Sox2 in the differentiation of cochlear progenitor cells

HMG domain transcription factor, Sox2, is a critical gene for the development of cochlear hair cells, the receptor cells for hearing, but this has been ascribed to expansion of the progenitors that become hair cells. Here, we show that Sox2 activated Atoh1, a transcription factor important for hair cell differentiation, through an interaction with the 3′ enhancer of Atoh1. Binding to consensus sequences in the Atoh1 enhancer was dependent on the level of Sox2, and the extent of enhancer binding correlated to the extent of activation. Atoh1 activation by Sox2 was required for embryonic hair cell development: deletion of Sox2 in an inducible mutant, even after progenitor cells were fully established, halted development of hair cells, and silencing also inhibited postnatal differentiation of hair cells induced by inhibition of γ-secretase. Sox2 is thus required in the cochlea to both expand the progenitor cells and initiate their differentiation to hair cells

Does stapedotomy improve high frequency conductive hearing?

Objectives: Stapedotomy is performed to address conductive hearing deficits. While hearing thresholds reliably improve at low frequencies (LF), conductive outcomes at high frequencies (HF) are less reliable and have not been well described. Herein, we evaluate post-operative HF air-bone gap (ABG) changes and measure HF air conduction (AC) thresholds changes as a function of frequency. Methods: Retrospective review of patients who underwent primary stapedotomy with incus wire piston prosthesis between January 2016 and May 2020. Pre- and postoperative audiograms were evaluated. LF ABG was calculated as the mean ABG of thresholds at 250, 500, and 1000 Hz. HF ABG was calculated at 4 kHz. Results: Forty-six cases met criteria. Mean age at surgery was 54.0 +/- 11.7 years. The LF mean preoperative ABG was 36.9 +/- 11.0 dB and postoperatively this significantly reduced to 9.35 +/- 6.76 dB, (P \u3c .001). The HF mean preoperative ABG was 31.1 +/- 14.4 dB and postoperatively, this also significantly reduced to 14.5 +/- 12.3 dB, (P \u3c .001). The magnitude of LF ABG closure was over 1.5 times the magnitude of HF ABG closure (P \u3c .001). The gain in AC decreased with increasing frequency (P \u3c .001). Conclusion: Hearing improvement following stapedotomy is greater at low than high frequencies. Postoperative air bone gaps persist at 4 kHz. Further biomechanical and histopathologic work is necessary to localize postoperative high frequency conductive hearing deficits and improve stapedotomy hearing outcomes. Level of Evidence: 4, retrospective study

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Idiopathic intracranial hypertension: A Retrospective Evaluation of the Management and Outcomes at One Large Tertiary Care Center (.pdf)

Idiopathic intracranial hypertension (IIH) is a common and potentially blinding disorder that affects most frequently young overweight women. The NORDIC IIH treatment trial defined the value of acetazolamide and weight loss in the management of IIH. The goal of this study was to reflect upon our outcomes based upon our traditional strategy for managing patients and also to explore outcomes across a greater range of visual disability than was studied in the IIH treatment trial study

Effect of Powered Air-Purifying Respirators on Speech Recognition Among Health Care Workers

Powered air-purifying respirators (PAPRs) are used as personalized protective equipment for health care personnel. PAPRs offer health care workers added protection when dealing with patients who have high-risk infectious disease such as COVID-19. Unfortunately, PAPRs can produce notable levels of background noise. We hypothesize that PAPR use may be associated with increased hearing thresholds and impaired word discrimination and may ultimately have a negative impact on effective communication. Herein, we (1) determined sound levels generated by PAPRs and (2) measured hearing thresholds and word discrimination with and without operational PAPRs. All participants had normal hearing. When the PAPR was operational, mean +/- SD thresholds increased from 4.5 +/- 3.6 to 38.6 +/- 5.6 dB HL (P \u3c .001). Word discrimination dropped from 100% in all participants in quiet to a mean 48% +/- 14% with operational PAPR (P \u3c .001). Thus, we find that use of PAPR hoods results in hearing impairment comparable to moderate to severe hearing loss, and we suspect that users will experience communication difficulties as a result. Level of Evidence. Prospective study

Transcanal endoscopic infracochlear vestibular neurectomy: A pilot cadaveric study

PURPOSE: Effective operative approaches for the treatment of refractory vertigo in Meniere\u27s disease are invasive. Vestibular neurectomy can preserve hearing and has been shown to be effective; however, current approaches require an extensive craniotomy. Transcanal endoscopic approaches to the internal auditory canal (IAC) with cochlear preservation have been recently described and may offer a minimally invasive approach to selectively sectioning the distal vestibular nerves while preserving residual hearing. MATERIALS AND METHODS: Three cadaveric human heads were imaged using high resolution computed tomography (CT). Anatomic analysis of preoperative CT scans showed adequate diameters ( \u3e 3mm) of the infracochlear surgical corridor for access to the IAC. A transcanal endoscopic approach was attempted to section the vestibular nerve. Post-operative CT scans were assessed to define the operative tract, determine cochlear preservation and assess cochlear and facial nerve preservation. RESULTS: Transcanal endoscopic approach was successfully performed (n=3) using 3mm-diameter, 14cm-length 0 degrees , 30 degrees , and 45 degrees endoscopes and microsurgical drills. In all cases the tympanomeatal flap and ossicular chain remained intact. Internal auditory canalotomy was performed using angled instruments and confirmed in real time via lateral skull base navigation. The vestibular nerves were readily identified and sectioned with preservation of the facial and cochlear nerves. Post-procedure CT showed no violation of the cochlea. CONCLUSION: A transcanal, infracochlear approach to the IAC may permit a minimally invasive approach to distal vestibular neurectomy in cadavers with appropriate anatomy

Vestibular Aqueduct Morphology Correlates With Endolymphatic Sac Pathologies in Menièreʼs Disease—A Correlative Histology and Computed Tomography Study

HYPOTHESIS: The vestibular aqueduct (VA) in Menière's disease (MD) exhibits different angular trajectories depending on the presenting endolymphatic sac (ES) pathology, i.e., 1) ES hypoplasia or 2) ES degeneration. BACKGROUND: Hypoplasia or degeneration of the ES was consistently found in inner ears affected by MD. The two etiologically distinct ES pathologies presumably represent two disease "endotypes," which may be associated with different clinical traits ("phenotypes") of MD. Recognizing these endotypes in the clinical setting requires a diagnostic tool. METHODS: 1) Defining the angular trajectory of the VA (ATVA) in the axial plane. 2) Measuring age-dependent normative data for the ATVA in postmortem temporal bone histology material from normal adults and fetuses. 3) Validating ATVA measurements from normative CT imaging data. 4) Correlating the ATVA with different ES pathologies in histological materials and CT imaging data from MD patients. RESULTS: 1) The ATVA differed significantly between normal adults and MD cases with ES degeneration, as well as between fetuses and MD cases with ES hypoplasia; 2) a strong correlation between ATVA measurements in histological sections and CT imaging data was found; 3) a correlation between the ATVA, in particular its axial trajectory in the opercular region (angle αexit), with degenerative (αexit  140°) was demonstrated. CONCLUSION: We established the ATVA as a radiographic surrogate marker for ES pathologies. CT-imaging-based determination of the ATVA enables endotyping of MD patients according to ES pathology. Future studies will apply this method to investigate whether ES endotypes distinguish clinically meaningful subgroups of MD patients.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0