Endoscopic Versus Microscopic Stapedotomy: A Single-Blinded Randomized Control Trial.

OBJECTIVE: To demonstrate non-inferiority of endoscopic stapedotomy to microscopic stapedotomy for the treatment of otosclerosis. STUDY DESIGN: Single-blinded randomized control trial. SETTING: Tertiary, academic otology-neurotology practice. PATIENTS: Adult subjects with a diagnosis of otosclerosis and a preoperative air-bone gap (ABG) more than or equal to 20 dB undergoing primary stapedotomy. INTERVENTION: Endoscopic or microscopic stapedotomy. MAIN OUTCOME MEASURES: Primary audiometric outcome was postoperative ABG. Secondary audiometric outcomes included speech reception threshold (SRT), word recognition score (WRS), bone- and air-conduction pure tone averages (PTA), change in ABG, and ABG closure rates to less than or equal to 10 dB and less than or equal to 20 dB. RESULTS: Twenty-two patients were recruited. Eleven patients underwent endoscopic stapedotomy and 11 underwent microscopic stapedotomy. The endoscopic group was non-inferior to the microscopic group in terms of postoperative audiometric outcomes (endoscope versus microscope, p-value): ABG (8.1 dB versus 8.1 dB, <0.001), SRT (27.7 dB versus 25.9 dB, <0.001), WRS (92% at 65 dB versus 98% at 62 dB, <0.001), air-conduction PTA (33.5 dB versus 30.8 dB, <0.01), and change in ABG (23.0 dB versus 20.7 dB, <0.0001). ABG closure rates to less than or equal to 10 dB (72.7% versus 81.2%, p = 1.0) and less than or equal to 20 dB (90.9% versus 100%, p = 1.0) were not significantly different. There was no significant difference in operative time, necessity of scutum curettage, or postoperative dysgeusia. No patients required chorda tympani sacrifice. Preoperative tinnitus resolved in three patients in each group postoperatively. CONCLUSIONS: This study is the first randomized control trial to demonstrate non-inferiority of endoscopic to microscopic stapedotomy.

Ambulatory tonsillectomy for children with severe obstructive sleep apnea without risk factors.

OBJECTIVES: Recommendations for polysomnography (PSG) in pediatric sleep disordered breathing (SDB) vary between the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the American Academy of Pediatrics (AAP). We determined the rates of preoperative PSG in children without risk factors outlined in the AAO-HNS Clinical Practice Guidelines and described the postoperative course of those patients following T&A. METHODS: Patients aged 3-17 undergoing T&A for SDB or OSA who did not have an indication for preoperative PSG were included. We conducted retrospective review to describe the rate, type, and timing of respiratory complications for patients with and without PSG following T&A, and discuss cases where disposition was changed due to PSG results. RESULTS: 1135 patients without risk factors underwent T&A for SDB or OSA. 196 (17%) had a preoperative PSG, of whom 85 (43.3%) had AHI >10 and 38 (24.8%) had an O2 nadir <80%. 69 (85%) patients with PSG-diagnosed severe OSA were admitted overnight. Of the entire cohort, 5 patients (0.44%) had hypoxemia requiring blow-by oxygen or repositioning. 4 (0.43%) patients without PSG experienced respiratory events and were converted to overnight stay. The timing of respiratory events for all children ranged from immediately following extubation in the operating room to 3 h postoperatively. CONCLUSION: PSG in children without risk factors results in admission of otherwise healthy patients following T&A who would have otherwise undergone ambulatory surgery. PSG alone in pediatric patients with no AAO-HNS risk factors should not influence postoperative disposition. These patients should be monitored for 3 h post-T&A and discharged in the absence of complications. EVIDENCE LEVEL: 2b.

Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles.

Ischemic stroke is a leading cause of disability and death worldwide. Current drug treatment for stroke remains inadequate due to the existence of the blood-brain barrier. We proposed an innovative nanotechnology-based autocatalytic targeting approach, in which the blood-brain barrier modulator lexiscan is encapsulated in nanoparticles to enhance blood-brain barrier permeability and autocatalytically augment the brain stroke-targeting delivery efficiency of chlorotoxin-anchored nanoparticles. The nanoparticles efficiently and specifically accumulated in the brain ischemic microenvironment and the targeting efficiency autocatalytically increased with subsequent administrations. When Nogo-66 receptor antagonist peptide NEP1-40, a potential therapeutic agent for ischemic stroke, was loaded, nanoparticles significantly reduced infarct volumes and enhanced survival. Our findings suggest that the autocatalytic targeting approach is a promising strategy for drug delivery to the ischemic microenvironment inside the brain. Nanoparticles developed in this study may serve as a new approach for the clinical management of stroke.

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging.

The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.

Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function.

Autophagy is a cytoprotective pathway used to degrade and recycle cytoplasmic content. Dysfunctional autophagy has been linked to both cancer and cardiomyopathies. Here, we show a role for the transcriptional regulator p8 in autophagy. p8 RNA interference (RNAi) increases basal autophagy markers in primary cardiomyocytes, in H9C2 and U2OS cells, and decreases cellular viability after autophagy induction. This autophagy is associated with caspase activation and is blocked by atg5 silencing and by pharmacological inhibitors. FoxO3 transcription factor was reported to activate autophagy by enhancing the expression of autophagy-related genes. P8 expression represses FoxO3 transcriptional activity, and p8 knockdown affects FoxO3 nuclear localization. Thus, p8 RNAi increases FoxO3 association with bnip3 promoter, a known proautophagic FoxO3 target, resulting in higher bnip3 RNA and protein levels. Accordingly, bnip3 knockdown restores cell viability and blocks apoptosis of p8-deficient cells. In vivo, p8 -/- mice have higher autophagy and express higher cardiac bnip3 levels. These mice develop left ventricular wall thinning and chamber dilation, with consequent impaired cardiac function. Our studies provide evidence of a p8-dependent mechanism regulating autophagy by acting as FoxO3 corepressor, which may be relevant for diseases associated with dysregulated autophagy, as cardiovascular pathologies and cancer.

Deficiency of transcriptional regulator p8 induces autophagy and causes impaired cardiac function.

Through autophagy cells adapt to nutrient availability, recycle cellular material and eliminate toxic proteins and damaged cellular organelles. Dysregulation of autophagy is implicated in the pathogenesis of various diseases, including cancer, neurodegeneration and cardiomyopathies. The transcription factor FoxO3 activates autophagy by enhancing the expression of several genes. We find a role for the transcriptional regulator p8 in controling autophagy by repressing FoxO3 transcriptional activity. p8 silencing increases the association of FoxO3 with the bnip3 promoter, a known pro-autophagic FoxO3 target, and results in increasead basal autophagy and decreased cellular viability. Likewise, p8 overexpression inhibits Bnip3 upregulation after autophagy activation. Thus, p8 appears to antagonize the promotion of autophagy mediated by the FoxO3-Bnip3 axis. Consistent with this, bnip3 knockdown restores viability in p8-deficient cells. In vivo, hearts from p8-/- mice have higher basal autophagy and bnip3 levels. These mice develop left ventricular wall thinning and chamber dilation, with consequent impaired cardiac function.