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Objective. The presence, in patients with primary and secondary Sjögren's syndrome (SS), of autoantibodies that acutely inhibit M 3 muscarinic receptor (M3R)-mediated bladder contractions is difficult to reconcile with the fact that symptoms of detrusor overactivity and other features of cholinergic hyperresponsiveness occur in this disease. This study was undertaken to examine the in vivo effects of these autoantibodies on bladder function by examining bladder responsiveness and compliance following passive transfer of patient IgG to mice.Methods. Contractile responses of isolated bladder strips both to the muscarinic agonist carbachol and to electrically evoked acetylcholine release were measured 48 hours after injection of mice with patient or control IgG. A whole bladder assay with intact neuronal pathways was developed to assess bladder wall compliance on filling cystometry. Expression of M3R in bladders from IgG-injected mice was assessed by immunohistochemistry.Results. Passive transfer of SS IgG with inhibitory anti-M3R activity produced a paradoxical increase in contractile responses of detrusor strips to cholinergic stimulation. Cystometry of whole bladders revealed a corresponding decrease in bladder wall compliance and phasic detrusor contractions upon filling, replicating the urodynamic features of an overactive bladder. The features of cholinergic hyperresponsiveness were associated with increased postsynaptic M3R expression and were reproduced by injecting mice with a rabbit antibody against the second extracellular loop of M3R.Conclusion. These findings are consistent with the notion that there is initial inhibition of parasympathetic neurotransmission by antagonistic autoantibodies to M3R, which produces a compensatory increase in M3R expression in vivo. The enhanced cholinergic responses during bladder distention result in detrusor overactivity. We conclude that the overactive bladder associated with SS is an autoantibody-mediated disorder of the autonomic nervous system, which may be part of a wider spectrum of cholinergic hyperresponsiveness.

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AimsTo develop and evaluate for the National Prescribing Service (N PS) a web-based interactive prescribing curriculum for Australian senior medical students based on the World Health Organization's Guide to Good Prescribing . MethodsTeachers of prescribing from all Australian medical schools in 2000 wrote 12 casebased modules which were converted to on-line format. Objective evidence was provided for selecting first-line medicines from available alternatives by comparing efficacy, safety, convenience and cost. ResultsBy 2004 the curriculum was used by nine of 11 possible medical schools. Uptake increased each year from 2001 and all 12 modules were accessed consistently. Student access was significantly ( P < 0.001) greater when prescribing was an assessable part of their course. Teachers' evaluations were uniformly supportive and the curriculum is seen as a valuable resource. Student responses came from a small proportion of those with password access but were also suppor tive. Over half of student respondents had created their own evidence-based formulary. ConclusionsA collaborative venture initiated by the NPS with Australian medical schools has been successfully implemented in most courses. Teachers find the resource of high quality. Student respondents find the curriculum valuable in developing their own prescribing skills. It is best delivered by self-directed study followed by tutorial discussion of prescribing decisions.

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