␣-Thujone is the toxic agent in absinthe, a liqueur popular in the 19th and early 20th centuries that has adverse health effects. It is also the active ingredient of wormwood oil and some other herbal medicines and is reported to have antinociceptive, insecticidal, and anthelmintic activity. This study elucidates the mechanism of ␣-thujone neurotoxicity and identifies its major metabolites and their role in the poisoning process. Four observations establish that ␣-thujone is a modulator of the ␥-aminobutyric acid (GABA) type A receptor. First, the poisoning signs (and their alleviation by diazepam and phenobarbital) in mice are similar to those of the classical antagonist picrotoxinin. Second, a strain of Drosophila specifically resistant to chloride channel blockers is also tolerant to ␣-thujone. Third, ␣-thujone is a competitive inhibitor of [ 3 H]ethynylbicycloorthobenzoate binding to mouse brain membranes. Most definitively, GABA-induced peak currents in rat dorsal root ganglion neurons are suppressed by ␣-thujone with complete reversal after washout. ␣-Thujone is quickly metabolized in vitro by mouse liver microsomes with NADPH (cytochrome P450) forming 7-hydroxy-␣-thujone as the major product plus five minor ones (4-hydroxy-␣-thujone, 4-hydroxy-␤-thujone, two other hydroxythujones, and 7,8-dehydro-␣-thujone), several of which also are detected in the brain of mice treated i.p. with ␣-thujone. The major 7-hydroxy metabolite attains much higher brain levels than ␣-thujone but is less toxic to mice and Drosophila and less potent in the binding assay. The other metabolites assayed are also detoxification products. Thus, ␣-thujone in absinthe and herbal medicines is a rapid-acting and readily detoxified modulator of the GABA-gated chloride channel.

Patients with focal dystonia take advantage of certain cutaneous or proprioceptive sensory inputs to alleviate their symptoms ("sensory trick"). We examined the effects of increasing muscle spindle activity by the tonic vibration reflex maneuver and decreasing it by intramuscular injection of lidocaine. The vibration was applied to the palm or the tendon of forearm muscles in 15 patients with writer's cramp and 15 age-matched normal subjects. In 11 patients, the vibration induced dystonic postures or movements typical of those seen during writing. Normal subjects showed either no response to the vibration or a gradually developing tonic vibration reflex only in the wrist and finger flexors, which produced visible movements with a significantly longer latency (12.5 +/- 6.7 seconds [mean +/- standard deviation]) than what was observed in the patients (2.7 +/- 2.5 seconds, p < 0.0001). Local injection of lidocaine (0.5%, 5-40 ml/muscle) attenuated the tendon reflex with relatively little effect on the M response. Injection into muscles with increased activity produced marked reduction of dystonic movements and significant clinical improvement in 13 patients, whereas injection into the other muscles had no effect. The clinical benefit lasted for 1 to 24 hours after injection. In 13 patients who had additional injections of 10% ethanol, which blocks sodium channels for a longer period than does lidocaine, the duration of action was prolonged to 5 to 21 days. These findings suggest that muscles causing dystonic movements have abnormal sensitivities to vibration at rest and that muscle afferents may play a pivotal role in producing dystonic movements.(ABSTRACT TRUNCATED AT 250 WORDS)

These data point to an independent relationship between psychosocial job stress and self-reported occupational injury in SMEs.

1 Anisatin, a toxic, insecticidally active component of Sikimi plant, is known to act on the GABA system. In order to elucidate the mechanism of anisatin interaction with the GABA system, wholecell and single-channel patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. 2 Repeated co-applications of GABA and anisatin suppressed GABA-induced whole-cell currents with an EC 50 of 1.10 mM. No recovery of currents was observed after washout with anisatin-free solution.3 However, pre-application of anisatin through the bath had no eect on GABA-induced currents. The decay phase of currents was accelerated by anisatin. These results indicate that anisatin suppression of GABA-induced currents requires opening of the channels and is use-dependent. 4 Anisatin suppression of GABA-induced currents was not voltage dependent. 5 Picrotoxinin attenuated anisatin suppression of GABA-induced currents. [ 3 H]-EBOB binding to rat brain membranes was competitively inhibited by anisatin. These data indicated that anisatin bound to the picrotoxinin site. 6 At the single-channel level, anisatin did not alter the open time but prolonged the closed time. The burst duration was reduced and channel openings per burst were decreased indicating that anisatin decreased the probability of openings.

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We have studied the antitumor activity and the novel DNA‐self‐strand‐breaking mechanism of CNDAC (1‐(2‐C‐cyano‐2‐deoxy‐β‐d‐arabino‐pentofuranosyl)cytosine) and its N4‐palmitoyl derivative (CS‐682). In vitro, CS‐682 showed strong cytotoxicity against human tumor cells comparable with that of CNDAC; both compounds displayed a similar broad spectrum. In vivo, however, orally administered CS‐682 showed a more potent activity against human tumor xenografts than CNDAC, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 2′,2′‐difluorodeoxycytidine. Moreover, CS‐682 was effective against various human organ tumor xenografts at a wide dose range and with low toxicity, and was effective against P388 leukemic cells resistant to mitomycin‐C, vincristine, 5‐fluorouracil or cisplatin in syngeneic mice. CNDAC, an active metabolite of CS‐682, had a prolonged plasma half‐life after repeated oral administrations of CS‐682 but not after oral administrations of CNDAC itself. This difference may partially explain the higher antitumor activity of CS‐682 relative to CNDAC. In both CNDAC‐ and CS‐682‐treated carcinoma cells, CNDAC 5′‐triphosphate (CNDACTP) was generated and incorporated into a DNA strand. High performance liquid chromatography (HPLC) and mass spectrometric analysis of the nucleosides prepared by digestion of the DNA from the CNDAC‐treated cells detected ddCNC (2′‐C‐cyano‐2′,3′‐didehydro‐2′,3′‐dideoxycytidine), which was shown to be generated only when the self‐strand‐breakage of CNDACTP‐incorporated DNA occurred. The cytotoxicity of CNDAC was completely abrogated by the addition of 2′‐deoxycytidine and was low against cells with decreased deoxycytidine kinase. Our results suggest that CNDAC is converted to CNDACMP by deoxycytidine kinase and that the resulting CNDACTP incorporated into a DNA strand as CNDACMP may induce DNA‐self‐strand‐breakage. This novel DNA‐self‐strand‐breaking mechanism may contribute to the potent antitumor activity of CS‐682. Int. J. Cancer 82:226–236, 1999. © 1999 Wiley‐Liss, Inc.

A cross-sectional study evaluated the contribution of daily sleep habits to occupational injuries. A self-administered questionnaire solicited answers about sleep, symptoms of depression, occupational injury, demographics, presence of diseases and lifestyle factors from 2,903 workers between the ages of 16-83 (mean 45) yr in small and medium-scale enterprises. Eight sleep habits were queried and dichotomized: 1) less or more than 6 hr of daily sleep, 2) taking more or less than 30 min to fall asleep (Difficulty initiating sleep; DIS), 3) awakening during sleep more or less than 3 times/wk (Difficulty maintaining sleep; DMS), 4) early morning awakening more or less than 3 times/wk (EMA), 5) definitely/somewhat difficulty waking up or not, 6) sleeping very poorly/not so well at night or not, 7) definitely/somewhat insufficient nightly sleep or not, and 8) difficulty in breathing during sleep more than once/week or less. Occupational injury was assessed by asking subjects 'Have you ever been injured during your work, including minor scratches and cuts (Yes/ No)?' Both sleep and injury were assessed over the previous one year period. One-third of workers answered that they had experienced injury. Workers with sleep features of DIS, sleeping poorly at night, insufficient sleep, and insomnia had a significantly higher prevalence for injury after adjusting for multiple confounders. The findings suggest that poor nocturnal sleep habits are associated with self-reported occupational injury.

The Prevalence and Correlates of Occupational Injuries in Small-Scale ManufacturingEnterprises: Akinori NAKATA, et al. National Institute of Occupational Safety and Health-Workers involved in small-scale manufacturing businesses are known to comprise a high-risk population for occupational injury. The present study investigated the prevalence and correlates of occupational injury in this population. A self-administered questionnaire that solicited answers about occupational information including injury, demographic characteristics, health conditions and lifestyle factors was collected from a sample of 1,298 workers in 228 small-scale manufacturing enterprises (defined as fewer than 50 workers) aged 16-78 (mean 46) yr in Yashio city, Saitama, Japan (response rate 65.5%). The enterprises were randomly selected from the 2000 edition of the city commercial directory corresponding to the distribution of types of businesses in the city. Occupational injury was assessed by asking subjects, 'Have you ever been injured during your work, including minor scratches and cuts in the previous 1-yr period?' The possible response was either 'yes' or 'no.' The prevalence of study-defined occupational injury among the workers was 35.6% (male 43.0%, female 17.9%). Among job types, manufacturing (44.2%) and driving (43.5%) had high rates of occupational injuries. Similarly, occupational injuries were high in the papermaking (54.5%) and machinery (47.7%) industries. For males, younger age, current or former smoking, insomnia symptoms, and disease(s) currently under treatment were correlated with injury, whereas for females, being unmarried, higher educational status, and insomnia symptoms were the correlating factors. Occupational injury is common among small-scale manufacturing businesses, and is associated with multiple controllable factors. Countermeasures such as prohibiting smoking during work, sleep health education, job safety training for young/inexperienced workers are appropriate methods for eliminating or reducing injuries. (J Occup Health 2006; 48: 366-376)