SSCD can present with a conductive hearing loss that mimics otosclerosis and could explain some cases of persistent conductive hearing loss after uneventful stapedectomy. Audiometric testing with attention to absolute bone-conduction thresholds, acoustic reflex testing, VEMP testing, laser vibrometry of the umbo, and computed tomograph scanning can help to identify patients with SSCD presenting with conductive hearing loss without vertigo.

A reliable and valid patient-based system to measure impairment and disability in facial paralysis has been developed. This system appears to be better than traditional, physician-graded scales for evaluating quality-of-life issues affected by facial disability.

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Infection with Mycobacterium ulcerans is characterised by tissue necrosis and immunosuppression due to mycolactone, the necessary and sufficient virulence factor for Buruli ulcer disease pathology. Many of its effects are known to involve down-regulation of specific proteins implicated in important cellular processes, such as immune responses and cell adhesion. We have previously shown mycolactone completely blocks the production of LPS-dependent proinflammatory mediators post-transcriptionally. Using polysome profiling we now demonstrate conclusively that mycolactone does not prevent translation of TNF, IL-6 and Cox-2 mRNAs in macrophages. Instead, it inhibits the production of these, along with nearly all other (induced and constitutive) proteins that transit through the ER. This is due to a blockade of protein translocation and subsequent degradation of aberrantly located protein. Several lines of evidence support this transformative explanation of mycolactone function. First, cellular TNF and Cox-2 can be once more detected if the action of the 26S proteasome is inhibited concurrently. Second, restored protein is found in the cytosol, indicating an inability to translocate. Third, in vitro translation assays show mycolactone prevents the translocation of TNF and other proteins into the ER. This is specific as the insertion of tail-anchored proteins into the ER is unaffected showing that the ER remains structurally intact. Fourth, metabolic labelling reveals a near-complete loss of glycosylated and secreted proteins from treated cells, whereas cytosolic proteins are unaffected. Notably, the profound lack of glycosylated and secreted protein production is apparent in a range of different disease-relevant cell types. These studies provide a new mechanism underlying mycolactone's observed pathological activities both in vitro and in vivo. Mycolactone-dependent inhibition of protein translocation into the ER not only explains the deficit of innate cytokines, but also the loss of membrane receptors, adhesion molecules and T-cell cytokines that drive the aetiology of Buruli ulcer.

Otosclerosis is a localized disease of bone remodeling within the otic capsule of the human temporal bone. Unlike other similar bone diseases, it does not occur outside of the temporal bone. These lesions seem to begin by resorption of stable otic capsule bone in adults, followed by a reparative phase with bone deposition. There are clearly genetic factors that lead to this disease, but measles virus infection and autoimmunity also may play contributing roles. Surgical correction of the conductive hearing loss is highly effective, but nonsurgical intervention has not yet been shown to prevent or slow the disease. Of the factors that may inhibit this process, fluorides, cytokine inhibitors, and bisphosphonates, third-generation bisphosphonates appear to hold the most promise.

The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans. In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome–nascent-chain–Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation.

Objective: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients.Study Design: Retrospective study. Setting: Tertiary referral centerPatients: 31 consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas.Main Outcome Measure: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a ≥20% decrease in tumor volume compared with baseline. Results:The median age was 26 years (range, 12-73). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41) with a total of 45 patient-years of follow up. A hearing response occurred in 13/23 (57%) evaluable patients, and a radiographic response in 17/31 (55%) of target vestibular schwannomas. The median time to response was 3 months for both endpoints. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient (ADC) value, a radiologic marker of edema (p=0.036). 90% of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years. 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated.Conclusion: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in over 50% of progressive vestibular schwannomas in NF2 patients. Stable or 2 improved hearing was retained in the majority of patients.3

Organelle identity depends on protein composition. How mistargeted proteins are selectively recognized and removed from organelles is incompletely understood. Here, we found that the orphan P5A–adenosine triphosphatase (ATPase) transporter ATP13A1 (Spf1 in yeast) directly interacted with the transmembrane segment (TM) of mitochondrial tail–anchored proteins. P5A-ATPase activity mediated the extraction of mistargeted proteins from the endoplasmic reticulum (ER). Cryo–electron microscopy structures of Saccharomyces cerevisiae Spf1 revealed a large, membrane-accessible substrate-binding pocket that alternately faced the ER lumen and cytosol and an endogenous substrate resembling an α-helical TM. Our results indicate that the P5A-ATPase could dislocate misinserted hydrophobic helices flanked by short basic segments from the ER. TM dislocation by the P5A-ATPase establishes an additional class of P-type ATPase substrates and may correct mistakes in protein targeting or topogenesis.