Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human patients. Innovative models became essential to develop more accurate knowledge. Tissue engineering provides some of those models, but it mostly relies on the use of prefabricated scaffolds on which cells are seeded. The self-assembly protocol has recently produced organ-specific human-derived three-dimensional models without the need for exogenous material. This strategy will help to achieve the 3R principles.

Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1β, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer–induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1–knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate–induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti–IL-1 therapies for pain management in patients with chronic inflammatory diseases.

Introduction: We evaluate the efficacy and safety of solifenacin to treat incontinence in children with non-neurogenic (DO) or neurogenic detrusor overactivity (NDO) refractory to oxybutinin or tolterodine. Methods: We updated and extended our previously published nonrandomized uncontrolled study on open-label use of adjusted-dose regimens of solifenacin (1.25-10 mg) in children with refractory incontinence. The follow-up included voiding diaries, post-void residuals, urine cultures, ultrasounds and urodynamic studies. Clinical data were updated as of September 2012. Subjective improvement was assessed with the Patient Perception of Bladder Condition (PPBC) scale. The primary end point was efficacy toward continence and secondary end points were tolerability and safety. Results: Overall, 244 patients (112 girls, 132 boys) were enrolled; 53 with NDO and 191 with DO. Minimal follow-up was 5 months, the mean duration of treatment was 21.0 months and the mean age at initiation was 9.2 years. Urodynamic capacity improved from 145 ± 76 mL to 339 ± 152 mL and the amplitude of uninhibited contractions decreased from 66 ± 26 to 20 ± 20 cmH 2 O (p < 0.0001). The overall success rate is 91%, and more specifically 94% for non-neurogenic and 79% for neurogenic, which is significantly different (p = 0.013). Twenty-three patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 175 patients, mild by 46, moderate by 9, and 14 withdrew due to their side effects. Ten patients developed post-void residuals of ≥20 mL. Conclusion: Although higher in the non-neurogenic group, high subjective and objective success rates were maintained over a longer follow-up with an adjusted-dose regimen of solifenacin to treat pediatric NDO or DO refractory to oxybutynin or tolterodine. Moreover, we found acceptable tolerability and safety profiles.

Introduction: In this study, we optimize pharmacotherapy in children who failed anticholinergic monotherapy by simultaneous administration of 2 anticholinergics (oxybutynin and/or tolterodine and/or solifenacin). Methods: This report is an update of our previously published study on double anticholinergic regimen in children with refractory incontinence due to neurogenic (NDO) and non-neurogenic (DO) detrusor overactivity. Patients with an insufficient response (clinically/urodynamically) to an optimized dose of a single anticholinergic (oxybutynin or tolterodine) received a second anticholinergic (tolterodine or solifenacin), in addition to the pre-existing medication. The primary end-point was efficacy (continence) and the secondary end-points were tolerability and safety. The Patient Perception of Bladder Condition (PPBC) scale was used to rate subjective improvement of patients. Results: In total, 56 patients with DO (n = 31) or NDO (n = 25) were enrolled at a mean age of 11.4 ± 3.5 years and were followed for a minimum of 3 months. The duration of double treatment was 36 ± 23 months. Our results found that 23 patients became dry, 18 improved significantly and 15 improved moderately. Urodynamic capacity improved from 158 ± 87 mL to 359 ± 148 mL and maximal pressure of contractions decreased from 76 ± 24 to 22 ± 22 cmH 2 O (p < 0.0001). The overall success rate was 82%, since 10 patients discontinued treatment for unsatisfactory clinical response or bothersome side effects. No side effects were reported by 28 patients, mild side effects by 20, moderate side effects by 8; 2 patients withdrew from the study due to their side effects. Of the 35 patients who voided spontaneously, 8 developed post-void residuals (>20%). Conclusions: With a larger cohort and prospective follow-up, we reiterated that double anticholinergic regimen in children with DO or NDO refractory to anticholinergic monotherapy is a feasible and efficient approach.

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