Rapid desensitization determines the pharmacology of glutamate neurotoxicity

Glutamate (Glu), the major excitatory neurotransmitter in the nervous system, is toxic to neurons when it accumulates at high concentrations in the extracellular space. Even though Glu is a mixed agonist, capable of activating N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, in many preparations Glu neurotoxicity is prevented by selective blockade of NMDA receptors. In cultures of hippocampal neurons, treatment with 500 microM Glu for 30 min killed more than 90% of the neurons. The simultaneous addition of the selective NMDA agonist methyl-10,11-dihydro-5-H-dibenzocyclo-hepten-5,10-imine (MK-801) reduced the cell loss to less than 30%. However, when Glu was combined with either diazoxide or cyclothiazide, two thiazides which dramatically diminish rapid Glu desensitization, MK-801 was no longer very protective and neuronal loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in combination with MK-801, was able to prevent most Glu neurotoxicity in the presence of these thiazides. These experiments show that there are circumstances under which Glu neurotoxicity is produced by overactivation of non-NMDA receptors. Our observations offer a possible explanation for the recent finding that blockade of non-NMDA receptors is much more beneficial than NMDA receptor blockade in protecting the brain in some in vivo models of global ischemia.     

Biobehavioral aspects of menopause: lessons from the Healthy Women Study

The Healthy Women Study is an ongoing natural history study of the menopause in a sample of relatively healthy women. We report data from this paper on the behavioral and biological changes that occur during the transition from pre- to postmenopausal status and argue for the importance of behavioral change interventions to prevent or attenuate some of the adverse changes due to the menopause.     

The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.     

Present systems and future needs for risk assessment of veterinary biologicals in Australia: the perspective of the regulator

The increasing range and complexity of biologicals, and the greater demand for these products, have resulted in a greater volume of trade in animal-based biological material. This has given rise, in turn, to many approaches to the regulation of importation of these materials, as countries seek protection against the introduction of disease. Harmonization of these regulatory approaches would contribute significantly to the availability of veterinary biologicals, to their manufacture and trade, and to disease security. Australia has developed systems for the categorisation and evaluation of biologicals, control by import permits, and specific procedures at point-of-entry and in institutions where these products are used. Computerised records and precedents assist in evaluation and in the issuing of permits. Recognition that some materials must be subject to further control has led to a system of registration of institutions based on levels of biosecurity, and approved use and disposal programmes. Institutions vary from high-security animal health laboratories to human in vitro fertilisation clinics, which use animal-derived media and materials. Such institutions are regulated through quality assurance contracts. Quarantine authorities have linkages with other agencies which have an interest in these products. These linkages reflect the administrative structures of government in Australia, and provide for management of all forms of risk. The author describes these systems and overviews their biological basis.