Tolerance to the discriminative stimulus effects of midazolam: evidence for environmental modification and dose fading

The ability of behavioral variables to modify the development of tolerance to the discriminative stimulus effects of midazolam was evaluated. Rats were trained to discriminate 0.32mg/kg s.c. or 1.0mg/kg i.p. midazolam from no-drug, under a two-lever procedure, in daily experimental sessions consisting of multiple discrete 20-min trials: 15-min time-out, followed by 5-min under a fixed-ratio 15 schedule of food pellet delivery. Generalization testing was accomplished by administering progressively increasing doses of midazolam before each time-out period. During the chronic phases, twice daily injections of 10mg/kg midazolam or saline were given while discrimination training was either suspended or continued; generalization gradients for midazolam were determined weekly for 4 weeks. Chronic saline given when training was continued or suspended produced slight fluctuations in the midazolam minimal discriminable dose (MDD) (the first dose of midazolam in an individual generalization gradient to produce >/=90% drug-lever responding). Tolerance developed to the discriminative stimulus effects of midazolam when chronic midazolam was given while training was suspended: at Week 4, chronic midazolam produced 3-to 57-fold rightward shifts in the midazolam generalization gradient. In contrast, continued training during chronic midazolam produced no tolerance to the discriminative stimulus effects of midazolam: at Week 4 of chronic midazolam the MDD of midazolam was not different from pre-chronic and not different from either saline condition. The effects of chronic midazolam on stimulus effects and response rates were differentiated: despite tolerance to the stimulus effects of midazolam, there were no consistent changes in response rates during chronic midazolam administration.     

Heroin in the United Kingdom: different forms, different origins, and the relationship to different routes of administration

Heroin exists in the United Kingdom in several different forms, which vary not only in their country of origin and purity, but also in their suitability for use by either injecting or by 'chasing the dragon'. The availability of these different forms of heroin has varied considerably over time. A review of the characteristics and availability of these various forms of heroin in recent years is presented, accompanied by consideration of their probable intended use by injection or by 'chasing the dragon'. Samples of black market heroin in the salt form are usually used by injection, whereas the base form is usually taken by 'chasing the dragon'. The heroin yield to the drug user from samples of heroin taken by 'chasing the dragon' varies according to its base or salt format and according to the presence of other drugs in the sample. Heroin samples from different countries of production mostly conform to either base or salt form. Novel approaches at the macro level to prevention and control of heroin-related problems through influence upon this complex heroin market-place should now be considered.     

Acid aspiration prophylaxis in 202 obstetric anaesthetic units in the UK

A postal survey of obstetric anaesthetic units in the UK was conducted by questionnaire to gain information about current acid aspiration prophylaxis. Information regarding the delivery rate and the caesarean section rate under regional techniques was also requested. Replies were received from 202 obstetric anaesthetic units in the UK, a 75% response rate. The results are compared to similar surveys carried out in 1984 and 1988. Sodium citrate and the H(2) antagonist ranitidine remain the drugs most commonly used for acid aspiration prophylaxis. However, the number of departments carrying out routine prophylaxis for patients in active labour has fallen from 75% in 1988 to 57% in the current survey.     

Discriminative-stimulus effects of azaspirodecanedione anxiolytics in baboons trained to discriminate beta-carboline-3-carboxylic acid ethyl ester or pentylenetetrazole

Baboons were trained to discriminate either pentylenetetrazole (PTZ) or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) from the no-drug condition. Both drugs specifically bind sites in the gamma-aminobutyric acid A (GABA(A)) receptor complex and decrease GABAergic transmission. beta-CCE occasioned drug-lever responding in baboons trained to discriminate PTZ and vice versa. Flumazenil, the benzodiazephine receptor antagonist, blocked beta-CCE, consistent with beta-CCE's receptor binding activity. The azaspirodecanedione anxiolytics buspirone and ipsapirone produced full generalization in all baboons; gepirone and tandospirone yielded full generalization in some baboons and partial in others. These anxiolytics are inactive in the GABA(A) complex and potently bind 5-HT(1A) sites. A specific 5-HT(1A) ligand, 8-hydroxy-2-(di-n-propylamino)tetralin, produced generalization similar to gepirone and tandospirone, which show the most specific 5-HT(1A) binding. The major azaspirodecanedione metabolite, 1-(2-pyrimidinyl)piperazine (an alpha(2)-adrenergic antagonist), occasioned the least drug-appropriate responding. Full generalization to buspirone and ipsapirone may have resulted from dopaminergic or alpha(1)-adrenergic activity combined with 5-HT(1A) activity. The molecular mechanism of the generalization profile for PTZ and beta-CCE shown by the present results is unclear. The data may reflect altered relationships between GABAergic and serotonergic transmission, and altered stimulus effects of the training drugs, in the context of chronically decreased GABAergic transmission.     

Expression of an ovalbumin-specific V{beta}8.2 TCR transgene inhibits collagen arthritis in B10.Q mice

Previous studies have illustrated the importance of T cellsbearing ß TCRs in the induction and development ofcollagen induced arthritis (CIA) in mice. However, the scopeof TCR usage in CIA has yet to be clearly defined. Given theinherent diversity of the TCR repertoire, the relative flexibilityof the arthritogenic TCR repertoire specific for type II collagen(CII) is not clear. Therefore, we chose to examine the influenceof a highly skewed TCR repertoire on CIA. Arthritis susceptibleB10.Q (H-2^q) mice were mated with C57L (H-2^b) animals expressingan ovalbuminspecific V_ß8.2 TCR transgene (Tg) andTg⁺ offspring were further backcrossed to B10.Q. HomozygousH-2^a/q, V_ß8.2 Tg⁺ mice displayed a high level of V_ß8.2⁺T cells in peripheral blood. However, expression of some endogenousV_ß TCR, such as V_ß14, was still detected.Upon immunization with bovine CII in adjuvant, V_ß8.2Tg⁺ mice were highly resistant to CIA when compared with Tg^–littermates. Analysis of sera demonstrated a marked reductionin antibody specific for homologous mouse CII as well as heterologousbovine CII in Tg⁺ animals. Interestingly, V_ß8.2 Tg⁺mice still mounted good antibody responses following immunizationwith human thyroglobulin, indicating that the skewed TCR repertoireaffected anti-CII but not antithyroglobulin responses. Thus,our findings show that constraints placed on the TCR repertoireInhibit pathogenic responses against CII and suggest that inH-2^q mice the arthritogenlc TCR repertoire bears only limitedflexibility.     

Heterosexual anal intercourse, health risks and drug use: a review with special attention to drug users

Research studying HIV risk-taking behaviour has tended to focus on specific populations who are characterized by particular behaviours. Such practices include the extent of unprotected anal intercourse among homosexual men, the sharing of injecting equipment among drug users and unprotected vaginal intercourse among female sex workers. There is often a failure among both researchers and practitioners to address specific risk behaviours outside of the defined risk group. Reviewed here are studies of heterosexual anal intercourse, with special attention to drug users and female sex workers.

Among the general population, the reporting of heterosexual anal intercourse varies greatly across time and cultural groups. However, a body of recent research suggests that, despite some geographical differences, rates in most countries are relatively high. Many studies have also found that associated condom usage is low. Although unprotected anal intercourse is known to be an efficient method for the transmission of HIV and other viral infections, it has rarely been addressed outside cohorts of men who have sex with men. Of particular concern is the interaction of risk behaviours among drug users and women engaging in prostitution, many studies having found high levels of unprotected anal intercourse among these groups. Harm reduction interventions must address all the health risk behaviours their target groups are engaging in, if the challenge of reducing the transmission of HIV and other viral infections is to be met.     

Diffuse lymphangiomatosis of bone

Two cases of lymphangiomatosis of bone, a very rare systemic condition characterized by both skeletal and parenchymal lesions, are presented. The skeletal changes have an appearance similar to haemangiomas in the spine, and soap-bubbly lesions in the flat bones. One case carried the diagnosis of eosinophilic granuloma for 18 years. The findings on MRI, which have not been previously well-established, are discussed.