Relative levels of cytoprotection produced by analogs of choline and the role of alpha7-nicotinic acetylcholine receptors

Several analogs of the acetylcholine precursor molecule choline have been widely studied as potential false cholinergic neurotransmitters with the therapeutic goal of using them to limit cholinergic neurotransmission. More recently, choline itself has been shown to act as a full, if low potency, agonist at the alpha7 subtype of the nicotinic acetylcholine receptor. This pharmacological property has been associated with the ability of nicotine and other related alpha7 receptor agonists to offer neuroprotection in a variety of experimental models. We confirm here that choline offers a significant degree of protection against the cytotoxicity induced by growth factor deprivation in differentiated PC-12 cells. Choline-induced cytoprotection ( approximately 1 mM) was about 3 orders of magnitude less potent than that for nicotine (EC(50) = 0.7 microM). Choline also exhibited only about 40% of the full cytoprotective effect of nicotine. Ethyl substitution for choline's N-methyl groups did not result in a significant improvement over choline as a cytoprotective agent. In contrast, pyrrolidinecholine exhibited much greater potency (EC(50) = 20 microM) and increased efficacy (about 55% of nicotine's effect) than choline. Like choline and nicotine, pyrrolidinecholine fully displaced [(125)I]alpha-bungarotoxin binding (K(i) = 33 microM) and chronic exposure to the analog increased cell surface binding sites. The cytoprotective effects of the analog were completely inhibited by coincubation with methyllycaconitine (MLA), a selective alpha7-nicotinic receptor antagonist. These findings are consistent with the possibility that the choline structure may serve as a template for the development of novel agents with both alpha7-nicotinic agonist activity and potential neuroprotective ability, as many of these compounds, including pyrrolidinecholine, are transported along with choline into the central nervous system.     

Life-course exposure to job strain and ambulatory blood pressure in men

This 1985-1995 study was designed to assess the association between blood pressure (measured by using an ambulatory monitor) and history of exposure to job strain. Items from the Job Content Questionnaire were completed by 213 employed men, aged 30-60 years at entry into the Work Site Blood Pressure Study in New York City, New York, for each previous job they had held. The systolic blood pressure of men employed for >/=25 years who were exposed to job strain for 50% of their work life was 4.8 mmHg (95% confidence interval: -3.7, 13.4) higher at work and 7.9 mmHg (95% confidence interval: 0.8, 15.0) higher at home than that of men with no past exposure, independent of current exposure. Evidence was inconsistent for the hypothesis of rapid induction of/recovery from the effects of job strain on blood pressure, and there was little effect of past job strain on diastolic blood pressure. These findings provide some support for the hypothesis of an effect of cumulative burden of exposure to job strain on systolic blood pressure.     

Deriving default dermal exposure values for use in a risk assessment toolkit for small and medium-sized enterprises

This paper describes the derivation of default task-based dermal exposure values for use in a risk assessment toolkit for small and medium-sized enterprises (SMEs). A set of separately determined dermal exposure modifiers have been applied to published studies of dermal exposure to obtain 'normalized' dermal exposure data sets. These data sets are grouped according to task and then further subdivided by making a distinction between processes involving solid and liquid products. For each of the resulting 12 groups, two default exposure rates are required: potential exposure rate to the hands and potential exposure rate to the body. Default values for risk assessment are then derived by taking a weighted average of the 75th percentiles of these normalized exposure distributions. In addition, a measure of peak surface concentration is required to take into account the risk of local skin effects. The higher of the (modified) hand and body exposure rates after applying the relevant penetration factors for clothing and gloves is used. Usually this will be the hand exposure rate. These default values serve as robust initial exposure estimates in a risk assessment toolkit for SMEs.     

Automated attention flags in chronic disease care planning

OBJECTIVES: To assess the value of computerised decision support in the management of chronic respiratory disease by comparing agreement between three respiratory specialists, general practitioners (care coordinators), and decision support software. METHODS: Care guidelines for two chronic obstructive pulmonary disease projects of the SA HealthPlus Coordinated Care Trial were formulated. Decision support software, Care Plan On-Line (CPOL), was created to represent the intent of these guidelines via automated attention flags to appear in patients' electronic medical records. For a random sample of 20 patients with care plans, decisions about the use of nine additional services (eg, smoking cessation, pneumococcal vaccination) were compared between the respiratory specialists, the patients' GPs and the CPOL attention flags. RESULTS: Agreement among the specialists was at the lower end of moderate (intraclass correlation coefficient [ICC], 0.48; 95% CI, 0.39-0.56), with a 20% rate of contradictory decisions. Agreement with recommendations of specialists was moderate to poor for GPs (kappa, 0.49; 95% CI, 0.33-0.66) and moderate to good for CPOL (kappa, 0.72; 95% CI, 0.55-0.90). CPOL agreement with GPs was moderate to poor (kappa, 0.41; 95% CI, 0.24-0.58). GPs were less likely than specialists or CPOL to decide in favour of an additional service (P<0.001). CPOL was 87% accurate as an indicator of specialist decisions. It gave a 16% false-positive rate according to specialist decisions, and flagged 61% of decisions where GPs said No and specialists said Yes. CONCLUSIONS: Automated decision support may provide GPs with improved access to the intent of guidelines; however, further investigation is required.     

Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study in rats

RATIONALE: Increasing concomitant abuse of cocaine and morphine-like opioids has prompted a number of studies aimed at understanding how these drugs interact. OBJECTIVE: The present study was designed to determine if variations in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline. One group of subjects (n=6) received morphine (5.6 mg/kg) 0.5 h, 1 h or 4 h prior to cumulative doses of cocaine (0.1-17.8 mg/kg). These pretreatment times were selected to overlap with states of acute opioid tolerance (approximately 1 h) or acute opioid dependence (approximately 4 h) as demonstrated by previous studies. A second group (n=6) was administered naloxone (0.3 mg/kg) 5 min prior to cumulative cocaine doses, with or without a 4-h morphine (5.6 mg/kg) or methadone (3.0 mg/kg) pretreatment. In a third procedure, the same subjects used in the second experiment were also tested for time-dependent changes in the analgesic effect of morphine using a hot-plate assay. RESULTS: Morphine pretreatment 1 h prior to assessment of the cocaine dose-response function significantly enhanced the discriminative stimulus effects of cocaine. However, neither 0.5-h or 4-h morphine pretreatment had any effect. In contrast, when naloxone was administered 4 h following either morphine or methadone and 5 min prior to assessment of the cocaine dose-response curve, the discriminative stimulus effects of cocaine were significantly attenuated. In assessing morphine-induced analgesia, paw-lick latency was significantly longer at 1 h and shorter at 4 h following morphine administration. CONCLUSIONS: The results illustrate the importance of temporal parameters for interactions between cocaine and mu opioid agonists.     

Effects of 12-h tobacco deprivation on event-related potentials elicited by visual smoking cues

RATIONALE: A cigarette smoker's reactivity to smoking cues, or cue-reactivity, traditionally has been indexed by self-report and/or measures of autonomic nervous system activity. Recent evidence suggests that measures of central nervous system activity in the form of event-related brain potentials (ERPs) may also index cue-reactivity in smokers. OBJECTIVE: The present study sought to confirm the sensitivity of ERPs to smoking cues and to investigate the question of whether 12 h of smoking deprivation would enhance ERP cue-reactivity to such stimuli. METHODS: Scalp ERPs were recorded to 80 smoking-related pictures and 80 neutral pictures, i.e., similar pictures with a nonsmoking theme, in 19 tobacco-deprived smokers, 17 nondeprived smokers, and 19 nonsmokers. RESULTS: Smokers' N300 amplitudes over fronto-central scalp were larger to neutral than to smoking-related stimuli, thus reflecting N300 smoking cue-reactivity. N300 cue-reactivity was greater for deprived than for nondeprived smokers. Smokers' P300 values were greater to smoking-related than to neutral stimuli, particularly over the centro-parietal area; however, nonsmokers also showed a P300 main effect to smoking cues. Smoking deprivation did not affect P300 cue-reactivity, nor did deprivation affect self-reported urges to smoking relative to neutral cues. CONCLUSIONS: These data confirm the sensitivity of ERPs to tobacco cues in smokers and suggest, additionally, that the cue-reactivity of the N300 component is modulated by smoking deprivation. N300 cue-reactivity may reflect an internally generated priming of the semantic network related to the smokers' need states. Stimulus-category differences in P300 may reflect cue-reactivity in smokers and/or nonaddiction-specific factors in both smokers and nonsmokers.     

Central and peripheral effects of angiotensin II on the cardiovascular response to exercise

The authors tested the hypothesis that angiotensin II modulates cardiovascular responses to dynamic exercise via peripheral and central effects on the autonomic nervous system. Ten subjects performed three identical exercise tests during treatment with placebo, valsartan (an angiotensin II type 1 receptor blocker), or enalapril (an angiotensin-converting enzyme inhibitor). With placebo, plasma concentrations of angiotensin II, norepinephrine, and epinephrine were elevated during cycling at 80% of heart rate reserve (HRR). Enalapril attenuated increases in heart rate, mean arterial pressure (MAP), and catecholamines during cycling, whereas valsartan only attenuated MAP and rate-pressure product above 60% HRR, and norepinephrine. The different responses provoked by the two drug treatments suggest that angiotensin-converting enzyme inhibition affects cardiovascular responses to exercise by mechanisms unrelated to production of angiotensin II. Indices of autonomic function during dynamic exercise were not changed by either drug. Attenuation of norepinephrine release during exercise by valsartan suggests that angiotensin II facilitates the release of norepinephrine from sympathetic postganglionic neurons. Angiotensin II, therefore, contributes to the pressor response to exercise by inducing peripheral vasoconstriction and facilitation of norepinephrine release from postganglionic sympathetic nerve endings that are unrelated to central activation of the autonomic nervous system.