Effects of cocaine alone and in combination with bromocriptine in human cocaine abusers.

This study was conducted to determine whether the acute administration of bromocriptine, a dopamine agonist, modulates the acute pharmacologic effects of i.v. cocaine in humans. Eight current users of i.v. cocaine who were not seeking treatment for their cocaine abuse completed the study while they were inpatients on a research unit. Twelve drug conditions were tested in all subjects in randomized order under double-blind, double-dummy conditions and included cocaine (0, 12.5, 25 and 50 mg, i.v.) in combination with bromocriptine (0, 1.2 and 2.5 mg given orally 2 hr before the cocaine injection). Physiologic and subject- and observer-rated responses were measured. Cocaine alone significantly increased pupil diameter, heart rate and blood pressure, and ratings of drug effect, good effects, liking and rush. Bromocriptine alone significantly increased pupil diameter and heart rate, decreased blood pressure and had only minor effects on subjective measures. There were significant cocaine/bromocriptine interactions on diastolic and mean arterial blood pressure, with combinations producing significantly smaller increases compared to cocaine alone, and on heart rate, with combinations producing significantly larger increases compared to cocaine alone. The physiologic and subjective effects of cocaine were not modified by pretreatment with bromocriptine in any other way that might indicate either a therapeutic benefit or a safety concern. However, bromocriptine alone produced undesirable effects (fainting) that should be considered before administration to outpatient cocaine abusers. Any possible therapeutic benefits of acute administration of bromocriptine in cocaine abuse are not likely to be due directly to modulation of the acute effects of cocaine.     

Enhancement of cocaine's abuse liability in methadone maintenance patients

The present study was conducted to determine whether methadone maintenance alters the pharmacodynamic effects of single doses of cocaine. Twenty-two current users of IV cocaine who were not seeking treatment for their illicit cocaine use participated while living on a research unit. Eleven were maintained on methadone 50 mg PO daily as treatment for their opioid abuse; 11 were opioid abusers who were not physically dependent on opioids and who provided opioid-free urines throughout the study. Each subject received acute cocaine challenge doses of 0, 12.5, 25, and 50 mg intravenously in random order under double-blind conditions in separate test sessions. Physiologic and subject-rated responses were measured before injection and for 2 h after. In the methadone maintenance group, cocaine challenge sessions occurred 15.5 h after the daily methadone dose. There were significant differences between the methadone-dependent and nondependent groups: 1) baseline differences related to chronic methadone administration and not associated with cocaine administration (lower respiration rates and pupil diameter; higher skin temperature) and 2) differences in response to cocaine administration; cocaine-induced increases in subject ratings of Drug Effect, Rush, Good Effects, Liking, and Desire for Cocaine and in heart rate were greater in the methadone maintenance patients compared to the non-dependent group. These results indicate that the positive subjective effects and some physiological effects of cocaine are enhanced in methadone-maintained individuals, suggesting a pharmacological basis for the high rates of cocaine abuse among methadone maintenance patients.Some of these data were presented at the annual meeting of the Committee on Problems of drug Dependence, Keystone, Colorado, June 1992     

Bilateral fracture dislocation of the sacroiliac joint

 We present a rare case of a 27-year-old man sustaining a bilateral fracture dislocation of the sacroiliac joints without disruption of the anterior pelvis, following a fall from a height. Reconstructed images in the coronal plane and three-dimensional CT images were invaluable in the diagnosis and assessment of this injury.     

Chameleon voices: Interpreting for deaf parents

As interpreters for their deaf parents, hearing children are a cultural link between two often separate worlds: the Deaf and the Hearing. Data from a 4 year study of adult hearing children throughout the United States indicate significant differences between hearing daughters and hearing sons. Not only were daughters more likely than sons (regardless of birth order or age differences) to interpret for their parents, but daughters were also far more likely to be bilingual: fluent in both spoken English and American Sign Language. A similar gender bias has been observed among the general hearing public: women are far more likely to attend sign language classes and to work as interpreters for the deaf. This paper explores the social mechanisms and cultural values which determine the gender of the way we communicate with one another. Informants' narratives suggest that sign language and the practice of interpreting often touched upon a larger pattern of socialization and status differences between women and men. The discussion then turns to consider how these differences affect the cultural identity of hearing sons versus hearing daughters.     

The scopolamine model of dementia: chronic transdermal administration

The transient impairments of memory produced by the muscarinic antagonist scopolamine have been adopted as a pharmacological model of Alzheimer-type dementia in normal volunteers. In this study we examined the effects of chronic (72 h) transdermal administration of scopolamine on memory, attention, sedation and visual function. The transdermal patches provided constant plasma levels of scopolamine for the duration of the study. Indices of the peripheral effects of scopolamine (visual near-point and pupil size) showed impairments that were sustained for 3 days. However, measures of sedation and memory revealed impairments that were maximal the day after patch application and which were no longer present 3 days after application. This pattern of results is discussed in relation to pharmacological modelling of Alzheimer's disease.     

Candidate gene analysis in human neural tube defects

Biochemical and developmental pathways, mouse models, and positional evidence have provided numerous candidate genes for the study of human neural tube defects. In a survey of 80 studies on 38 candidate genes, few found significant results in human populations through case-control or family-based association studies. While the folate pathway has been explored extensively, only the MTHFR 677C > T polymorphism was significant, and only in an Irish population. Developmental pathways such as the Wnt signaling pathway and Hox genes have also been explored without positive results. More than 90 mouse candidates have been identified through spontaneous and knockout mutations, but only the T locus (mouse Brachyury gene) showed association in an initial study that was not confirmed on follow-up. Positional candidates have been derived from cytogenetic evidence, but preliminary genomic screens have limited power due to small sample sizes. Future studies would increase their power to detect association by using more samples. In addition a clarification of the phenotype would be beneficial as many studies used different inclusion criteria. Incorporating several types of data could highlight better candidates, as would looking beyond the traditional sources for candidate genes. Recent studies of an energy metabolism gene (UCP2) and vitamin B metabolism (Transcoalbumin) have produced promising results. Utilizing other model organisms may also be beneficial, as in a recent study from a chick model of NTDs in NCAM1. New approaches combined with traditional methods and increased sample sizes will help prioritize human NTD candidate genes and clarify the complex etiology of this condition.     

Vagal stimulation and somatostatin potentiate cardiac vagal action in the toad, Bufo marinus.

Cholinergic postganglionic neurones of the cardiac vagus in the toad, Bufo marinus, have been shown to contain the peptide somatostatin (SOM), which causes direct negative inotropic and chronotropic effects on the heart. In anaesthetised toads, high frequency stimulation (10 Hz) of cardiac vagus nerves results in prolonged cardiac slowing and potentiation of the cardiac slowing measured in response to a train of vagal stimuli at low frequency. Intravenous administration of the tetradecapeptide form of SOM also results in prolonged cardiac slowing and potentiation of cardiac vagal action. Effects on heart rate of small bolus doses of acetylcholine (ACh) were unaltered by administration of SOM, at the same time as cardiac vagal slowing was enhanced. It is suggested that SOM is released from vagal nerve endings by high frequency stimulation and enhances cardiac vagal action by a presynaptic mechanism.