N10‐carbonyl‐substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress

During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure–activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure–activity relationships. A representative compound N‐(3,5‐dimethyl‐4H‐1,2,4‐triazol‐4‐yl)‐10H‐phenothiazine‐10‐carboxamide (DT‐PTZ‐C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30‐ to 100‐fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug‐like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress.     

A composite bacteriophage alters colonization by an intestinal commensal bacterium

The mammalian intestine is home to a dense community of bacteria and its associated bacteriophage (phage). Virtually nothing is known about how phages impact the establishment and maintenance of resident bacterial communities in the intestine. Here, we examine the phages harbored by Enterococcus faecalis, a commensal of the human intestine. We show that E. faecalis strain V583 produces a composite phage (ϕV1/7) derived from two distinct chromosomally encoded prophage elements. One prophage, prophage 1 (ϕV1), encodes the structural genes necessary for phage particle production. Another prophage, prophage 7 (ϕV7), is required for phage infection of susceptible host bacteria. Production of ϕV1/7 is controlled, in part, by nutrient availability, because ϕV1/7 particle numbers are elevated by free amino acids in culture and during growth in the mouse intestine. ϕV1/7 confers an advantage to E. faecalis V583 during competition with other E. faecalis strains in vitro and in vivo. Thus, we propose that E. faecalis V583 uses phage particles to establish and maintain dominance of its intestinal niche in the presence of closely related competing strains. Our findings indicate that bacteriophages can impact the dynamics of bacterial colonization in the mammalian intestinal ecosystem.     

Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements

Background: Varenicline (VAR) is a partial nicotinic receptor agonist that is an effective smoking cessation medication. Preliminary evidence indicates that it may also reduce alcohol consumption, but the underlying mechanism is not clear. For example, VAR may reduce alcohol consumption by attenuating its subjectively rewarding properties or by enhancing its aversive effects. In this study, we examined the effects of an acute dose of VAR upon subjective, physiological, and objective responses to low and moderate doses of alcohol in healthy social drinkers. Methods: Healthy men and women (N = 15) participated in 6 randomized sessions; 3 sessions each with 2 mg VAR and placebo (PL) followed 3 hours later by a beverage containing PL, low‐dose alcohol (0.4 g/kg), or high‐dose alcohol (0.8 g/kg). Subjective mood and drug effects (i.e., stimulation, drug liking), physiological measures (heart rate, blood pressure), and eye tracking tasks were administered at various intervals before and after drug and alcohol administration. Results: VAR acutely increased blood pressure, heart rate, ratings of dysphoria and nausea, and also improved eye tracking performance. After alcohol drinking (vs. PL), VAR increased dysphoria and tended to reduce alcohol liking ratings. It also attenuated alcohol‐induced eye‐tracking impairments. These effects were independent of the drug’s effects on nausea before drinking. Conclusions: Our data support the theory that VAR may reduce drinking by potentiating aversive effects of alcohol. VAR also offsets alcohol‐induced eye movement impairment. The evidence suggests that VAR may decrease alcohol consumption by producing effects, which oppose the rewarding efficacy of alcohol.     

Short-term effects of thrust versus nonthrust mobilization/manipulation directed at the thoracic spine in patients with neck pain: a randomized clinical trial

BACKGROUND AND PURPOSE: Evidence supports the use of manual physical therapy interventions directed at the thoracic spine in patients with neck pain. The purpose of this study was to compare the effectiveness of thoracic spine thrust mobilization/manipulation with that of nonthrust mobilization/manipulation in patients with a primary complaint of mechanical neck pain. The authors also sought to compare the frequencies, durations, and types of side effects between the groups. SUBJECTS: The subjects in this study were 60 patients who were 18 to 60 years of age and had a primary complaint of neck pain. METHODS: For all subjects, a standardized history and a physical examination were obtained. Self-report outcome measures included the Neck Disability Index (NDI), a pain diagram, the Numeric Pain Rating Scale (NPRS), and the Fear-Avoidance Beliefs Questionnaire. After the baseline evaluation, the subjects were randomly assigned to receive either thoracic spine thrust or nonthrust mobilization/manipulation. The subjects were reexamined 2 to 4 days after the initial examination, and they again completed the NDI and the NPRS, as well as the Global Rating of Change (GROC) Scale. The primary aim was examined with a 2-way repeated-measures analysis of variance (ANOVA), with intervention group (thrust versus nonthrust mobilization/manipulation) as the between-subjects variable and time (baseline and 48 hours) as the within-subject variable. Separate ANOVAs were performed for each dependent variable: disability (NDI) and pain (NPRS). For each ANOVA, the hypothesis of interest was the 2-way group x time interaction. RESULTS: Sixty patients with a mean age of 43.3 years (SD=12.7) (55% female) satisfied the eligibility criteria and agreed to participate in the study. Subjects who received thrust mobilization/manipulation experienced greater reductions in disability, with a between-group difference of 10% (95% confidence interval [CI]=5.3-14.7), and in pain, with a between-group difference of 2.0 (95% CI=1.4-2.7). Subjects in the thrust mobilization/manipulation group exhibited significantly higher scores on the GROC Scale at the time of follow-up. No differences in the frequencies, durations, and types of side effects existed between the groups. DISCUSSION AND CONCLUSION: The results suggest that thoracic spine thrust mobilization/manipulation results in significantly greater short-term reductions in pain and disability than does thoracic nonthrust mobilization/manipulation in people with neck pain.