Background-Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signaling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas.Method-Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells, and mouse Nf2 −/− Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase 1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice, and immunohistochemistry were performed.Results-OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC 50 of OSU-03012 at 48 hours was approximately 3.1 μM for VS cells and 2.6 μM for HMS-97 cells, compared with the IC 50 of greater than 12 μM for human Schwann cells. Similarly, mouse Nf2 −/− schwannoma and Nf2 −/− Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 Tantigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well-tolerated and inhibited the growth of *Corresponding authors: Tel.: 1 614 355 2658; fax: 1 614 722 5895; E-mail address: E-mail: lchang@chi.osu.edu (L.-S. Chang). Conflict of interest statementAll authors do not have any disclosure of potential conflict of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HMS-97 schwannoma xenografts by 55% after nine weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation. NIH Public AccessConclusion-OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.

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The purpose of this study was to describe the prevalence of hearing loss and tinnitus in a cohort of Iraq and Afghanistan Veterans (IAV) with common post-deployment conditions, including traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), and other typical post-concussive conditions such as headaches and vertigo/dizziness. This retrospective observational study used data from the national Veterans Health Administration (VA) data repository from fiscal years 2001-2014. Veteran data was included if there were at least three years of VA care, with one or more years of care in 2007 or after. We identified comorbidities that may be associated with post-deployment hearing loss or tinnitus including TBI, PTSD, depression, and common post-concussive symptoms using International Classification of Diseases, 9th Revision, Clinical Modification codes. A multinomial logistic regression analysis was used to examine conditions associated with hearing loss or tinnitus. Among IAV, 570,332 were included in the final analysis. Of these, 7.78% of these were diagnosed with hearing loss alone, 6.54% with tinnitus alone, and 6.24% with both hearing loss and tinnitus. Comorbid TBI, PTSD, and depression were significantly associated with increased rates of hearing loss, tinnitus, or both conditions together. Older individuals, males, and those with TBI, PTSD, or vertigo/dizziness were significantly more likely to have hearing loss, tinnitus, or both. In order to provide more holistic post-deployment support, this myriad of conditions should be carefully considered in the planning of clinical care and beyond.

The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

With increased knowledge of the pathologic mechanisms and interacting proteins associated with merlin, the research community is poised to begin trials of targeted interventions in vitro and in the current mouse models.

Measurements of perilymph hydrodynamics in the human cochlea are scarce, being mostly limited to the fluid pressure at the basal or apical turn of the scalae vestibuli and tympani. Indeed, measurements of fluid pressure or volumetric flow rate have only been reported in animal models. In this study we imaged the human ear at 6.7 and 3-μm resolution using μCT scanning to produce highly accurate 3D models of the entire ear and particularly the cochlea scalae. We used a contrast agent to better distinguish soft from hard tissues, including the auditory canal, tympanic membrane, malleus, incus, stapes, ligaments, oval and round window, scalae vestibule and tympani. Using a Computational Fluid Dynamics (CFD) approach and this anatomically correct 3D model of the human cochlea, we examined the pressure and perilymph flow velocity as a function of location, time and frequency within the auditory range. Perimeter, surface, hydraulic diameter, Womersley and Reynolds numbers were computed every 45 degrees of rotation around the central axis of the cochlear spiral. CFD results showed both spatial and temporal pressure gradients along the cochlea. Small Reynolds number and large Womersley values indicate that the perilymph fluid flow at auditory frequencies is laminar and its velocity profile is plug-like. The pressure was found 102–106° out of phase with the fluid flow velocity at the scalae vestibule and tympani, respectively. The average flow velocity was found in the sub-μm/s to nm/s range at 20–100 Hz, and below the nm/s range at 1–20 kHz.

The objectives of this research were to 1) summarize the available evidence on the impact of hearing loss on quality of life (QOL) among U.S. active-duty service members, 2) describe the QOL instruments that have been used to quantify the impact of hearing loss on quality of life, 3) examine national population-level secondary databases and report on their utility for studying the impact of hearing loss on QOL among active-duty service members, and 4) provide recommendations for future studies that seek to quantify the impact of hearing loss in this population. There is a lack of literature that addresses the intersection of hearing impairment, the military population, and quality of life measures. For audiological research, U.S. military personnel offer a unique research population, as they are exposed to noise levels and blast environments that are highly unusual in civilian work settings and can serve as a model population for studying the impact on QOL associated with these conditions. Our team recommends conducting a study on the active-duty service member population using a measurement instrument suitable for determining decreases in QOL specifically due to hearing loss.

Hearing is an extremely complex phenomenon, involving a large number of interrelated variables that are difficult to measure in vivo. In order to investigate such process under simplified and well-controlled conditions, models of sound transmission have been developed through many decades of research. The value of modeling the hearing system is not only to explain the normal function of the hearing system and account for experimental and clinical observations, but to simulate a variety of pathological conditions that lead to hearing damage and hearing loss, as well as for development of auditory implants, effective ear protections and auditory hazard countermeasures. In this paper, we provide a review of the strategies used to model the auditory function of the external, middle, inner ear, and the micromechanics of the organ of Corti, along with some of the key results obtained from such modeling efforts. Recent analytical and numerical approaches have incorporated the nonlinear behavior of some parameters and structures into their models. Few models of the integrated hearing system exist; in particular, we describe the evolution of the Auditory Hazard Assessment Algorithm for Human (AHAAH) model, used for prediction of hearing damage due to high intensity sound pressure. Unlike the AHAAH model, 3D finite element models of the entire hearing system are not able yet to predict auditory risk and threshold shifts. It is expected that both AHAAH and FE models will evolve towards a more accurate assessment of threshold shifts and hearing loss under a variety of stimuli conditions and pathologies.