The effects of alcohol dose, exposure to an in-vehicle alcohol feedback device, and subjective responses to alcohol on the decision to drink-drive in young drivers.

BACKGROUND: Several factors may influence the decision to drink-drive (DD) in young drivers, such as the amount of alcohol consumed, exposure to an in-vehicle alcohol feedback device, and subjective responses to alcohol. Understanding of their influence on DD is lacking and may be key for targeted intervention. This randomized controlled, double-blinded, driving simulation experiment tested three main hypotheses; young drivers are more likely to engage in DD with: i) lower alcohol dose; ii) lack of exposure to an in-vehicle alcohol feedback (FB) device; and iii) lower subjective responses to alcohol intoxication (SR). Interactions between the decision to DD and SR, FB and sex were also explored. METHODS: Males (n = 80) and females (n = 80) aged 20-24 years old were randomly assigned to two conditions: i) alcohol dose (0.45 g/kg or 0.65 g/kg); and ii) exposure to an in-vehicle alcohol feedback device (no or yes). Assessment of participants' SR following alcohol intake was based upon two measures: i) subjective intoxication measured by the discrepancy between an objective measure of intoxication and their subjective estimate of intoxication; and ii) perception of capacity to drive safely under alcohol (for both variables, a higher score represents lower SR). Participants were then asked to make either a negative or positive decision to DD while confronted with time-based contingencies related to their decision. Logistic regression and moderation analyses tested hypotheses. RESULTS: Approximately 60 % of participants decided to DD. Higher odds of DD were found in participants reporting higher capacity to drive (adjusted odds ratio [ß] = 1.03, 95 % confidence interval [CI] = 1.01-1.05) and who were males (ß  = 7.70; 95 % CI = 1.34-5.57). A main effect of either FB exposure or alcohol dose was not detected. Moderation analysis showed that lower SR, represented by higher perceived capacity to drive safely under alcohol was selectively predictive of greater likelihood of a decision to DD in participants not exposed to FB (effect = .054, p < .001, 95 % CI = .026-.083). CONCLUSIONS: Lower SR was found to be associated with a greater likelihood of the decision to DD in young drivers, while exposure to an in-vehicle FB device had no effect on DD. Importantly, FB exposure appeared to disrupt the relationship between lower SR and the decision to DD, signaling that FB may be selectively effective for young drivers possessing lower SR. Future studies are needed to clarify whether FB technology, and other interventions, can be targeted to deter DD in the young drivers most likely to benefit.

Linking mind wandering tendency to risky driving in young male drivers.

Risky driving is a significant contributor to road traffic crashes, especially in young drivers. Transient mind wandering states, an internal form of distraction, are associated with faster driving, reduced headway distance, slower response times, reduced driver vigilance, and increased crash risk. It is unclear whether a trait tendency to mind wander predicts risky driving, however. Mind wandering is also associated with poor executive control, but whether this capacity moderates the putative link between mind wandering tendency and risky driving is uncertain. The present study tested whether mind wandering tendency predicts risky driving behaviour in young male drivers aged 18-21 (N=30) and whether this relationship is mediated by driver vigilance and moderated by executive control capacity. Mind wandering was measured with the Sustained Attention to Response Task (SART) and the Daydreaming Frequency Scale (DDFS). Risky driving was assessed by mean speed in a driving simulator and driver vigilance was quantified by horizontal eye movements measured with eye tracking. Results showed that greater mind wandering tendency based on SART performance significantly predicts faster mean speed, confirming the main hypothesis. Neither driver vigilance mediated nor executive control capacity moderated this relationship as hypothesized. These findings speak to the complexity of individual differences in mind wandering. Overall, mind wandering tendency is a significant marker of risky driving in young drivers, which could guide the development of targeted interventions.

Relationships between frequency of driving under the influence of cannabis, self-reported reckless driving and risk-taking behavior observed in a driving simulator.

INTRODUCTION: The role of cannabis consumption in traffic crashes is unclear and the causal link between cannabis and collisions is still to be demonstrated. While cannabis use is very likely to impair driving ability, there is as yet no overwhelming evidence that cannabis use in isolation contributes more to collisions than other characteristics inherent to cannabis users. As noted in a growing body of literature, individuals driving under the influence of cannabis (DUIC) seem to exhibit a general reckless driving style putting them at higher risk to be involved in traffic crashes. METHOD: This study aims at investigating the relationship between self-reported DUIC and reckless driving by means of self-reported measures and direct observations made in a driving simulator. Participants (n=72) were required to be between 18 and 25 years of age, to hold a valid driver's license, and to drive at least twice a week. They completed standard driving simulation tasks recreating everyday on-road trivial conditions. RESULTS: Results show that people admitting that they commit more real-life dangerous driving behaviors reached higher maximum speed and demonstrated more reckless driving behaviors on the driving simulation tasks. Self-reported DUIC is associated with a risky driving style including a broad range of reckless on-road behaviors and support the problem driving behavior theory. Moreover, beyond confounding factors, both self-report DUIC and observed dangerous behaviors are associated with real-life traffic violations. PRACTICAL APPLICATIONS: Since DUIC appears to be related to an overall reckless style of driving, it is proposed that public safety policies should be more holistic, simultaneously targeting multiple on-road dangerous behaviors for intervention.

Thyroid hormone response element half-site organization and its effect on thyroid hormone mediated transcription.

Thyroid hormone (TH) exerts its effects by binding to the thyroid hormone receptor (TR), which binds to TH response elements (TREs) to regulate target gene expression. We investigated the relative ability of liganded homodimers TR and retinoid X receptor (RXR), and the heterodimer TR/RXR, to regulate gene expression for the TRE half-site organizations: direct repeat 4 (DR4), inverted repeat 0 (IR0) and everted repeat 6 (ER6). Luciferase reporter assays using a DR4 TRE suggest that both the TR homodimer and TR/RXR heterodimer regulate luciferase expression in the presence of their respective ligands. However, in the presence of the IR0 TRE, transfection with TR/RXR and RXR alone increased luciferase activity and there was no effect of TR alone. The presence of 9-cis-retinoic acid was necessary for luciferase expression, whereas TH treatment alone was insufficient. For the ER6 TRE, transfection with TR/RXR, TR alone and RXR alone (in the presence of their respective ligands) all caused a significant increase in luciferase activity. When both ligands were present, transfection with both TR/RXR caused more activation. Finally, we investigated the efficacy of the TR-antagonist 1-850 in inhibiting transcription by TR or TR/RXR at DR4 and ER6 TREs. We found that 1-850 did not suppress luciferase activation in the presence of TR/RXR for the ER6 TRE, suggesting conformational changes of the ligand binding domain of the TR when bound to different TRE half-site organizations. Collectively, the findings indicate that there are fundamental differences between TRE configurations that affect nuclear receptor interactions with the response element and ability to bind ligands and antagonists.

Thyroid hormone-regulated gene expression in juvenile mouse liver: identification of thyroid response elements using microarray profiling and in silico analyses.

BACKGROUND: Disruption of thyroid hormone signalling can alter growth, development and energy metabolism. Thyroid hormones exert their effects through interactions with thyroid receptors that directly bind thyroid response elements and can alter transcriptional activity of target genes. The effects of short-term thyroid hormone perturbation on hepatic mRNA transcription in juvenile mice were evaluated, with the goal of identifying genes containing active thyroid response elements. Thyroid hormone disruption was induced from postnatal day 12 to 15 by adding goitrogens to dams' drinking water (hypothyroid). A subgroup of thyroid hormone-disrupted pups received intraperitoneal injections of replacement thyroid hormones four hours prior to sacrifice (replacement). An additional group received only thyroid hormones four hours prior to sacrifice (hyperthyroid). Hepatic mRNA was extracted and hybridized to Agilent mouse microarrays. RESULTS: Transcriptional profiling enabled the identification of 28 genes that appeared to be under direct thyroid hormone-regulation. The regulatory regions of the genome adjacent to these genes were examined for half-site sequences that resemble known thyroid response elements. A bioinformatics search identified 33 thyroid response elements in the promoter regions of 13 different genes thought to be directly regulated by thyroid hormones. Thyroid response elements found in the promoter regions of Tor1a, 2310003H01Rik, Hect3d and Slc25a45 were further validated by confirming that the thyroid receptor is associated with these sequences in vivo and that it can bind directly to these sequences in vitro. Three different arrangements of thyroid response elements were identified. Some of these thyroid response elements were located far up-stream (> 7 kb) of the transcription start site of the regulated gene. CONCLUSIONS: Transcriptional profiling of thyroid hormone disrupted animals coupled with a novel bioinformatics search revealed new thyroid response elements associated with genes previously unknown to be responsive to thyroid hormone. The work provides insight into thyroid response element sequence motif characteristics.

Thyroid hormone may regulate mRNA abundance in liver by acting on microRNAs.

MicroRNAs (miRNAs) are extensively involved in diverse biological processes. However, very little is known about the role of miRNAs in mediating the action of thyroid hormones (TH). Appropriate TH levels are known to be critically important for development, differentiation and maintenance of metabolic balance in mammals. We induced transient hypothyroidism in juvenile mice by short-term exposure to methimazole and perchlorate from post natal day (PND) 12 to 15. The expression of miRNAs in the liver was analyzed using Taqman Low Density Arrays (containing up to 600 rodent miRNAs). We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls. Among the miRNAs, miRs-1, 206, 133a and 133b exhibited a massive increase in expression (50- to 500-fold). The regulation of TH on the expression of miRs-1, 206, 133a and 133b was confirmed in various mouse models including: chronic hypothyroid, short-term hyperthyroid and short-term hypothyroid followed by TH supplementation. TH regulation of these miRNAs was also confirmed in mouse hepatocyte AML 12 cells. The expression of precursors of miRs-1, 206, 133a and 133b were examined in AML 12 cells and shown to decrease after TH treatment, only pre-mir-206 and pre-mir-133b reached statistical significance. To identify the targets of these miRNAs, DNA microarrays were used to examine hepatic mRNA levels in the short-term hypothyroid mouse model relative to controls. We found transcripts from 92 known genes were significantly altered in these hypothyroid mice. Web-based target predication software (TargetScan and Microcosm) identified 14 of these transcripts as targets of miRs-1, 206, 133a and 133b. The vast majority of these mRNA targets were significantly down-regulated in hypothyroid mice, corresponding with the up-regulation of miRs-1, 206, 133a and 133b in hypothyroid mouse liver. To further investigate target genes, miR-206 was over-expressed in AML 12 cells. TH treatment of cells over-expressing miR-206 resulted in decreased miR-206 expression, and a significant increase in two predicted target genes, Mup1 and Gpd2. The results suggest that TH regulation of these genes may occur secondarily via miR-206. These studies provide new insight into the role of miRNAs in mediating TH regulation of gene expression.