RESUMO
BACKGROUND: The non-surgical solution for Pelvic Organ Prolapse (POP) typically consists of a pessary fitting. We aimed to assess patient satisfaction and symptom improvement 6 months after a pessary fitting and to identify risk factors associated with pessary failure. METHODS: Six months after a pessary fitting, patient satisfaction was assessed by the PGII score; symptoms and quality of life were assessed using validated questionnaires (PFDI-20, ICIQ-SF, PISQ-12, USP, and PFIQ-7). RESULTS: Of the 190 patients included in the study (mean age of 66.7 years), 141 (74%) and 113 (59%) completed the follow-up questionnaires at 1 and 6 months, respectively. Nearly all the women were menopausal (94.6%) and 45.2% declared being sexually active at inclusion. The satisfaction rate was 84.3% and 87.4% at 1 and 6 months, respectively. The global symptom score PFDI-20 had significantly improved at 6 months. A high body mass index (RR = 1.06, CI95%: [1.02-1.09]), as well as high PFDI-20 (1.05 [1.01-1.09]), PFIQ7 (1.04 [1.01, 1.08]), and PISQ12 scores at inclusion (0.75 [0.60, 0.93]), as well as higher GH and GH/TVL measurements (1.49 [1.25-1.78] and 1.39 [1.23-1.57], respectively) were associated with pessary failure. CONCLUSIONS: Pessary seems to be an effective treatment for POP with high patient satisfaction. Higher BMI, higher symptom scores, and greater genital hiatus measurements before insertion are risk factors for failure at 6 months.
RESUMO
DSCAM and DSCAML1 are immunoglobulin and cell adhesion-type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self-avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high-throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ-secretase-dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain-of-function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full-length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane-to-nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.
