The miRNA pathway controls rapid changes in activity-dependent synaptic structure at the Drosophila melanogaster neuromuscular junction.

It is widely accepted that long-term changes in synapse structure and function are mediated by rapid activity-dependent gene transcription and new protein synthesis. A growing amount of evidence suggests that the microRNA (miRNA) pathway plays an important role in coordinating these processes. Despite recent advances in this field, there remains a critical need to identify specific activity-regulated miRNAs as well as their key messenger RNA (mRNA) targets. To address these questions, we used the larval Drosophila melanogaster neuromuscular junction (NMJ) as a model synapse in which to identify novel miRNA-mediated mechanisms that control activity-dependent synaptic growth. First, we developed a screen to identify miRNAs differentially regulated in the larval CNS following spaced synaptic stimulation. Surprisingly, we identified five miRNAs (miRs-1, -8, -289, -314, and -958) that were significantly downregulated by activity. Neuronal misexpression of three miRNAs (miRs-8, -289, and -958) suppressed activity-dependent synaptic growth suggesting that these miRNAs control the translation of biologically relevant target mRNAs. Functional annotation cluster analysis revealed that putative targets of miRs-8 and -289 are significantly enriched in clusters involved in the control of neuronal processes including axon development, pathfinding, and growth. In support of this, miR-8 regulated the expression of a wingless 3'UTR (wg 3' untranslated region) reporter in vitro. Wg is an important presynaptic regulatory protein required for activity-dependent axon terminal growth at the fly NMJ. In conclusion, our results are consistent with a model where key activity-regulated miRNAs are required to coordinate the expression of genes involved in activity-dependent synaptogenesis.

The diagnosis and management of lower urinary tract symptoms in multiple sclerosis patients.

Sixty-five percent of multiple sclerosis patients have moderate to severe urinary symptoms and up to 14% initially present with urinary symptomatology. Urinary retention, neurogenic detrusor overactivity, and detrusor sphincter dyssynergia, all increase the risk for urinary tract infections in patients with multiple sclerosis, and these infections may exacerbate their immune response, leading to symptom progression. Fewer than half of the patients with urinary symptoms have seen a specialist and only half have been treated for their neurogenic detrusor overactivity. Several treatments including pelvic floor muscle therapy, pelvic floor electrical stimulation, anticholinergics, desmopressin, sacral nerve neuromodulation, posterior tibial nerve stimulation, cannabinoids, and intravesical therapy with vanniloids, as well as botulinum toxin, have all been shown to be effective in treating urinary symptoms in those with multiple sclerosis. Clean intermittent catheterization is invaluable in patients with persistent urinary retention to avoid infection and upper tract dysfunction. Indwelling transurethral catheterization should be avoided because of the high risk of infection. Identification and successful treatment of these urinary conditions will improve the health and quality of life for these men and women.

Measuring the success of combined intravesical dimethyl sulfoxide and triamcinolone for treatment of bladder pain syndrome/interstitial cystitis.

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to investigate change in bladder capacity as a measure of response to combined intravesical dimethyl sulfoxide (DMSO) and triamcinolone instillations for the treatment of newly diagnosed bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: 141 newly diagnosed women were identified retrospectively. 79 were treated with weekly DMSO/triamcinolone instillations. Change in bladder capacity with bladder retrofill, daytime urinary frequency, nocturia episodes per night, and Likert scale symptom scores were reviewed. Wilcoxon signed-rank tests, Wilcoxon rank-sum tests, Spearman's rank correlations, COX regression analysis, and a Kaplan-Meier survival curve were performed. RESULTS: Significant changes (median (25(th)-percentile to 75(th)-percentile) were noted for bladder capacity (75 mL (25 to 130 mL), p < 0.0001), inter-void interval (0 hrs (0 to 1 hour), p < 0.0001), nocturia episodes per night (-1 (-2 to 0), p < 0.0001), and aggregate Likert symptom scores (-2 points (-5 to 0), p < 0.0001). Percent change in bladder capacity correlated positively with percent change in inter-void interval (p = 0.03) and negatively with percent changes in nocturia (p = 0.17) and symptom scores (p = 0.01). Women without detrusor overactivity (DO) had greater percent changes in capacity than women with DO (62.5 % vs. 16.5 %, p = 0.02). 61.3 % of patients were retreated with a 36 weeks median time to retreatment and no difference in time to retreatment based upon DO. Greater capacity was protective against retreatment (hazard ratio = 0.997 [95 % CI 0.994,0.999], p = 0.02). CONCLUSIONS: Percent change in bladder capacity is a useful objective measure of response to intravesical DMSO/triamcinolone for newly diagnosed BPS/IC. Clinical outcomes do not differ based upon presence of DO.