the expert opinion leader for colorectal cancer. In the treatment group the local Opinion Leader for colorectal cancer was detailed by the expert opinion leader for colorectal cancer and received a toolkit. Forty-two centres agreed to have the expert opinion leader for colorectal cancer come and give a formal continuing medical education session that lasted between 50 minutes and 4 hours. No centres refused the intervention. These sessions were generally well attended by most surgeons, pathologists and other health care professionals at each centre. In addition all but one of the local opinion leaders for colorectal cancer met with the expert opinion leader for colorectal cancer for the academic detailing session that lasted between 15 and 30 minutes. DISCUSSION: We have enacted a unique study that has attempted to induce practice change among surgeons and pathologists using an adapted social marketing model that utilized the influence of both expert and local opinion leaders for colorectal cancer in a large geographic area with diverse practice settings

Risk Adjustment Measures and Outcome Measures for Prehospital Trauma Research: Recommendations from the Emergency Medical Services Outcomes Project (EMSOP)

Objectives:  The objectives were to conduct a comprehensive, systematic review of the literature for risk adjustment measures (RAMs) and outcome measures (OMs) for prehospital trauma research and to use a structured expert panel process to recommend measures for use in future emergency medical services (EMS) trauma outcomes research. Methods:  A systematic literature search and review was performed identifying the published studies evaluating RAMs and OMs for prehospital injury research. An explicit structured review of all articles pertaining to each measure was conducted using the previously established methodology developed by the Canadian Physiotherapy Association (“Physical Rehabilitation Outcome Measures”). Results:  Among the 4,885 articles reviewed, 96 RAMs and/or OMs were identified from the existing literature (January 1958 to February 2010). Only one measure, the Glasgow Coma Scale (GCS), currently meets Level 1 quality of evidence status and a Category 1 (strong) recommendation for use in EMS trauma research. Twelve RAMs or OMs received Category 2 status (promising, but not sufficient current evidence to strongly recommend), including the motor component of GCS, simplified motor score (SMS), the simplified verbal score (SVS), the revised trauma score (RTS), the prehospital index (PHI), EMS provider judgment, the revised trauma index (RTI), the rapid acute physiology score (RAPS), the rapid emergency medicine score (REMS), the field trauma triage (FTT), the pediatric triage rule, and the out‐of‐hospital decision rule for pediatrics. Conclusions:  Using a previously published process, a structured literature review, and consensus expert panel opinion, only the GCS can currently be firmly recommended as a specific RAM or OM for prehospital trauma research (along with core measures that have already been established and published). This effort highlights the paucity of reliable, validated RAMs and OMs currently available for outcomes research in the prehospital setting and hopefully will encourage additional, methodologically sound evaluations of the promising, Category 2 RAMs and OMs, as well as the development of new measures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87101/1/j.1553-2712.2011.01148.x.pd

The Role of Individual Variables, Organizational Variables and Moral Intensity Dimensions in Libyan Management Accountants’ Ethical Decision Making

This study investigates the association of a broad set of variables with the ethical decision making of management accountants in Libya. Adopting a cross-sectional methodology, a questionnaire including four different ethical scenarios was used to gather data from 229 participants. For each scenario, ethical decision making was examined in terms of the recognition, judgment and intention stages of Rest’s model. A significant relationship was found between ethical recognition and ethical judgment and also between ethical judgment and ethical intention, but ethical recognition did not significantly predict ethical intention—thus providing support for Rest’s model. Organizational variables, age and educational level yielded few significant results. The lack of significance for codes of ethics might reflect their relative lack of development in Libya, in which case Libyan companies should pay attention to their content and how they are supported, especially in the light of the under-development of the accounting profession in Libya. Few significant results were also found for gender, but where they were found, males showed more ethical characteristics than females. This unusual result reinforces the dangers of gender stereotyping in business. Personal moral philosophy and moral intensity dimensions were generally found to be significant predictors of the three stages of ethical decision making studied. One implication of this is to give more attention to ethics in accounting education, making the connections between accounting practice and (in Libya) Islam. Overall, this study not only adds to the available empirical evidence on factors affecting ethical decision making, notably examining three stages of Rest’s model, but also offers rare insights into the ethical views of practising management accountants and provides a benchmark for future studies of ethical decision making in Muslim majority countries and other parts of the developing world

Transmission Dynamics of Schistosoma japonicum in the Lakes and Marshlands of China

Background: Schistosoma japonicum is a major public health concern in China, with over one million people infected and another 40 million living in areas at risk of infection. Unlike the disease caused by S. mansoni and S. haematobium, schistosomiasis japonica is a zoonosis, involving a number of different mammalian species as reservoir hosts. As a result of a number of published reports from China, it has long been considered that bovines, particularly water buffaloes, play a major role in human S. japonicum transmission there, and a drug-based intervention study (1998-2003) around the Poyang Lake in Jiangxi Province provided proof of concept that water buffaloes are, indeed, major reservoirs of human infection in this setting. Methods and Findings: In this study we incorporated recently obtained epidemiological information to model the steady-state S. japonicum transmission as well as the impact of the removal of S. japonicum transmission attributable to water buffaloes on human infection rates across six different endemic scenarios within three villages in the Dongting (Hunan) and Poyang (Jiangxi) lakes of southern China. Similar results were obtained for all scenarios. Steady-state S. japonicum infection rates remained constant and human prevalence and incidence were predicted to fall considerably over time. The model showed that the contribution of S. japonicum water buffalo transmission to human infection ranged from 39.1% to 99.1% and predicted that the removal of water buffalo transmission would reduce parasite reproductive rates below 1. This indicates that without the contribution of water buffaloes, S. japonicum transmission is interrupted and unsustainable. These scenarios are generalizable to other endemic villages in the lake and marshland areas of China where a similar cycle of snail infection and infection/reinfection of humans and bovines occurs. Conclusions: Along with previous epidemiological data, our findings strongly support water buffaloes as an important component of the transmission cycle that affects humans in the lake and marshlands region of China, a feature which appears to differ from the situation prevalent in the Philippines where their contribution is less pronounced. Our conclusions underscore the rationale for removal, replacement or treatment of water buffaloes, and for the development and deployment of a transmission blocking buffalo vaccine against S. japonicum for this setting to achieve the goal of transmission control. The Chinese Government has recently commenced a new integrated national strategy to improve on existing approaches to control schistosomiasis in the lake and marshlands region by reducing bovines and humans as a source of S. japonicum infection to Oncomelania snails

Time-varying correlation between oil and stock market volatilities: Evidence from oil-importing and oil-exporting countries

This paper investigates the time-varying conditional correlation between oil price and stock market volatility for six major oil-importing and oil-exporting countries. The period of the study runs from January 2000 until December 2014 and a Diag-BEKK model is employed. Our findings report the following regularities. (i) The correlation between the oil and stock market volatilities changes over time fluctuating at both positive and negative values. (ii). Heterogeneous patterns in the time-varying correlations are evident between the oil-importing and oil-exporting countries. (iii) Correlations are responsive to major economic and geopolitical events, such as the early-2000 recession, the 9/11 terrorist attacks and the global financial crisis of 2007-2009. These findings are important for risk management practices, derivative pricing and portfolio rebalancing

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy