INTRODUCTION: Nocturnal enuresis is a common pediatric condition with limited treatment options. In older children, pharmacologic therapy is often the preferred treatment. Pharmacologic therapies including desmopressin (DDAVP) or imipramine are effective in 40-50% of children. However, imipramine has serious safety concerns. Desmopressin in combination with a fixed dose anticholinergic has been shown to be useful in individuals who fail desmopressin monotherapy, but still fails to achieve success rates greater than 60%. OBJECTIVE: The goal was to explore the efficacy and safety of using combination therapy desmopressin plus oxybutynin with increasing dose of oxybutynin in patients refractory to standard combination therapy. STUDY DESIGN: This was a single institution, IRB-approved, retrospective chart review of 61 patients (ages 7-18 years) including those with monosymptomatic primary nocturnal enuresis and non-monosymptomatic enuresis with controlled daytime voiding symptoms (CDVS) treated initially with desmopressin. All patients who failed initial therapy with desmopressin were started on combination therapy desmopressin (0.6 mg) plus standard dose (5 mg) oxybutynin. In patients who failed standard combination therapy, the dose of oxybutynin was titrated upwards until a response or the maximum dose of 10 mg was achieved. Demographic and medical history data were evaluated to determine predictive factors associated with response/failure to different therapy groups. RESULTS: The use of escalating doses of oxybutynin in combination with desmopressin achieved an overall response rate of 96.7% defined as a 2-week period without any enuretic events following initiation of treatment. Low-dose combination therapy (LDCT) (0.6 mg of desmopressin+5 mg of oxybutynin) had a response rate of 68% (Table). Advanced dose combination therapy (ADCT) (0.6 mg of desmopressin+7.5-10 mg of oxybutynin) had a response rate of 75.0%. A statistically significant relationship was found correlating both attention deficit disorder/attention-deficit hyperactivity disorder(ADD/ADHD) and CDVS with failure on monotherapy. No patients in the study reported any adverse events or side effects from the medications. DISCUSSION: The overall success rate of 96.7% with titrated doses of oxybutynin in combination with desmopressin is considerably higher than the response rates on fixed dose combination therapy quoted in the literature and supports the need for further evaluation in larger studies. Additionally, we found a statistically significant association between monotherapy failure and children with either ADD/ADHD or controlled daytime voiding symptoms. Our study is limited by small numbers and larger studies are needed to confirm these results. CONCLUSION: Our results suggest that ADCT is a safe and effective treatment option for primary nocturnal enuresis refractory to standard and low-dose combination therapy.

Background: Nocturnal enuresis is a common pediatric condition with limited treatment options. In older children, pharmacologic therapy is often the preferred treatment. Pharmacologic therapies including Desmopressin (DDAVP) or Imipramine are effective in 40-50% of children. However Imipramine has serious safety concerns. DDAVP in combination with a fixed dose anticholinergic has been shown to be useful in individuals who fail DDAVP monotherapy, but still fails to achieve success rates greater than 60%. Objective: Our goal is to explore the efficacy and safety of using combination therapy DDAVP plus Oxybutynin with increasing dose ofOxybutynin in patients refractory to standard combination therapy. Study Design: A single institution, IRB approved, retrospective chart review of 61 patients (ages 7-18) including those with monosymptomatic primary nocturnal enuresis and non-monosymptomatic enuresis with Controlled Daytime Voiding Symptoms (CDVS) treated initially with DDAVP. All patients who failed initial therapy with DDAVP were started on combination therapy DDAVP (0.6 mg) plus standard dose (5 mg) Oxybutynin. In patients who failed standard combination therapy, the dose of Oxybutynin was titrated upwards until response or maximum dose 10 mg was achieved. Demographic and medical history data were evaluated to determine predictive factors associated with response/failure to different therapy groups. Results: The use of escalating doses of Oxybutynin in combination with DDAVP achieved an overall response rate of 96.7% defined as a two-week period without any enuretic events following initiation oftreatment. Low Dose Combination Therapy (LDCT) (0.6mg DDAVP + 5 mg Oxybutynin) had a response rate of 68%. Advanced Dose Combination Therapy (ADCT) (0.6 mg DDAVP + 7.5-10 mg Oxybutynin) had a response rate of75.0%. A statistically significant relationship was found correlating both ADD/ADHD and CDVS with failure on monotherapy. No patients in the study reported any adverse events or side effects from the medications. Discussion: The overall success rate of 96.7% with titrated doses of Oxybutynin in combination with DDAVP is considerably higher than the response rates on fixed dose combination therapy quoted in the literature and supports the need for further evaluation in larger studies. Additionally, we found a statistically significant association between monotherapy failure and children with either ADD/ADHD or controlled daytime voiding symptoms. Our study is limited by small numbers and larger studies are needed to confirm these results. Conclusion: Our results suggest that ADCT is a safe and effective treatment option for primary nocturnal enuresis refractory to standard and low dose combination therapy.

Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.