Workshop on the Chernoff/Kavlock preliminary developmental toxicity test

The Chernoff/Kavlock assay, proposed as a preliminary screen for teratogenic potential, was the subject of a 2-day workshop sponsored by the National Institute for Occupational Safety and Health. Data from three large testing programs were presented, representing tests of 165 chemicals, of which 33 were tested at least twice. Applications of the test in industrial laboratories and product development, hazard identification, and risk assessment were discussed. Workshop participants recognized the assay as one of several valid ways to preliminarily evaluate chemicals with unknown developmental toxicity. Other preliminary tests were also discussed in terms of their relationship to this test, which was seen as having the advantage of providing information on neonatal viability. Other techniques, particularly an abbreviated conventional teratology study, were also recognized as appropriate screens. The preferred test in a particular laboratory will be dependent upon the particular skills and objectives of that laboratory. Standardized protocols were suggested, but flexibility in experimental design was considered necessary, and many variations on the basic test could be appropriate. This preliminary test has been used most often as a single-dose test in mice, but might provide more generally useful data if conducted in rats using two dose levels. Workshop participants viewed the test as highly reliable in correctly identifying developmentally toxic chemicals and suggested that a negative finding in a properly conducted Chernoff/Kavlock test could be a sufficient basis for regulatory agencies to determine that conventional teratology tests in the same species are not warranted.     

Inhibition of platelet aggregation following chronic in vivo treatment of rats with nicotine: prevention by simultaneous application of propranolol

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5'-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 mumol/L in nicotine-treated animals, as compared with 0.67 mumol/L in controls (p less than 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the beta blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 mumol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1 (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, prolonged application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by beta-catecholaminergic stimulation of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Provider satisfaction with office-based treatment of opioid dependence: a systematic review.

PURPOSE: New federal regulations allow for office-based treatment of opioid dependent patients with opioid agonist medication (e.g., buprenorphine). We sought to evaluate the literature on office-based physicians' acceptance of this practice. METHODS: We searched the MEDLINE database for original research examining office-based providers' acceptance or satisfaction with office-based treatment. Articles included in the analysis met the following criteria: (1) discussed the treatment of patients with substance abuse disorders, (2) focused on the treatment of opioid dependent patients, (3) discussed treatment with opioid agonist therapy, (4) discussed treatment by office-based physicians, (5) presented original research, and (6) provided data examining physician acceptance or satisfaction. RESULTS: Eight studies met the criteria. Their heterogeneity precluded aggregate analysis. Four of 8 studies revealed that providers had a positive perception concerning the efficacy of opioid agonist treatment, 4/8 indicated that providers believed that opioid dependent patients were more complex than others in their practices, and 3/8 studies indicated the need for additional support services. CONCLUSIONS: There are few studies of provider satisfaction with office-based treatment of opioid dependence. This literature reveals overall provider acceptance of this practice but highlights the need for support services. Further research, designed to identify the barriers to provider satisfaction with office-based opioid agonist therapy, is needed to ensure that these barriers do not limit expansion of this practice.     

The impact of the Texas 1989 motorcycle helmet law on total and head-related fatalities, severe injuries, and overall injuries.

The State of Texas implemented a mandatory total motorcycle helmet law for all operators and passengers, effective September 1, 1989. In this study the impact of this intervention on frequency of both total and head-related fatalities, severe injuries, and overall injuries for operators during the subsequent year was quantified. This quantification is important because 26 states in the United States fail to have strict, mandatory helmet laws. The Box-Tiao time-series intervention methodology is used to estimate secular trends before and changes after the implementation of the law, analyzing Department of Public Safety monthly injury accident data for a period of 6 years collected from traffic accident reports filed for each motorcycle injury accident. Trends in fatalities and injuries (except for head-related deaths) estimated before implementation of the law approximated the 9.4% average annual decline in motorcycle registrations. Additional declines of 12.6% and 57.0%, respectively, were estimated for total and head-related fatalities during the year after the law was implemented. Declines of 13.1% and 54.6% were estimated for severe injuries for total and head-related accidents. Declines of 12.3% and 52.9% were found for total and head-related injuries overall.     

Initial cranial CT scan for the assessment of prognosis in head injury

Summary A total of 208 multiple trauma patients with head injury (HI) were investigated who had been treated in the period from 1990 to 1995. The average age was 35.2 ± 17.7 years; the injury severity according to ISS was 30.2 ± 8.6 points; 20.5 % died as a result of the HI; the mortality of all patients was 26.5 %. The Glasgow Coma Scale (GCS) was determined at an average of 22 min after trauma (8.0 ± 4.3 points) at the scene of accident. The patients were classified according to GCS into minor HI (group 1: 14–15 points), moderate HI (group 2: 9–13 points) and severe HI (group 3: 3–8 points). Patient outcome was assessed by the Glasgow Outcome Scale (GOS) and was classified as good (GOS 4 and 5) and poor (GOS 1, 2 and 3) outcome. At the latest, 2 h after trauma, a CT scan of the head (CCT) was done. The HI groups are compared regarding frequency of types of injury. In all HI groups the fractures of the bony face occurred at the same frequency (36.0–38.9 %). The frequency of calotte fractures (Kal-Fx) increased from group 1 (8.0 %) to 2 (19.2 %) and 3 (25.6 %); fractures of the skull base significantly differed between group 1 (16.0 %), 2 (7.8 %) and 3 (33.4 %). Epidural hemorrhage (EDB) appeared only in group 2 (7.8 %) and 3 (6.7); subdural hemorrhage was found in group 1 (2.7 %), 2 (7.8 %) and 3 (10.0 %). Subarachnoid hemorrhage (SAB) was significantly more frequently seen, dependent on HI severity, in group 3 (26.7 %) compared to group 2 (11.7 %) and 1 (8.0 %). Intracerebral contusion (ICK) significantly increased from group 1 (12.0 %) to 2 (27.3) and 3 (45.6 %). Brain swelling (BS) also significantly increased from group 1 (8.0 %) to 2 (19.5 %) and 3 (49.0 %) and lesions of ventricles (VL) from group 1 (2.7 %) to 2 (11.7 %) and 3 (20.0 %). Midline shift (13.4 %) and signs of herniation (4.5 %) only occurred in group 3. The analysis of correlation/regression and receiver operating characteristics was able to predict 79 % of patients' outcome accurately using GCS (r 0.54; P < 0.0001) alone, using CCT (r 0.65; P < 0.0001) 87 % were correctly predicted with significant variables Cal-Fx, EDB, SAB and BS. CCT with GCS (r 0.74; P < 0.0001) were able to predict 88 % accurately with significant variables Cal-Fx, EDB, BS and GCS. The combination of CCT with GCS, age and ISS (r 0.78; P < 0.0001) was able to predict only 87 % correctly, although the r value was the highest; significant variables were Kal-Fx, EDB, BS, VL, GCS, age and ISS.      

Role of Alcohol-induced Hypothermia in Mediating the Teratogenic Effects of Alcohol in C57BL/6 J Mice

The purpose of this study was to determine the role of alcohol-induced maternal hypothermia in the teratogenic actions of alcohol. C57BL/6J mice were administered an acute dose of alcohol (5.8 g/kg orally) or isocaloric sucrose on day 10 of gestation. One half of each group was placed for 6 hr in an incubator set at 32 degrees C and the other half was housed in the incubator at room temperature (22 degrees C). As expected, acute prenatal alcohol exposure at this time of gestation was associated with decreased birth weight and an increase in limb and kidney malformations. The significant alcohol x environmental temperature interaction on these dependent variables indicated that the teratogenic insult was not attenuated, but was in fact even greater for the 32 degrees C/alcohol group. An absence of a main effect of environmental temperature indicated that the 32 degrees C environment, per se, was not teratogenic. Thus, maternal hypothermia is probably not an etiological factor in animal models of fetal alcohol syndrome. Moreover, antagonism of alcohol-induced maternal hypothermia exacerbates the teratogenic actions of alcohol observed at room temperature.