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Johnson K.P.,Oak Street Health | Johnson K.P.,University of Florida
Proceedings. Biological sciences / The Royal Society

The rate of DNA mutation and divergence is highly variable across the tree of life. However, the reasons underlying this variation are not well understood. Comparing the rates of genetic changes between hosts and parasite lineages that diverged at the same time is one way to begin to understand differences in genetic mutation and substitution rates. Such studies have indicated that the rate of genetic divergence in parasites is often faster than that of their hosts when comparing single genes. However, the variation in this relative rate of molecular evolution across different genes in the genome is unknown. We compared the rate of DNA sequence divergence between humans, chimpanzees and their ectoparasitic lice for 1534 protein-coding genes across their genomes. The rate of DNA substitution in these orthologous genes was on average 14 times faster for lice than for humans and chimpanzees. In addition, these rates were positively correlated across genes. Because this correlation only occurred for substitutions that changed the amino acid, this pattern is probably produced by similar functional constraints across the same genes in humans, chimpanzees and their ectoparasites. Source

Bested A.C.,Oak Street Health | Logan A.C.,CAMNR | Selhub E.M.,Harvard University
Gut Pathogens

Mental health disorders, depression in particular, have been described as a global epidemic. Research suggests that a variety of lifestyle and environmental changes may be driving at least some portion of the increased prevalence. One area of flourishing research involves the relationship between the intestinal microbiota (as well as the related functional integrity of the gastrointestinal tract) and mental health. In order to appreciate the recent scientific gains in this area, and its potential future directions, it is critical to review the history of the topic. Probiotic administration (e.g. Lactobacillus) and fecal microbiota transfer for conditions associated with depression and anxiety is not a new concept. Here, in the first of a 3-part series, we begin by reviewing the origins of the contemporary research, providing a critical appraisal of what has become a revisionist history of the controversial term 'autointoxication'. We argue that legitimate interests in the gut-brain-microbiota connection were obscured for decades by its association with a narrow historical legacy. Historical perspectives provide a very meaningful context to the current state of the contemporary research as outlined in parts II and III. © 2013 Bested et al.; licensee BioMed Central Ltd. Source

Kiang T.K.L.,University of British Columbia | Wilby K.J.,Qatar University | Ensom M.H.H.,University of British Columbia | Ensom M.H.H.,Oak Street Health
Clinical Pharmacokinetics

This article provides an unbiased review of the pharmacokinetic, pharmacodynamic, and drug-drug interaction data of telaprevir, an NS3/4A protease inhibitor. Telaprevir is well absorbed with fatty food, moderately protein bound (59-76 %) with a large volume of distribution (~252 L), primarily metabolized by cytochrome P450 (CYP) 3A4 and P-glycoprotein, and is largely excreted into feces. Pharmacokinetic and pharmacodynamic parameters are well described in healthy subjects and individuals infected with hepatitis C virus (HCV), although only limited data are available in specific patient subpopulations. Telaprevir is recommended to be given at 750 mg by mouth every 8 h for 12 weeks, in combination with peginterferon and ribavirin (the standard care). The addition of telaprevir to the standard care regimen results in increased sustained virological response in treatment-naïve patients (30 %) and treatment-experienced patients (up to 50 %), and works synergistically to lower viral resistance. Telaprevir is a substrate and/or inhibitor of CYP3A4 and P-glycoprotein, and drug-drug interaction studies in humans have focused on these pathways. Based on our analysis, a few reported drug-drug interactions may be classified as clinically significant, but more experiments under dosing conditions that resemble those given in the clinic are needed to understand the relevance of some of the reported interactions. Future studies should focus on the pharmacokinetics/pharmacodynamics of telaprevir in special populations or patients with concomitant conditions that will likely co-exist with HCV infection, with an emphasis on establishing pharmacokinetic-pharmacodynamic relationships. In vitro characterization of other phase 1-3 metabolic pathways could assist in elucidating the mechanisms of the drug-drug interactions observed in humans. © 2013 Springer International Publishing Switzerland. Source

Weiss M.D.,Oak Street Health | Salpekar J.,George Washington University
CNS Drugs

An estimated 2550 of children and adolescents with attention-deficit hyperactivity disorder (ADHD) experience problems with sleep. The most common sleep problems reported in children with ADHD include delayed sleep onset, sleep or bedtime resistance, prolonged tiredness upon waking and daytime sleepiness. Higher incidences of sleep disorders such as restless legs syndrome, periodic limb movement disorder and sleep-disordered breathing have been reported in paediatric ADHD populations compared with control populations. In some cases, medications for ADHD andor co-morbid disorders may also contribute to sleep disturbances. Assessment tools, such as parent-child questionnaires and sleep diaries, can help clinicians evaluate sleep disturbances. Sleep problems may potentially exacerbate ADHD symptoms, and interventions targeted at ensuring adequate sleep (including behavioural, dietary, specific pharmacological agents for treatment-induced insomnia, and melatonin) could in turn potentially attenuate symptoms associated with ADHD, such as irritability. Whether metabolic or neurological pathways common to both sleep and ADHD may be disrupted, and whether targeting treatments to these pathways may simultaneously improve both ADHD and sleep symptoms, needs further elucidation. © 2010 Adis Data Information BV. All rights reserved. Source

The aim of this study is to examine key features within the cultural context in a Canadian Paediatric Intensive Care Unit (PICU) environment as experienced by nurses and to identify what these influences are and how they shape nurses' intentions to remain at critically ill children's bedsides for the duration of their careers.This is a qualitative study which follows a critical ethnographic approach. Over 20. hours of observation and face-to-face semi-structured interviews were conducted. Approximately one third of the nursing population at the research site PICU were interviewed (N=31).Participants describe a complex process of becoming an expert PICU nurse that involved several stages. By the time participants became experts in this PICU they believed they had significantly narrowed the power imbalance that exists between nursing and medicine. This study illuminates the role both formal and informal education plays in breaking the power barrier for nurses in the PICU. This level of expertise and mutual respect between professions aids in retaining nurses in the PICU. The lack of autonomy and/or respect shown to nurses by administrators appears to be one of the major stressors in nurses' working lives and can lead to attrition from the PICU.Family Centred Care (FCC) is practiced in paediatrics and certainly accentuated in the PICU as there is usually only one patient assigned per nurse, who thus afforded the time to provide comprehensive care to both the child and the family. This is considered one of the satisfiers for nurses in the PICU and tends to encourage retention of nurses in the PICU. However, FCC was found to be an inadequate term to truly encompass the type of holistic care provided by nurses in the PICU. © 2013 Elsevier Ltd. Source

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