IGF-1 Mediated Neuroprotective Effects of Olfactory-Derived Mesenchymal Stem Cells on Auditory Hair Cells.

IMPORTANCE: Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of tissues, their specific surface marker profiles and growth factor secretions can be different. We hypothesized that MSCs derived from different sources might also have different neuroprotective potential. OBJECTIVE: In this study, we extracted MSCs from rodent olfactory mucosa and compared their neuroprotective effects on auditory hair cell survival with MSCs extracted from rodent adipose tissue. METHODS: Organ of Corti explants were dissected from 41 cochlea and incubated with olfactory mesenchymal stem cells (OMSCs) and adipose mesenchymal stem cells (AMSCs). After 72 hours, Corti explants were fixed, stained, and hair cells counted. Growth factor concentrations were determined in the supernatant and cell lysate using Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Co-culturing of organ of Corti explants with OMSCs resulted in a significant increase in inner and outer hair cell stereocilia survival, compared to control. Comparisons between both stem cell lines, showed that co-culturing with OMSCs resulted in superior inner and outer hair cell stereocilia survival rates over co-culturing with AMSCs. Assessment of growth factor secretions revealed that the OMSCs secrete significant amounts of insulin-like growth factor 1 (IGF-1). Co-culturing OMSCs with organ of Corti explants resulted in a 10-fold increase in IGF-1 level compared to control, and their secretion was 2 to 3 times higher compared to the AMSCs. CONCLUSIONS: This study has shown that OMSCs may mitigate auditory hair cell stereocilia degeneration. Their neuroprotective effects may, at least partially, be ascribed to their enhanced IGF-1 secretory abilities compared to AMSCs.

Sound Exposure Promotes Intratympanic Drug Delivery to the Inner Ear.

OBJECTIVE: To investigate the impact of sound exposure, with the resultant windows vibration on perilymphatic concentrations following intratympanic (IT) dexamethasone and gentamicin in an animal model. STUDY DESIGN: Animal model blinded study. SETTING: Animal facility of a tertiary medical center. METHODS: Bilateral IT dexamethasone or gentamicin was applied to 15 tested rats. Following injections, each rat was exposed for 3 minutes to free field 30 dB sound pressure level (SPL), 512 vHz noise, with 1 external auditory canal plugged (contralateral control). Following noise exposure, perilymph was obtained from both ears. Drug concentrations were measured using ultrahigh-performance liquid chromatography-mass spectrometer. RESULTS: For dexamethasone, the average (±SD) perilymphatic steroidal concentration was 0.417 µg/mL (±0.549) in the control ears versus 0.487 µg/mL (±0.636) in the sound-exposed ears (P = .008). The average (±SD) gentamicin perilymphatic concentration was 8.628 µg/mL (±2.549) in the sound-exposed ears, compared to 4.930 µg/mL (±0.668) in the contralateral control (nonsound exposed) ears. Sound exposure promoted steroidal and gentamicin diffusion to the inner ear by an averaged (±SD) factor of 1.431 and 1.730 (±0.291 and 0.339), respectively. CONCLUSION: Low-intensity noise (30 dB SPL) was found to enhance dexamethasone phosphate and gentamicin diffusion to the inner ear (by an averaged factor of ∼1.4 and 1.7, respectively) in a murine model.

Balloon dilation of the eustachian tube using endovascular balloon under local anesthesia-a case series and systematic literature review.

Objective: To report a novel technique in Balloon Dilation of Eustachian Tube (BDET) using an endovascular balloon (EVB), in a prospective cohort. The results are compared with reported outcomes using standard balloons. Methods: Demographic information and clinical parameters were collected prospectively fora series of patients with obstructive eustachian tube dysfunction (OETD). Balloon dilation Eustachian tuboplasty was performed under local anesthesia in a tertiary referral center, using the EVB. Systematic literature review was used for comparison, using Medline via "PubMed", "Embase", and "Web of Science". Results: Eight OETD candidates (12 ears) were enrolled; 5 males and 3 females. Average age was 48 (range -23 to 63) years. The most common presenting symptom was aural fullness (9/12), followed by ear pressure (7/12), hearing loss (5/12) and tinnitus (4/12). Otoscopically, tympanic membrane retraction was evident in 10/12 ears, the majority of which was class II-Sade classification. Pre-operative tympanogram was type B and C in 7 and 5 ears, respectively. All BDETs were performed without complications. Post-operative tympanometry was A in 8/12 ears. Post-operatively, Eustachian Tube Dysfunction Questionnaire-7 results reduced to within normal limits (average score ≤3) in 11/12 ears (p = 0.0014). The systematic literature review included 6 papers (193 patients, 262 ETs) with comparable results, most also with little adverse effects. Conclusion: BDET using an EVB is a safe and effective option for OETD. It is well tolerated under local anesthesia in properly selected individuals. The reduced procedural cost may be an important factor in certain healthcare jurisdictions.

How standardised are antibiotic regimens in otologic surgery?

BACKGROUND: Within otologic surgery, a paucity of well-controlled studies assessing the use of systemic antibiotic to reduce surgical site infections exists. Moreover, discrepancies in wound classification of procedures challenge consensus in antimicrobial prescribing patterns. We sought to compare surgeons from two different health systems to examine how surgeons' prescribing habits compared to practice guidelines for numerous otologic procedures. METHODS: An online questionnaire was distributed to 33 Canadian and 32 Austrian surgeons who regularly perform otologic surgery. Current systemic antibiotic prescribing habits for cochlear implantation, cholesteatoma surgery, stapes surgery, and tympanoplasty ± ossiculoplasty were collected. RESULTS: Eighteen of 33 (54.5%) Canadian surgeons provided responses, while 18 of 32 (56.3%) of Austrian surgeons answered. Clear consistency with clinical practice guidelines exists for pre-operative antibiotics use in cochlear implant surgery and infected cholesteatoma surgery. However, for stapes surgery and tympanoplasty ± ossiculoplasty, consensus is lacking for both pre- and post-operative antibiotic prescribing habits. Notable differences between the two countries include post-operative antibiotics for cochlear implant surgery (Austria: 36.4%, Canada: 71.4%) and uninfected cholesteatoma surgery (Austria: 33.3%, Canada: 77.8%). Across all procedures, both induction and post-operative antibiotic administration was not significantly associated with surgeon seniority when stratified by five-year increments. CONCLUSION: The lack of consensus among each country's otologic surgeons underscores the uncertainty in wound classification and thus, adherence to clinical practice guidelines.

Using augmented reality to guide bone conduction device implantation.

Exact placement of bone conduction implants requires avoidance of critical structures. Existing guidance technologies for intraoperative placement have lacked widespread adoption given accessibility challenges and significant cognitive loading. The purpose of this study is to examine the application of augmented reality (AR) guided surgery on accuracy, duration, and ease on bone conduction implantation. Five surgeons surgically implanted two different types of conduction implants on cadaveric specimens with and without AR projection. Pre- and postoperative computer tomography scans were superimposed to calculate centre-to-centre distances and angular accuracies. Wilcoxon signed-rank testing was used to compare centre-to-centre (C-C) and angular accuracies between the control and experimental arms. Additionally, projection accuracy was derived from the distance between the bony fiducials and the projected fiducials using image guidance coordinates. Both operative time (4.3 ± 1.2 min. vs. 6.6 ± 3.5 min., p = 0.030) and centre-to-centre distances surgery (1.9 ± 1.6 mm vs. 9.0 ± 5.3 mm, p < 0.001) were significantly less in augmented reality guided surgery. The difference in angular accuracy, however, was not significantly different. The overall average distance between the bony fiducial markings and the AR projected fiducials was 1.7 ± 0.6 mm. With direct intraoperative reference, AR-guided surgery enhances bone conduction implant placement while reduces operative time when compared to conventional surgical planning.

Examining the Spatial Varying Effects of Sociodemographic Factors on Adult Cochlear Implantation Using Geographically Weighted Poisson Regression.

OBJECTIVE: To (i) demonstrate the utility of geographically weighted Poisson regression (GWPR) in describing geographical patterns of adult cochlear implant (CI) incidence in relation to sociodemographic factors in a publicly funded healthcare system, and (ii) compare Poisson regression and GWPR to fit the aforementioned relationship. STUDY DESIGN: Retrospective study of provincial CI Program database. SETTING: Academic hospital. PATIENTS: Adults 18 years or older who received a CI from 2020 to 2021. INTERVENTIONS: Cochlear implant. MAIN OUTCOME MEASURES: CI incidence based on income level, education attainment, age at implantation, and distance from center, and spatial autocorrelation across census metropolitan areas. RESULTS: Adult CI incidence varied spatially across Ontario (Moran's I = 0.04, p < 0.05). Poisson regression demonstrated positive associations between implantation and lower income level (coefficient = 0.0284, p < 0.05) and younger age (coefficient = 0.1075, p < 0.01), and a negative association with distance to CI center (coefficient = -0.0060, p < 0.01). Spatial autocorrelation was significant in Poisson model (Moran's I = 0.13, p < 0.05). GWPR accounted for spatial differences (Moran's I = 0.24, p < 0.690), and similar associations to Poisson were observed. GWPR further identified clusters of implantation in South Central census metropolitan areas with higher education attainment. CONCLUSIONS: Adult CI incidence demonstrated a nonstationary relationship between implantation and the studied sociodemographic factors. GWPR performed better than Poisson regression in accounting for these local spatial variations. These results support the development of targeted interventions to improve access and utilization to CIs in a publicly funded healthcare system.

The feasibility and safety of eustachian tube dilation with a standard endovascular balloon: a clinical pilot study.

BACKGROUND: Obstructive eustachian tube dysfunction is a common pathology, generally accepted as the underlying cause for chronic ear diseases. Eustachian tube dilation has shown promising results in randomized controlled trials, but is a costly procedure. The aim of the current study was to assess the feasibility of transnasal balloon dilatation of the eustachian tube with an endovascular balloon in the context of ease of use, maneuverability, and safety. METHODS: Clinical pilot study carried out at a university tertiary care facility. In total, twelve patients, were included over a period of 6 months. All patients underwent tympanoplasty or tympanomastoidectomy surgeries. Eustachian tube dilation was carried out transnasal using an endovascular balloon. A computed tomography was carried out after surgery to assess for any potential damages and compared to preoperative imaging studies. Postoperative endoscopy was performed intraoperatively and at follow up to assess for any potential damages. RESULTS: All eustachian tube dilations were carried out successfully. No severe adverse events were noted during the procedure, in the postoperative period, or on imaging studies. Minor adverse events such as mild intraoperative bleeding was managed in a routine fashion. CONCLUSIONS: Balloon dilation of the eustachian tube with the endovascular balloon was feasible and safe in all cases. It is likely a more cost-effective alternative to commercially available balloons with similar designs and specifications. Trial registration The study was registered at clinicaltrials.gov; NCT04809753, initial release February 24th, 2021.

Magnetic Targeting of Gadolinium Contrast to Enhance MRI of the Inner Ear in Endolymphatic Hydrops.

OBJECTIVES: 1. Determine the feasibility and efficiency of local magnetic targeting delivery of gadolinium (Gad) contrast to the inner ear in rodents. 2. Assess any potential ototoxicity of magnetic targeting delivery of Gad in the inner ear. 3. Study the utility of magnetic targeting delivery of Gad to visualize and quantify endolymphatic hydrops (EH) in a transgenic mouse model. STUDY DESIGN: Controlled in vivo animal model study. METHODS: Paramagnetic Gad was locally delivered to the inner ear using the magnetic targeting technique in both rat and mouse models. Efficiency of contrast delivery was assessed using magnetic resonance imaging (MRI). Ototoxicity of Gad was examined with histology of the cochlea and functional audiological tests. The Phex mouse model was used to study EH, hearing loss, and balance dysfunction. Magnetic targeting delivery of Gad contrast was used in the Phex mouse model to visualize the effects of EH using MRI. RESULTS: Magnetic targeting improved the delivery of Gad to the inner ear and the technique was reproducible in both rat and mouse models. The delivery method did not result in microstructural damage or any significant hearing loss in a normal animal. Magnetic targeting of Gad in the Phex mouse model allowed detailed visualization and quantification of EH. CONCLUSION: This study provided the first evidence of the effectiveness and efficiency of the local magnetic targeting delivery of gadolinium contrast to the inner ear and its application to the visualization and quantification of EH. Laryngoscope, 133:914-923, 2023.

Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss.

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.

Neural responses to naturalistic audiovisual speech are related to listening demand in cochlear implant users.

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and "real-world" listening environments and stimuli. Speech in the real world is often accompanied by visual cues, background environmental noise, and is generally in a conversational context, all factors that could affect listening demand. Thus, our objectives were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high-density electroencephalogram (EEG) while CI users listened/watched a naturalistic stimulus (i.e., the television show, "The Office"). We used continuous EEG to quantify "speech neural tracking" (i.e., TRFs, temporal response functions) to the show's soundtrack and 8-12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show, mimicking a natural noisy environment. The task also included an audio-only (no video) condition. After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they understood. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). Increasing background noise affected speech neural tracking at a group level, in addition to eliciting strong individual differences. Mixed effect modeling showed that listening demand and conversation understanding were correlated to early cortical speech tracking, such that high demand and low conversation understanding occurred with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power, where higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between clinical speech perception and quality-of-life in CI users. However, physiological responses to complex natural speech may provide an objective measure of aspects of quality-of-life measures like self-perceived listening demand.

The Feasibility of Eustachian Tube Dilation With a Standard Endovascular Balloon: A Comparative Cadaver Study.

BACKGROUND: Balloon dilation of the eustachian tube is a new therapeutic option for eustachian tube dysfunction. One of the limiting factors of wider adoption of this technique in many parts of the world is the high cost of the devices, in spite of regulatory approval of safety. OBJECTIVE: Evaluate the performance and usability of standard less-expensive endovascular balloons for eustachian tube dilation in comparison to an approved device in a preclinical study. STUDY DESIGN: Comparative cadaver feasibility study. SETTING: University tertiary care facility. METHODS: Ten eustachian tube dilations were performed with an approved eustachian tube dilation device. Ten other procedures were carried out with an endovascular balloon of similar dimensions. Cone beam computerized tomography was performed to evaluate the extent of dilation and possible damages. The lumen and mucosal lining were inspected endoscopically post-dilation. Volume measurements were compared before and after the procedure in both groups using contrast enhancement. RESULTS: All 20 eustachian tube dilations were carried out successfully. No tissue damages could be identified on cone-beam computerized tomography or via endoscopic examination. There was a statistically significant difference of eustachian tube volumes between pre- and post-dilations, with no statistically significant difference between the devices. CONCLUSION: Eustachian tube dilation with a less costly endovascular balloon achieved similar results to an approved eustachian tube dilation device. No damages or any other safety concerns were identified in a cadaver study.

Pain Management Following Otological Surgery: A Prospective Study of Different Strategies.

OBJECTIVES: The aim of this study was to prospectively assess pain and associated analgesic consumption after otological surgery comparing two prescription patterns. STUDY DESIGN: A prospective nonrandomized consecutive cohort study. METHODS: 125 adult patients undergoing ambulatory otologic surgery-cochlear implantation and endaural middle ear surgery, were assigned (according to surgeon's preference) and prospectively studied in two arms: 1) acetaminophen 500 mg + ibuprofen 400 mg; 2) acetaminophen 500 mg + codeine 30 mg. Pain levels, medication dose, disposal patterns of opioids, and suspected side effects were evaluated. RESULTS: All patients reported mild to moderate pain. There was a statistically significant reduction of pain from day to day, which was on average 0.26 lower than the day before. Sufficient pain control could be achieved with both drug regimens with no significant difference in pain levels. Only 50% of patients who were prescribed opioids used them. Additionally, the median tablet intake was 3 tablets while 10 to 20 tablets were prescribed. The majority of patients (97%) did not dispose of these drugs safely. CONCLUSION: Adequate analgesia was achieved in both arms of this study. Pain control following otologic surgery with a combination of acetaminophen and nonsteroidal anti-inflammatory drugs is recommended unless contraindications or chronic opioid use are present. If opioids such as codeine (30 mg) are prescribed, the amount should be reduced as low as possible, such as five tablets, based on our studied population. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:204-211, 2022.

Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury.

Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno-associated virus (AAV) vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF) gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes the SPION-tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, auditory brainstem response (ABR) wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL.

Is otologic surgery contributing to the opioid epidemic?

BACKGROUND: The opioid epidemic is a significant public health crisis challenging the lives of North Americans. Interestingly, this problem does not exist to the same extent in Europe. Surgeons play a significant role in prescribing opioids, especially in the context of post-operative pain management. The aim of this study was to compare the post-surgical prescribing patterns of otologists comparing Canada and Austria. METHODS: An online questionnaire was sent to 33 Canadian and 32 Austrian surgeons, who perform otologic surgery on a regular basis. Surgeons were asked to answer some questions about their background as well as typical prescribing patterns for postoperative pain medication for different ear surgeries (cochlear implant, stapedotomy, tympanoplasty). In addition, surgeons were asked about the typical use of local anesthetics for pain control at the end of a procedure. Otologists gave an estimate how confident they were that their therapy and prescriptions provide sufficient pain control to their patients. RESULTS: Analysis of the returned questionnaires showed that opioids are more commonly prescribed in Canada than in Austria. Nonsteroidal anti-inflammatory drugs are used for postoperative pain more regularly after ear surgery in Austria, as opposed to Canada. Some of the prescribed drugs by European otologists are not available in North America. The use of local anesthetics at the end of surgery is not common in Austria. Surgeons´ confidence that the prescribed pain medication was sufficient to control postoperative symptoms was higher in the group not prescribing opioids than in the group that did routinely prescribe opioids. CONCLUSION: Prescribing patterns differ substantially between the two evaluated countries. This data suggests an opportunity to reduce opioid prescriptions after otologic surgeries. Studies to evaluate pain after these operations as well as efficacy of analgesics following ear surgery are an important next step.

Vestibular Neuritis: Recent Advances in Etiology, Diagnostic Evaluation, and Treatment.

Purpose of Chapter: This chapter highlights the recent advances in etiology, diagnostic evaluation, and management of vestibular neuritis (VN). Recent Findings: The viral hypothesis has been strengthened with new evidence as the main etiology of VN. Recent evidence indicates that bedside oculomotor findings play a critical role in differentiating VN from stroke. The implementation of cervical and ocular vestibular evoked myogenic potential, and video head impulse test in vestibular function testing has made it possible to diagnose selective damage of the vestibular nerves. The management of the acute phase of VN is primarily medical, while long-term treatment is designed to improve vestibular compensation. Summary: VN is clearly defined as an important viral inner ear disorder.

Characterization of an Orthotopic Rat Model of Glioblastoma Using Multiparametric Magnetic Resonance Imaging and Bioluminescence Imaging.

Glioblastoma multiforme (GBM) is the most common primary brain tumor, with most patients dying within 15-18 months of diagnosis despite aggressive therapy. Preclinical GBM models are valuable for exploring GBM progression and for evaluating new therapeutics or imaging approaches. The rat C6 glioma model shares similarities with human GBM, and application of noninvasive imaging enables better study of disease progression. Here, multiparametric magnetic resonance imaging (mpMRI) and bioluminescence imaging (BLI) were applied to characterize longitudinal development of orthotopic luciferase-expressing C6 tumors. Across all rats (n = 11), a large variability was seen for BLI signal, a relative measure of C6 cell viability, but in most individuals, BLI signal peaked at day 11 and decreased thereafter. T2 and contrast-enhanced T1 tumor volumes significantly increased over time (P < .05), and volume measures did not correlate with BLI signal. After day 11, tumor regions of noncontrast enhancement appeared in postcontrast T1-weighted magnetic resonance imaging, and had significantly higher apparent diffusion coefficient values compared with contrast-enhanced regions (P < .05). This suggests formation of ill-perfused, necrotic regions beyond day 11, which were apparent at end-point-matched tissue sections. Our study represents the first combined use of BLI and mpMRI to characterize the progression of disease in the orthotopic C6 rat model, and it highlights the variability in tumor growth, the complementary information from BLI and mpMRI, and the value of multimodality imaging to better characterize tumor development. Future application of these imaging tools will be useful for evaluation of treatment response, and should be pertinent for other preclinical models.

Mannitol and the blood-labyrinth barrier.

BACKGROUND: Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. STUDY DESIGN: Controlled animal research project. METHODS: Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. RESULTS: Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. CONCLUSIONS: Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph.

GABAergic Interneuron Differentiation in the Basal Forebrain Is Mediated through Direct Regulation of Glutamic Acid Decarboxylase Isoforms by Dlx Homeobox Transcription Factors.

GABA is the key inhibitory neurotransmitter in the cortex but regulation of its synthesis during forebrain development is poorly understood. In the telencephalon, members of the distal-less (Dlx) homeobox gene family are expressed in, and regulate the development of, the basal ganglia primodia from which many GABAergic neurons originate and migrate to other forebrain regions. The Dlx1/Dlx2 double knock-out mice die at birth with abnormal cortical development, including loss of tangential migration of GABAergic inhibitory interneurons to the neocortex (Anderson et al., 1997a). We have discovered that specific promoter regulatory elements of glutamic acid decarboxylase isoforms (Gad1 and Gad2), which regulate GABA synthesis from the excitatory neurotransmitter glutamate, are direct transcriptional targets of both DLX1 and DLX2 homeoproteins in vivo Further gain- and loss-of-function studies in vitro and in vivo demonstrated that both DLX1 and DLX2 are necessary and sufficient for Gad gene expression. DLX1 and/or DLX2 activated the transcription of both Gad genes, and defects in Dlx function disrupted the differentiation of GABAergic interneurons with global reduction in GABA levels in the forebrains of the Dlx1/Dlx2 double knock-out mouse in vivo Identification of Gad genes as direct Dlx transcriptional targets is significant; it extends our understanding of Dlx gene function in the developing forebrain beyond the regulation of tangential interneuron migration to the differentiation of GABAergic interneurons arising from the basal telencephalon, and may help to unravel the pathogenesis of several developmental brain disorders.SIGNIFICANCE STATEMENT GABA is the major inhibitory neurotransmitter in the brain. We show that Dlx1/Dlx2 homeobox genes regulate GABA synthesis during forebrain development through direct activation of glutamic acid decarboxylase enzyme isoforms that convert glutamate to GABA. This discovery helps explain how Dlx mutations result in abnormal forebrain development, due to defective differentiation, in addition to the loss of tangential migration of GABAergic inhibitory interneurons to the neocortex. Reduced numbers or function of cortical GABAergic neurons may lead to hyperactivity states such as seizures (Cobos et al., 2005) or contribute to the pathogenesis of some autism spectrum disorders. GABAergic dysfunction in the basal ganglia could disrupt the learning and development of complex motor and cognitive behaviors (Rubenstein and Merzenich, 2003).

Current insights in noise-induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options.

BACKGROUND: Noise-induced hearing loss is one of the most common forms of sensorineural hearing loss, is a major health problem, is largely preventable and is probably more widespread than revealed by conventional pure tone threshold testing. Noise-induced damage to the cochlea is traditionally considered to be associated with symmetrical mild to moderate hearing loss with associated tinnitus; however, there is a significant number of patients with asymmetrical thresholds and, depending on the exposure, severe to profound hearing loss as well. MAIN BODY: Recent epidemiology and animal studies have provided further insight into the pathophysiology, clinical findings, social and economic impacts of noise-induced hearing loss. Furthermore, it is recently shown that acoustic trauma is associated with vestibular dysfunction, with associated dizziness that is not always measurable with current techniques. Deliberation of the prevalence, treatment and prevention of noise-induced hearing loss is important and timely. Currently, prevention and protection are the first lines of defence, although promising protective effects are emerging from multiple different pharmaceutical agents, such as steroids, antioxidants and neurotrophins. CONCLUSION: This review provides a comprehensive update on the pathophysiology, investigations, prevalence of asymmetry, associated symptoms, and current strategies on the prevention and treatment of noise-induced hearing loss.

Role of Facial Nerve Motor-Evoked Potential Ratio in Predicting Facial Nerve Function in Vestibular Schwannoma Surgery Both Immediate and at 1 Year.

OBJECTIVE: To determine whether transcranial electrical stimulation-induced facial motor-evoked potential (FMEP) monitoring of the facial nerve (FN) during vestibular schwannoma (VS) tumor resection can predict both immediate and 1 year postoperative FN functional outcome. DESIGN: Prospective consecutive non-comparative observational case series. SETTING: Tertiary referral center. MAIN OUTCOME MEASURES: Facial function, immediate post operation and at 1 year using House-Brackmann (HB) grading scale. METHODS: The study included 367 consecutive patients (men 178; women 189; age 13-81 years) monitored during primary sporadic VS microsurgery between November 2002 and April 2015. Neurofibromatosis type II, revision surgery, previous radiotherapy treatment, preoperative facial nerve weakness, and non-VS cases were excluded retrospectively during analysis of data. Data of facial function were missing from eight patients at 1 year and were excluded. The correlation between the final-to-baseline FMEP ratio and immediate and 1 year facial nerve function was examined. RESULTS: Using logistic regression model, the cut-off points of FMEP ratio were 0.62 (PPV 0.96) and 0.59 (PPV 0.98) which predicted satisfactory FN function (HB grades 1 or 2) immediately postoperative and at 1 year after surgery, respectively. CONCLUSION: Transcranial electrical stimulation FMEP is a valuable tool for monitoring facial nerve function during resection of vestibular schwannoma. Maintaining a FMEP event-to-baseline ratio of 60% or greater is predictive of satisfactory long-term FN function.