Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing

Peripheral conduit artery flow-mediated dilatation decreases with ageing in humans. The underlying mechanisms and efficacy of preventive strategies are unknown. Brachial artery flow-mediated dilatation was determined at baseline and after ascorbic acid (vitamin C) intravenous infusion and chronic supplementation (500 mg day⁻¹ for 30 days) in three groups of healthy men: young sedentary ( n = 11; 25 ± 1 years, mean ± s.e.m. ), older sedentary ( n = 9; 64 ± 2), and older endurance-exercise trained ( n = 9; 64 ± 2). At baseline, flow-mediated dilatation (normalized for the hyperaemic stimulus) was ∼45% lower in the older (0.015 ± 0.001) versus young (0.028 ± 0.004) sedentary men ( P < 0.01), but was preserved in older exercising men (0.028 ± 0.004). Ascorbic acid infusion increased plasma concentrations > 15-fold in all groups and restored flow-mediated dilatation in the sedentary older men (to 0.023 ± 0.002; P > 0.1 versus other groups), with no effects in the other two groups. Oral ascorbic acid supplementation did not affect flow-mediated dilatation in any group. Brachial artery endothelium-independent dilatation (sublingual nitroglycerin) did not differ among the groups at baseline nor change with ascorbic acid administration. These results provide the first evidence for an important role of oxidative stress in both the impairment in peripheral conduit artery flow-mediated dilatation with sedentary human ageing and the preservation of flow-mediated dilatation with physically active ageing.     

Serotonergic mechanisms of cocaine effects in humans

The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine high were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.     

An assessment of a urinary biomarker for total human environmental exposure to benzo[a]pyrene

Urinary banzo[a]pyrene (BaP) metabolite levels were compared to human environmental exposure to BaP through inhalation and dietary ingestion to assess the predictive validity of the exposure biomarker. These measurements were made for 14 adult volunteers over 14 consecutive days, once during summer/fall, again during winter periods. Based on personal air monitoring, median potential inhalation doses of 11.0 and 2.3 ng/day were estimated for the winter and summer/fall studies, respectively. A median potential ingested dose of 176 ng/day, estimated from duplicate plate sampling, exceeded inhalation by 6-and 122-fold for the winter and summer/fall studies, respectively. Total urinary BaP metabolites were measured using a published reverse metabolism (BaP) method of analysis. Median rates of urinary BaP metabolite elimination for the winter and summer/fall studies were 121 and 129 ng/day, respectively. The changes in inhaled and ingested potential doses were regressed on the change in urinary metabolite elimination from week 1 to week 2 to test the predictive validity of the biomarker measurement. The regression was statistically significant (r = 0.620, p = 0.015, n = 25) when body weight was included and two extreme values were removed. Consistent with the exposure measurements showing diet as the dominant route of exposure, most of the variation in urinary metabolite elimination was explained by the ingested dose. It is concluded that the measurement of urinary BaP by reverse metabolism is qualitative and of marginal predictive validity as an exposure biomarker due to the method's low recoveries and the large unexplained variance.     

Accumulation of exogenous polyamines in gerbil brain after ischemia

Regionally selective delayed neuronal degeneration is a characteristic sequel of cerebral ischemia. Recent evidence indicates that changes in brain polyamine metabolism may be critical for nerve cell survival after ischemia. Within hours after ischemia, intracellular putrescine levels are greatly increased and remain elevated for days, whereas only minor changes are noted in the levels of the polyamines spermine and spermidine. In contrast, the extracellular levels of all polyamines are low after ischemia. Injections of polyamines following ischemia, however, can protect neurons in the gerbil brain from delayed cell death, with spermine being the most potent of the polyamines. In the present study, therefore, we sought to determine if increased polyamine uptake occurs in the brain after ischemia. In the hippocampal slice preparation, temperature-dependent uptake was unique for spermine, but not for spermidine or putrescine. Uptake of [¹⁴C]spermine was transiently increased after ischemia, peaking at 150% of control by 12–13 h and subsiding by 24 h. Intravenous injections of [³H]spermidine resulted in a postischemic accumulation of this polyamine throughout the forebrain parenchyma. We conclude that:

1. Active cellular uptake of spermine is transiently increased early after ischemia;
2. A nonspecific accumulation of exogenous polyamines occurs early after ischemia probably owing to a compromised blood-brain barrier, and
3. The findings indicate that exogenous polyamines can exert their effect directly in the brain after ischemia.

     

Abstinence-induced changes in self-report craving correlate with event-related FMRI responses to smoking cues.

Drug cues have been shown to activate brain regions involved in attention, motivation, and reward in addicted users. However, as studies have typically measured responses in only one state (ie drug abstinence), it is unclear whether observed activations represent amplification by abstinence or stable responses. Thus, the present study was designed to evaluate the stability of event-related responses to visual drug cues in dependent smokers (n=13) using event-related functional magnetic resonance imaging measures. Imaging was conducted following smoking as usual and following overnight abstinence, and self-reported craving measures were obtained before, during, and after scanning. Analysis of hemodynamic response (HDR) amplitudes in each of 13 regions of interest revealed larger responses to smoking compared to control cues in ventral anterior cingulate gyrus (vACG) and superior frontal gyrus. Responses to smoking cues in these and all other regions revealed no effects of abstinence/satiety, thus supporting the notion that cue-elicited brain responses are relatively stable. However, while the abstinence manipulation did not alter group-level responses to smoking cues, at the individual level, abstinence-induced changes in craving (abstinence minus satiety) were positively correlated with changes in HDR amplitude to smoking cues in frontal regions including left inferior frontal gyrus, left vACG, and bilateral middle frontal gyrus. These results suggest that brain responses to smoking cues, while relatively stable at the group level following short-term abstinence, may be modulated by individual differences in craving in response to abstinence-particularly in regions subserving attention and motivation.     

Connecting the dots: an association between opioids and acute hippocampal injury

Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.