Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Natural History of Cystic Vestibular Schwannomas.

OBJECTIVE: To determine the natural history of cystic vestibular schwannomas (VS). STUDY DESIGN: Retrospective cohort. SETTING: Single tertiary academic hospital. PATIENTS: Adults diagnosed with cystic VS who had at least 2 MRIs performed at least 6 months apart between 2008 and 2016 with no intervening treatment. MAIN OUTCOME MEASURES: Volumetric growth rates of both the entire tumor and individual cystic and solid components were measured. Linear growth rate of the entire tumor was assessed using the largest diameter parallel to the petrous face at the cerebellopontine angle (CPA). RESULTS: Twenty-one patients met inclusion criteria. The average volumetric growth rate of the tumor was 1.1 ± 2 (range: -1.2 to 7.8), while the average growth rate of the cystic component was 0.8 ± 1.6 (range: -0.5 to 5.3) cm3/year. The CPA diameter of the tumor demonstrated an average linear growth rate of was 1.2 ± 4.4 (range: -8to 13.5) mm/year. With regards to tumor diameter, 9/21 (42.9%) remained stable, 3/21 (14.2%) decreased in size, while 9/21 (42.9%) increased in size. CONCLUSIONS: Cystic tumors demonstrate a wide variability in growth rate. Larger, multi-center studies will be required to further compare this relationship to solid tumors.

Canalplasty for Exostosis Removal Comparing Microscopic Versus Endoscopic Ear Surgery Techniques.

OBJECTIVE: To compare an endoscopic versus microscopic approach to removal of exostoses and osteomas in canalplasty procedures. STUDY DESIGN: Retrospective case review. SETTING: Private and tertiary referral centers. PATIENTS: Adult patients requiring canalplasty procedures performed either microscopically or endoscopically for removal of exostosis or osteoma and/or canal stenosis. INTERVENTION: Microscopic or endoscopic canalplasty. MAIN OUTCOME MEASURE: Major outcome measures included assessment of hearing improvement as well as rates of major and minor complications. Standard audiological data were collected before and after the operative procedure. Major complications queried included stenosis, perforation of the tympanic membrane, hearing loss, facial palsy, and osteomyelitis. Minor complications queried included signs of poor wound healing, graft failure, and bleeding or discharge. RESULTS: Forty three canalplasties were performed on 36 patients. Audiometric tests did not significantly differ between endoscopic and microscopic surgeries. There was a moderate linear relationship between date of surgery and duration of surgery for the endoscopic technique, with more recent surgeries taking less time. No major complications were noted. However, significantly fewer endoscopic cases had evidence of minor postoperative complications relative to microscopic cases. CONCLUSIONS: An endoscopic approach to canalplasty is a safe and minimally invasive technique. Significantly fewer postoperative complications occurred after endoscopic canalplasty procedures as compared with microscopic procedures. Endoscopic repair may be preferred to microscopic repairs due to the improved view of the end of the instruments while maintaining a minimally invasive approach with what is likely a decreased operative time as well.

Rhythmic Wave Patterns on Ambient Pressure Tympanometry in Patients With Objective Tinnitus-associated Pathologies.

OBJECTIVE: To introduce the concept of ambient pressure tympanometry (APT) and its association with pathologies that may present with objective tinnitus. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Audiologists performed APT on adult patients as part of routine audiological testing. Ears with myoclonus and patulous Eustachian tube (PET) were identified via review of patient history and physical examination. All other conditions were verified via computed tomography (CT) temporal bone imaging. Ears with conditions that could impair tympanic membrane compliance, such as otosclerosis or tympanic membrane perforation, were excluded. APT findings were analyzed via a novel algorithm. RESULTS: A radiographic finding associated with objective tinnitus was confirmed in 67 ears that underwent CT imaging; 45 (67%) of these ears displayed rhythmic APT wave patterns. These included 28 ears with superior semicircular canal dehiscence, 4 ears with sigmoid sinus dehiscence, 6 ears with internal carotid artery dehiscence, 4 ears with glomus tumor, and 3 ears with encephalocele. In addition, we identified three ears with myoclonus and one ear with PET. In a subset of 30 ears with objective tinnitus symptoms that underwent CT imaging, 22 displayed rhythmic waves; of these 22 ears, 20 (91%) had a radiographic finding associated with objective tinnitus. CONCLUSIONS: Rhythmic APT wave patterns are common and may be associated with numerous temporal bone pathologies that may present with objective tinnitus. APT is a simple, rapid, and widely available tool that warrants further study to determine its value in screening of these otologic conditions.

Molecular therapy for genetic and degenerative vestibular disorders.

PURPOSE OF REVIEW: The primary purpose of this review is to summarize current literature in the field of vestibular regeneration with a focus on recent developments in molecular and gene therapies. RECENT FINDINGS: Since the discovery of limited vestibular hair cell regeneration in mammals in the 1990s, many elegant studies have improved our knowledge of mechanisms of development and regeneration of the vestibular system. A better understanding of the developmental pathways of the vestibular organs has fueled various biological strategies to enhance regeneration, including novel techniques in deriving vestibular hair cells from embryonic and induced pluripotent stem cells. In addition, the identification of specific genetic mutations responsible for vestibular disorders has opened various opportunities for gene replacement therapy. SUMMARY: Vestibular dysfunction is a significant clinical problem with limited therapeutic options, warranting research on biological strategies to repair/regenerate the vestibular organs to restore function. The use of gene therapy appears promising in animal models of vestibular dysfunction.

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

OBJECTIVES: Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. METHODS: In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). RESULTS: Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ±â€Š2.22, P < 0.0001; ΔSOWS = 12.48 ±â€Š11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ±â€Š2.39, P < 0.0001; ΔSOWS = 12.21 ±â€Š10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. CONCLUSION: We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Technological advances shed light on left ventricular cardiac disturbances in cystic fibrosis.

Cystic fibrosis (CF), the most common autosomal recessive lethal disease in Caucasians, causes chronic pulmonary disease and can lead to cor pulmonale with right ventricular dysfunction. The presence of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiac myocardia has prompted debate regarding possible defective ion channel-induced cardiomyopathy. Clinical heart disease in CF is considered rare and is restricted to case reports. It has been unclear if this is due to the lack of physiological importance of CFTR in the heart, the relatively short lifespan of those with CF, or a technical inability to detect subclinical disease. Extensive echocardiographic investigations have yielded contradictory results, leading to the dogma that left ventricular defects in CF occur secondary to lung disease. In this review, we consider why studies examining heart function in CF have not provided clarity on this topic. We then focus on data from new echocardiographic and magnetic resonance imaging technology, which are providing greater insight into cardiac function in CF and demonstrating that, in addition to secondary effects from pulmonary disease, there may be an intrinsic primary defect in the CF heart. With advancing lifespans and activity levels, understanding the risk of cardiac disease is vital to minimizing morbidity in adults with CF.