The association between impulsivity and alcohol/drug use among prison inmates

Background: Few studies have examined the relation between impulsivity and drug involvement with prison inmates, in spite of their heavy drug use. Among this small body of work, most studies look at clinically relevant drug dependence, rather than drug use specifically. Method: N = 242 adult inmates (34.8% female, 52% White) with an average age of 35.58 (SD = 9.19) completed a modified version of the 15-item Barratt Impulsiveness Scale (BIS) and measures assessing lifetime alcohol, opiate, benzodiazepine, cocaine, cannabis, hallucinogen, and polysubstance use. Lifetime users also reported the frequency of use for the 30 days prior to incarceration. Results: Impulsivity was higher among lifetime users (versus never users) of all substances other than cannabis. Thirty day drug use frequency was only related to impulsivity for opiates and alcohol. Discussion: This study extends prior work, by showing that a lifetime history of non-clinical substance use is positively associated with impulsivity among prison inmates. Implications for drug interventions are considered for this population, which is characterized by high rates of substance use and elevated impulsivity

Estimated sweat loss, fluid and CHO intake, and sodium balance of male major junior, AHL, and NHL players during on-ice practices

Several previous studies have reported performance decrements in team sport athletes who dehydrated approximately 1.5–2% of their body mass (BM) through sweating. This study measured on-ice sweat loss, fluid intake, sodium balance, and carbohydrate (CHO) intake of 77 major junior (JR; 19 ± 1 years), 60 American Hockey League (AHL; 24 ± 4 years), and 77 National Hockey League (NHL; 27 ± 5 years) players. Sweat loss was calculated from pre- to post-exercise BM plus fluid intake minus urine loss. AHL (2.03 ± 0.62 L/hr) and NHL (2.02 ± 0.74 L/hr) players had higher sweat rates (p  .05). Sodium deficits (sodium loss − intake) were greater (p 2% BM) during 60 min of practice. However, ∼15%, 41%, and 48% of the JR, AHL, and NHL players, respectively, may have reached mild dehydration and increased risk of performance decrements in a 90-min practice

Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides

Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications have been limited by off target effects. Development of antiviral ribonucleosides for treatment of hepatitis C virus (HCV) infection has been hampered by appearance of toxicity during clinical trials that evaded detection during preclinical studies. It is well established that the human mitochondrial DNA polymerase is an off target for deoxyribonucleoside reverse transcriptase inhibitors. Here we test the hypothesis that triphosphorylated metabolites of therapeutic ribonucleoside analogues are substrates for cellular RNA polymerases. We have used ribonucleoside analogues with activity against HCV as model compounds for therapeutic ribonucleosides. We have included ribonucleoside analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents that are non-obligate chain terminators of the HCV RNA polymerase. We show that all of the anti-HCV ribonucleoside analogues are substrates for human mitochondrial RNA polymerase (POLRMT) and eukaryotic core RNA polymerase II (Pol II) in vitro. Unexpectedly, analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents were inhibitors of POLRMT and Pol II. Importantly, the proofreading activity of TFIIS was capable of excising these analogues from Pol II transcripts. Evaluation of transcription in cells confirmed sensitivity of POLRMT to antiviral ribonucleosides, while Pol II remained predominantly refractory. We introduce a parameter termed the mitovir (mitochondrial dysfunction caused by antiviral ribonucleoside) score that can be readily obtained during preclinical studies that quantifies the mitochondrial toxicity potential of compounds. We suggest the possibility that patients exhibiting adverse effects during clinical trials may be more susceptible to damage by nucleoside analogs because of defects in mitochondrial or nuclear transcription. The paradigm reported here should facilitate development of ribonucleosides with a lower potential for toxicity

Environmental change strategies targeting drug abuse prevention

The purpose of this paper is to highlight the three articles included in a special focus of Drugs: Education, Prevention, and Policy that address environmental change strategies targeting drug abuse prevention. We define environmental change strategies and their effectiveness in public health domains such as alcohol abuse, smoking, and obesity. We then discuss the three articles, each of which addresses different aspects of how environmental change strategies might be best implemented and measured. The first paper by Agley et al. (2014) examines the challenges of implementing an evidence-based practice, specifically screening, brief intervention, and referral to treatment to address drug abuse in primary care settings. The second paper by Kreiner et al. looks at encouraging providers to implement safe prescribing practices for controlled substances and to translate work being done in the medical community to the prevention specialist domain. The third paper by Quinlan et al. conducts a review of the literature on environmental change strategies targeting nonmedical use of marijuana and provides results showing the most and least effective of these interventions. This special focus is intended to build the evidence base for effective environmental change strategies to prevent drug abuse, generate critical analyses, and spur future research that will help improve the implementation and evaluation of such interventions

Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides

<div><p>Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications have been limited by off target effects. Development of antiviral ribonucleosides for treatment of hepatitis C virus (HCV) infection has been hampered by appearance of toxicity during clinical trials that evaded detection during preclinical studies. It is well established that the human mitochondrial DNA polymerase is an off target for deoxyribonucleoside reverse transcriptase inhibitors. Here we test the hypothesis that triphosphorylated metabolites of therapeutic ribonucleoside analogues are substrates for cellular RNA polymerases. We have used ribonucleoside analogues with activity against HCV as model compounds for therapeutic ribonucleosides. We have included ribonucleoside analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents that are non-obligate chain terminators of the HCV RNA polymerase. We show that all of the anti-HCV ribonucleoside analogues are substrates for human mitochondrial RNA polymerase (POLRMT) and eukaryotic core RNA polymerase II (Pol II) in vitro. Unexpectedly, analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents were inhibitors of POLRMT and Pol II. Importantly, the proofreading activity of TFIIS was capable of excising these analogues from Pol II transcripts. Evaluation of transcription in cells confirmed sensitivity of POLRMT to antiviral ribonucleosides, while Pol II remained predominantly refractory. We introduce a parameter termed the mitovir (<em><u>mito</u></em>chondrial dysfunction caused by anti<em><u>vir</u></em>al ribonucleoside) score that can be readily obtained during preclinical studies that quantifies the mitochondrial toxicity potential of compounds. We suggest the possibility that patients exhibiting adverse effects during clinical trials may be more susceptible to damage by nucleoside analogs because of defects in mitochondrial or nuclear transcription. The paradigm reported here should facilitate development of ribonucleosides with a lower potential for toxicity.</p> </div

Intracellular metabolism, cytotoxicity (CC₅₀), anti-HCV replicon activity (EC₅₀) and anti-NS5B activity (IC₅₀)^a.

a<p>Values rounded to two significant figures. All values are the mean ± s.d. of at least 3 independent experiments done in duplicate or triplicate except for CC₅₀ Huh-7 for 3-deazaadenosine and 6-methylpurine-riboside, which are the average of replicate wells from one experiment.</p>b<p>Intracellular metabolism [TP] is the amount of nucleoside triphosphate determined from LC/MS/MS analysis and converted from pmol per million cells to intracellular concentration (µM) using a cellular volume of 2 pL per cell. All data for 10 µM 24 h incubations except where noted otherwise.</p>c<p>Compounds that showed toxicity in MT4 cells at 10 µM. Incubations were done at 0.1 µM and the intracellular levels dose normalized assuming proportional increase in intracellular metabolites with extracellular concentrations.</p>d<p>not determined.</p>e<p>Tested in the form of monophosphate prodrug GS-7977.</p