IN VITRO HEPATIC OXIDATIVE BIOTRANSFORMATION OF TRIMETHOPRIM

Introduction: Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly used antibiotic often associated with idiosyncratic adverse drug reactions (IADRs). Historically, bioactivation of SMX to a reactive intermediate has been implicated in IADRs. Recently, the bioactivation of TMP has been described as TMP N-acetyl cysteine (NAC) adducts were identified following human liver microsome (HLM) incubations and in the urine of children taking TMP, suggesting cytochrome P450 enzymes (P450s) catalyze TMP bioactivation. In this study, we identified the P450s involved in the formation of six TMP primary metabolites. Methods: A panel of characterized HLMs (n=16), c-DNA expressed P450s, and pooled HLMs in the presence and absence of selective P450 inhibitors were incubated with therapeutic concentrations of TMP. Reactive metabolites were trapped with NAC, and metabolite formation was quantified by UPLC/MS/MS. Correlation coefficients between the rates of metabolite formation and P450 marker reaction rates were determined using least-squares regression analysis and evaluated at α=0.05. Results: 1-NO-TMP, Cα-NAC-TMP and Cα-OH-TMP were formed by CYP3A4 and inhibited by ketoconazole (CYP3A inhibitor). 4'-demethylation was catalyzed by several P450s including CYP3A4, correlated with multiple CYPs, and inhibited primarily with ketoconazole suggesting CYP3A4 contributed to 4'-demethylation. 3-NO-TMP was formed by CYP1A and inhibited by α-naphthoflavone (CYP1A inhibitor). 3'-demethylation was catalyzed by multiple P450s including CYP2C9, correlated with CYP2C9 activity and inhibited by sulphafenazole (CYP2C9 inhibitor). Conclusion: These findings suggest that P450s were responsible for the primary metabolism of TMP with CYPs 2C9 and 3A4 being the most significant contributors to TMP primary metabolism. Factors modulating activity of these enzymes may affect the risk of IADRs

New Thoughts on Thought Disorders in Parkinson's Disease: Review of Current Research Strategies and Challenges

Psychosis is a frequent nonmotor complication in Parkinson's disease (PD), characterized by a broad phenomenology and likely due to a variety of intrinsic (i.e., PD-related) and extrinsic factors. Safe and effective therapies are greatly needed as PD psychosis contributes significantly to morbidity, mortality, nursing home placement, and quality of life. Novel research strategies focused on understanding the pharmacology and pathophysiology of PD psychosis, utilizing translational research including animal models, genetics, and neuroimaging, and even looking beyond the dopamine system may further therapeutic advances. This review discusses new research strategies regarding the neurobiology and treatment of PD psychosis and several associated challenges

What We Don\u27t Know Can Help Us: Eliciting Out-of-Discipline Knowledge for Work with Intractable Conflicts

In this article, the authors present the results of a study in which a diverse variety of experts in fields outside the traditional conflict domain were interviewed about their ideas regarding intractable conflicts. The purpose of this study was to gather frame-breaking insights and practical approaches that could shed new light on complex, persistent conflict that has been particularly resistant to resolution. The authors argue that outsiders to the field are more likely to provide fresh perspective and radical approaches to the conflict field’s most intransigent problems because they are not constrained by the field’s pre-existing normative frames. This article examines some of their findings—from ideas on how globalization has exacerbated intractable conflicts, to ways that Biblical metaphors can be used to promote reconciliation, to an analysis of how philosophical concepts such as morality and impartiality can be used to produce fair outcomes, to ideas on the creation of an independent, international regional facilitation corps. In addition to a summary of content findings, methodological recommendations for future similar studies are offered

Cricket South Africa’s Protea Fire brand

Subject area Marketing, Sports marketing and Social media marketing. Study level/applicability Graduate level. Case overview This case, based on field research and multiple secondary sources, documents the 12-month period since early 2014 during which Cricket South Africa (CSA) developed the Protea Fire brand for their national men’s cricket team, known as the Proteas. In mid-2014, Marc Jury, the Commercial and Marketing manager of CSA set up a project team to take the previously in-house Protea Fire brand public. With the 2015 Cricket World Cup in Australia and New Zealand less than a year away, Jury worked with a diverse project team of Proteas players, cricket brand managers and external consultants to build a public brand identity for the national team, to nurture greater fan affinity and to mobilize South Africans behind their team for the World Cup. The project team developed a range of Protea Fire multimedia content as the core of the campaign. These included video diaries, scripts which were written by the Proteas players themselves, player profile videos, motivational team-talk videos and good luck video messages featuring ordinary and famous South Africans. Having invested in creating this content, the project team faced the difficult task of allocating a limited media budget to broadcast and amplify the content. Another significant challenge was to ensure that the Proteas team values were authentically communicated across all content, including via the social media strategy using Twitter, Instagram and YouTube. As the World Cup tournament kicked off on February 14th 2015, South Africa was well placed to overcome their previous inability to reach a final, although Jury wondered whether another exit in the knockout round would weaken the strong and positive emotions the Protea Fire campaign had ignited. With the last two balls remaining in South Africa’s semi-final game against New Zealand on March 24th 2015, and the home team requiring just five runs to win, Jury joined 60 million South Africans hoping that Protea Fire was strong enough. The case concludes with South Africa losing the semi-final game and Jury turning his attention to how the #ProteaFire campaign should respond. Expected learning outcomes This study aimed to analyse the development of a sport team brand and a megaevent campaign; to assess the efficiency and effectiveness of a marketing campaign; and to consider appropriate brand responses to the team’s failure to deliver on expectations. Subject code CSS 8: Marketing. </jats:sec

Variability in antifungal and antiviral use in hospitalized children

We analyzed antifungal and antiviral prescribing among high-risk children across freestanding children’s hospitals. Antifungal and antiviral days of therapy varied across hospitals. Benchmarking antifungal and antiviral use and developing antimicrobial stewardship strategies to optimize use of these high cost agents is needed.Infect Control Hosp Epidemiol2017;38:743–746</jats:p

Supportive technologies for group discussion in MOOCs

A key hurdle that prevents MOOCs from reaching their transformative potential in terms of making valuable learning experiences available to the masses is providing support for students to make use of the resources they can provide for each other. This paper lays the foundation for meeting this challenge by beginning with a case study and computational modeling of social interaction data. The analysis yields new knowledge that informs design and development of novel, real-time support for building healthy learning communities that foster a high level of engagement and learning. We conclude by suggesting specific areas for potential impact of new technology