Mitochondrial biogenesis requires the import of approximately 1,000 different proteins through a labyrinth of channels to reach the appropriate sub-organellar location. A new study now reports that, in response to stalled import complexes, an adaptive transcriptional response dubbed the mitoCPR is triggered to extract these stalled complexes into the cytosol for degradation.

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.

AIMS/HYPOTHESIS: During pregnancy, adipose tissue (AT) must expand to support the growing fetus and the future nutritional needs of the offspring. Limited expandability of AT is associated with insulin resistance, attributed to ectopic lipid deposition. This study aimed to investigate human AT expandability during pregnancy and its role in the pathogenesis of gestational diabetes mellitus (GDM). METHODS: This cross-sectional study of omental (OM) and subcutaneous (SQ) AT collected at Caesarean delivery included 11 pregnant and three non-pregnant women with normal glucose tolerance (NGT), five with GDM, three with type 2 diabetes mellitus. Adipocyte size, capillary density, collagen content and capillary growth were measured. Affymetrix arrays and real-time PCR studies of gene expression were performed. RESULTS: Mean OM adipocyte size was greater in women with GDM than in those with NGT (p = 0.004). Mean OM and SQ capillary density was lower in GDM compared with NGT (p = 0.015). Capillary growth did not differ significantly between groups. The most differentially expressed AT transcript when comparing non-pregnant and pregnant women corresponded to the IGF binding protein (IGFBP)-5, the expression levels of which was found by subsequent quantitative real-time PCR to be lower in women with GDM vs women with NGT (p < 0.0001). CONCLUSIONS/INTERPRETATION: The relative OM adipocyte hypertrophy and decreased OM and SQ capillary density are consistent with impaired AT expandability in GDM. The induction of adipose tissue IGFBP5 in pregnancy and its decrease in GDM point to the importance of the IGF-1 signalling pathway in AT expansion in pregnancy and GDM susceptibility.