1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of w-phosphonic x-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 When tested on dorsal root-evoked ventral root potentials, members of the homologous series from 2-amino-5-phosphonovaleric acid to 2-amino-8-phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectively motoneuronal depolarizations induced by N-methyl-D-aspartate. of this substance had a relatively weak and non-selective antagonist action on depolarizations induced by N-methyl-D-aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)-form was more potent than the (-)-form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)-form produced depolarization. This action was blocked by 2-amino-5-phosphonovalerate.

While it is important for the evidence supporting practice guidelines to be current, that is often not the case. The advent of living systematic reviews has made the concept of "living guidelines" realistic, with the promise to provide timely, up-to-date and high-quality guidance to target users. We define living guidelines as an optimization of the guideline development process to allow updating individual recommendations as soon as new relevant evidence becomes available. A major implication of that definition is that the unit of update is the individual recommendation and not the whole guideline. We then discuss when living guidelines are appropriate, the workflows required to support them, the collaboration between living systematic reviews and living guideline teams, the thresholds for changing recommendations, and potential approaches to publication and dissemination. The success and sustainability of the concept of living guideline will depend on those of its major pillar, the living systematic review. We conclude that guideline developers should both experiment with and research the process of living guidelines.

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Electrophysiological studies indicate the existence of several types of receptors for excitatory amino acids. Thus, responses induced by N-methyl-D-aspartate (NMDA) are potently and selectively blocked by D(-)-2-amino-5-phosphonopentanoic acid (D-AP5), while responses induced by such agonists as kainate and quisqualate are relatively resistant to this antagonist. Evidence is mounting that excitatory amino acid receptors are involved in synaptic excitation in many regions of the central nervous system (see refs 1 and 4 for reviews). Although the identity of the transmitter(s) acting at these receptors remains uncertain, L-aspartate has been considered the most likely transmitter at NMDA receptors and L-glutamate at kainate/quisqualate receptors. Other endogenous acidic amino acids proposed as possible transmitters include a range of sulphur-containing amino acids and the tryptophan metabolite, quinolinic acid. Ligand-binding studies offer a means not only of assessing receptor densities in different brain regions but also of comparing affinities of transmitter candidates for these receptors. However, to avoid difficulties of interpretation arising from the use of ligands which bind to more than one type of receptor, such as [3H]-L-glutamate and [3H]-L-aspartate (for example, refs 8-12), ligands with high receptor selectivity are required. Here, we report that [3H]-D-AP5 binds specifically to rat brain membranes, that the hippocampus and cerebral cortex are enriched in these sites relative to other brain areas and that L-glutamate has higher affinity for these receptors than have all other transmitter candidates tested.

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