Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Bordetella pertussis Infection Exacerbates Influenza Virus Infection through Pertussis Toxin-Mediated Suppression of Innate Immunity

Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on subsequent influenza virus (PR8) infection in mouse models and the role of pertussis toxin (PT) in this effect. BALB/c mice infected with a wild-type strain of B. pertussis (WT) and subsequently (up to 14 days later) infected with PR8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice similarly infected with a PT-deficient mutant strain (ΔPT) and PR8. Substitution of WT infection by intranasal treatment with purified active PT was sufficient to replicate the exacerbating effects on PR8 infection in BALB/c and C57/BL6 mice, but the effects of PT were lost when toxin was administered 24 h after virus inoculation. PT had no effect on virus titers in primary cultures of murine tracheal epithelial cells (mTECs) in vitro, suggesting the toxin targets an early immune response to increase viral titers in the mouse model. However, type I interferon responses were not affected by PT. Whole genome microarray analysis of gene expression in lung tissue from PT-treated and control PR8-infected mice at 12 and 36 h post-virus inoculation revealed that PT treatment suppressed numerous genes associated with communication between innate and adaptive immune responses. In mice depleted of alveolar macrophages, increase of pulmonary viral titers by PT treatment was lost. PT also suppressed levels of IL-1β, IL-12, IFN-γ, IL-6, KC, MCP-1 and TNF-α in the airways after PR8 infection. Furthermore PT treatment inhibited early recruitment of neutrophils and NK cells to the airways. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated influenza infection by countering protective innate immune responses that control virus titers

Nucleotide sequence determination of bacteriophage T4 glycine transfer ribonucleic acid

The nucleotide sequence of a T4 tRNA with an anticodon for glycine has been determined using (32)P-labeled material from T4-infected cultures of Escherichia coli. The sequence is: pGCGGAUAUCGUAUAAUGmGDAUUACCUCAGACUUCCAAψCUGAUGAUGUGAGTψCGAUUCUCAUUAUCCGCUCCA-OH. The 74 nucleotide sequence can be arranged in the classic cloverleaf pattern for tRNAs. The anticodon of T4 tRNA(Gly) is UCC with a possible modification of the U. The tRNA molecule would thus be expected to recognize the glycine codons GGG and GGA. Comparative analysis of tRNAs(Gly) from T2 and T6 indicate that their sequences are identical with that from T4

When Knowing Becomes Remembering: Individual Differences in Susceptibility to Suggestion

In two experiments, the authors explored factors that might influence a person\u27s tendency to make source-monitoring errors about autobiographical memories. In the first experiment, undergraduates retrieved a memory from childhood (a) that was known about but not remembered, (b) that was remembered, or (c) for which they were unsure of their memory\u27s source. After writing down the memory, experimental groups listened to a guided visualization tape and answered questions about the event--interventions designed to help them focus on details of their memory. Controls also retrieved and wrote down a memory; however, instead of visualizing the memory, they were instructed to conduct a visual search task. Results indicated that guided visualization led participants to rate known memories closer to remembered events. A second experiment examined individual difference variables that might be related to this know-to-remember shift. Results indicated that extraversion, external locus of control, a memory that conveyed fear, and overall affective content predicted this rating. The applicability of these findings to the psychotherapy process is discussed

The Brief Aggression Questionnaire : structure, validity, reliability, and generalizability

In contexts that increasingly demand brief self-report measures (e.g., experience sampling, longitudinal and field studies), researchers seek succinct surveys that maintain reliability and validity. One such measure is the 12-item Brief Aggression Questionnaire (BAQ; Webster et al., 2014), which uses 4 3-item subscales: Physical Aggression, Verbal Aggression, Anger, and Hostility. Although prior work suggests the BAQ's scores are reliable and valid, we addressed some lingering concerns. Across 3 studies (N = 1,279), we found that the BAQ had a 4-factor structure, possessed long-term test–retest reliability across 12 weeks, predicted differences in behavioral aggression over time in a laboratory experiment, generalized to a diverse nonstudent sample, and showed convergent validity with a displaced aggression measure. In addition, the BAQ's 3-item Anger subscale showed convergent validity with a trait anger measure. We discuss the BAQ's potential reliability, validity, limitations, and uses as an efficient measure of aggressive traits