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.     

Measurement of initial N-acetyl aspartate concentration by magnetic resonance spectroscopy and initial infarct volume by MRI predicts outcome in patients with middle cerebral artery territory infarction.

BACKGROUND AND PURPOSE: (1)H MR spectroscopy can be used to study biochemical changes occurring in the brain in stroke. We used it to examine the relationship between metabolite concentration (N-acetyl aspartate [NAA], lactate, cholines and creatines), size of infarct, clinical deficit, and 3-month clinical outcome in patients with middle cerebral artery (MCA) territory infarction. METHODS: Thirty-one patients with acute MCA territory infarction were recruited within 72 hours of the onset of symptoms. Single-voxel short echo time stimulated echo acquistion mode spectroscopy was used to obtain metabolite data from the infarct core. Metabolite concentrations were determined with use of variable projection time domain-fitting analysis. Infarct size was determined with T2-weighted images. Patient outcome groups at 3 months were "independent," "dependent," or "dead." RESULTS: All patients (100%; 95% CI 75% to 100%) who had an infarct >70 mL did poorly. Eighteen of 20 patients (90%; 95% CI 68% to 99%) with a core NAA concentration <7 mmol/L did poorly at 3 months, whereas 7 of 11 patients (64%; 95% CI 31% to 89%) with an initial NAA concentration >7 mmol/L did well. Combining these results showed that all patients who had an initial infarct volume >70 mL did poorly, irrespective of the NAA concentration. Of those patients with infarcts <70 mL, those who had a core NAA concentration >7 mmol/L did well (88%; 95% CI 47% to 100%), whereas those with a lower NAA concentration did poorly (80%; 95% CI 44% to 97%). There was no association between other metabolite concentrations and outcome. CONCLUSIONS: Infarct volume and NAA concentration can together predict clinical outcome in MCA infarction in humans.     

The epidemiology of acute hepatitis A in north Queensland, 1996-1997.

Details on all cases of hepatitis A notified in North Queensland in 1996 and 1997 were prospectively collected. There were two substantial outbreaks and a total of 225 cases during this period. The total incidence rate (per 100,000) was 11.0 in 1996 and 27.0 in 1997. Aborigines and Torres Strait Islanders constituted 29% of cases and had incidence rates of 75.2 and 62.7 per 100,000 for 1996 and 1997 respectively. Thirty-nine cases (17.3%) were admitted to hospital for a total of 202 bed-days and a 4 year old died with fulminating hepatitis. A probable source of infection was identified for 69% of cases. The common risk categories for infection were: living in or visiting a rural Aboriginal or Torres Strait Islander community, injecting drug use, contact with a known case of hepatitis A, and travel to countries with endemic hepatitis A.     

Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.