Catchment Profile of Large Cochlear Implant Centers in the United States.

OBJECTIVE: To characterize the catchment area and patient profile of large cochlear implant (CI) centers in the United States. STUDY DESIGN: Multi-institutional retrospective case series. SETTING: Tertiary referral CI centers. METHODS: Patients who underwent CI surgery at 7 participating CI centers between 2015 and 2020 were identified. Patients' residential zip codes were used to approximate travel distances and urban vs rural residential areas. RESULTS: Over the 6-year study period (2015-2020), 6313 unique CI surgical procedures occurred (4529 adult, 1784 pediatric). Between 2015 and 2019, CI procedures increased by 43%. Patients traveled a median 52 miles (interquartile range, 21-110) each way; patients treated at rural CI centers traveled greater distances vs those treated at urban centers (72 vs 46 miles, P < .001). Rural residents represented 61% of the patient population and traveled farther than urban residents (73 vs 24 miles, P < .001). Overall, 91% of patients lived within a 200-mile radius of the institution, while 71% lived within a 100-mile radius. In adults, multiple regression analysis redemonstrated an association between greater travel distances and (1) older age at the time of CI and (2) residential rural setting (both P < .001, r2 = 0.2). CONCLUSIONS: While large CI centers serve geographically dispersed populations, most patients reside within a 200-mile radius. Strategies to expand CI utilization may leverage remote programming, telemedicine, and strategic placement of new centers and satellite clinics to ameliorate travel burden.

Relationship Between Intraoperative Electrocochleography and Hearing Preservation.

OBJECTIVES: To compare intraoperative intracochlear electrocochleography (ECochG) with hearing preservation outcomes in cochlear implant (CI) subjects. DESIGN: Intraoperative electrocochleography was performed in adult CI subjects who were recipients of Advanced Bionics' Bionics LLC precurved HiFocus MidScala or straight HiFocus SlimJ electrode arrays. ECochG responses were recorded from the most apical electrode contact during insertion. No changes to the insertions were made due to ECochG monitoring. No information about insertion resistance was collected. ECochG drops were estimated as the change in amplitude from peak (defined as maximum amplitude response) to drop (largest drop) point after the peak during insertion was measured following the peak response. Audiometric thresholds from each subject were obtained before and approximately 1 month after CI surgery. The change in pure tone average for frequencies between 125 Hz and 500 Hz was measured after surgery. No postoperative CT scans were collected as part of this study. RESULTS: A total of 68 subjects from five surgical centers participated in the study. The study sample included 30 MidScala and 38 SlimJ electrodes implanted by approximately 20 surgeons who contributed to the study. Although a wide range of results were observed, there was a moderate positive correlation (Pearson Correlation coefficient, r = 0.56, p < 0.01) between the size of the ECochG drop and the magnitude of pure tone average change. This trend was present for both the MidScala and SlimJ arrays. The SlimJ and MidScala arrays produced significantly different hearing loss after surgery. CONCLUSION: Large ECochG amplitude drops observed during electrode insertion indicated poorer hearing preservation. Although the outcomes were variable, this information may be helpful to guide surgical decision-making when contemplating full electrode insertion and the likelihood of hearing preservation.

Intracochlear Electrocochleography and Speech Perception Scores in Cochlear Implant Recipients.

OBJECTIVES/HYPOTHESIS: Previous studies have demonstrated that electrocochleography (ECochG) measurements made at the round window prior to cochlear implant (CI) electrode insertion can account for 47% of the variability in 6-month speech perception scores. Recent advances have made it possible to use the apical CI electrode to record intracochlear responses to acoustic stimuli. Study objectives were to determine 1) the relationship between intracochlear ECochG response amplitudes and 6-month speech perception scores and 2) to determine the relationship between behavioral auditory thresholds and ECochG threshold estimates. The hypothesis was that intracochlear ECochG response amplitudes made immediately after electrode insertion would be larger than historical controls (at the extracochlear site) and explain more variability in speech perception scores. STUDY DESIGN: Prospective case series. METHODS: Twenty-two adult CI recipients with varying degrees of low-frequency hearing had intracochlear ECochG measurements made immediately after CI electrode insertion using 110 dB SPL tone bursts. Tone bursts were centered at five octave-spaced frequencies between 125 and 2,000 Hz. RESULTS: There was no association between intracochlear ECochG response amplitudes and speech perception scores. But, the data suggest a mild to moderate relationship between preoperative behavioral audiometric testing and intraoperative ECochG threshold estimates. CONCLUSION: Performing intracochlear ECochG is highly feasible and results in larger response amplitudes, but performing ECochG before, rather than after, CI insertion may provide a more accurate assessment of a patient's speech perception potential. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2681-E2688, 2021.

Survival of Young Versus Old Patients With Oral Cavity Squamous Cell Carcinoma: A Meta-Analysis.

OBJECTIVE/HYPOTHESIS: To assess whether young patients with oral cavity squamous cell carcinoma (OCSCC) demonstrate worse oncologic outcomes than older patients after definitive therapy. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A medical librarian composed a search strategy to identify relevant studies in Medline, Embase, Scopus, and other major databases (Prospero registration number CRD42019127974). Inclusion criteria were adults with histologically diagnosed OCSCC that underwent treatment, comparator groups with an age cutoff of 40 years old, and reported survival outcomes. Articles were excluded if they contained patients with oropharyngeal squamous cell carcinoma or patients treated for palliative intent. Overall survival hazard ratios were analyzed with a meta-analysis. RESULTS: There were 23,382 patients with OCSCC that were treated with definitive therapy from 22 included studies. The pooled cohort contained 2,238 (10%) patients ≤40 years of age. Oral tongue was the most common subsite in both the younger (n = 1,961, 91%) and older (n = 18,047, 88%) cohorts. The majority of OCSCCs were either T1 or T2, representing 859 (80%) malignancies in younger patients and 8,126 (77%) malignancies in older patients. A meta-analysis of nine studies demonstrated that younger patients did not experience worse survival outcomes than older patients (hazard ratio = 0.97, 95% confidence interval = 0.66-1.41). CONCLUSIONS: Young adults with OCSCC experienced similar oncologic outcomes as older patients with OCSCC after definitive treatment. Until compelling evidence demonstrates clinically relevant differences between these two cohorts, their approach to management should be similar. Future studies should consider comorbidities and using age 40 as a standard age cutoff to provide more uniform data moving forward. Laryngoscope, 131:1310-1319, 2021.

Is cochlear synapse loss an origin of low-frequency hearing loss associated with endolymphatic hydrops?

There is a strong association between endolymphatic hydrops and low-frequency hearing loss, but the origin of the hearing loss remains unknown. A reduction in the number of cochlear afferent synapses between inner hair cells and auditory nerve fibres may be the origin of the low-frequency hearing loss, but this hypothesis has not been directly tested in humans or animals. In humans, measurements of hearing loss and postmortem temporal-bone based measurements of endolymphatic hydrops are generally separated by large amounts of time. In animals, there has not been a good objective, physiologic, and minimally invasive measurement of low-frequency hearing. We overcame this obstacle with the combined use of a reliable surgical approach to ablate the endolymphatic sac in guinea pigs and create endolymphatic hydrops, the Auditory Nerve Overlapped Waveform to measure low-frequency hearing loss (≤ 1 kHz), and immunohistofluorescence-based confocal microscopy to count cochlear synapses. Results showed low- and mid-(1-4 kHz) frequency hearing loss at all postoperative days, 1, 4, and 30. There was no statistically significant loss of cochlear synapses, and there was no correlation between synapse loss and hearing function. We conclude that cochlear afferent synaptic loss is not the origin of the low-frequency hearing loss in the early days following endolymphatic sac ablation. Understanding what is, and is not, the origin of a hearing loss can help guide preventative and therapeutic development.

A Revised Surgical Approach to Induce Endolymphatic Hydrops in the Guinea Pig.

Endolymphatic hydrops is an enlargement of scala media that is most often associated with Meniere's disease, though the pathophysiologic mechanism(s) remain unclear. In order to adequately study the attributes of endolymphatic hydrops, such as the origins of low-frequency hearing loss, a reliable model is needed. The guinea pig is a good model because it hears in the low-frequency regions that are putatively affected by endolymphatic hydrops. Previous research has demonstrated that endolymphatic hydrops can be induced surgically via intradural or extradural approaches that involve drilling on the endolymphatic duct and sac. However, whether it was possible to create an endolymphatic hydrops model using an extradural approach that avoided dangerous drilling on the endolymphatic duct and sac was unknown. The objective of this study was to demonstrate a revised extradural approach to induce experimental endolymphatic hydrops at 30 days post-operatively by obliterating the endolymphatic sac and injuring the endolymphatic duct with a fine pick. The sample size consisted of seven guinea pigs. Functional measurements of hearing were made and temporal bones were subsequently harvested for histologic analysis. The approach had a success rate of 86% in achieving endolymphatic hydrops. The risk of cerebrospinal fluid leak was minimal. No perioperative deaths or injuries to the posterior semicircular canal occurred in the sample. The presented method demonstrates a safe and reliable way to induce endolymphatic hydrops at a relatively quick time point of 30 days. The clinical implications are that the presented method provides a reliable model to further explore the origins of low-frequency hearing loss that can be associated endolymphatic hydrops.

Clinical Practice Guideline: Ménière's Disease.

OBJECTIVE: Ménière's disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid (endolymph) volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Conventional imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many and typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. PURPOSE: The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging.

Clinical Practice Guideline: Ménière's Disease Executive Summary.

OBJECTIVE: Ménière's disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many, and approaches typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. PURPOSE: The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging.

Intracochlear Electrocochleography: Influence of Scalar Position of the Cochlear Implant Electrode on Postinsertion Results.

HYPOTHESIS: Electrocochleography (ECochG) recorded during cochlear implant (CI) insertion from the apical electrode in conjunction with postinsertion ECochG can identify electrophysiologic differences that exist between groups with and without a translocation of the array from the scala tympani (ST) into the scala vestibuli (SV). BACKGROUND: Translocation of the CI electrode from ST into SV can limit performance postoperatively. ECochG markers of trauma may be able to aid in the ability to detect electrode array-induced trauma/scalar translocation intraoperatively. METHODS: Twenty-one adult CI patients were included. Subjects were postoperatively parsed into two groups based on analysis of postoperative imaging: 1) ST (n = 14) insertion; 2) SV (n = 7) insertion, indicating translocation of the electrode. The ECochG response elicited from a 500 Hz acoustic stimulus was recorded from the lead electrode during insertion when the distal electrode marker was at the round window, and was compared to the response recorded from a basal electrode (e13) after complete insertion. RESULTS: No statistically significant change in mean ECochG magnitude was found in either group between recording intervals. There was a mean loss of preoperative pure-tone average of 52% for the nontranslocation group and 94% for the translocation group. CONCLUSIONS: Intraoperative intracochlear ECochG through the CI array provides a unique opportunity to explore the impact of the CI electrode on the inner ear. Specifically, a translocation of the array from ST to SV does not seem to change the biomechanics of the cochlear region that lies basal to the area of translocation in the acute period.

Chemotherapy-Induced First Bite Syndrome: A Case Report in a Patient With Hodgkin Lymphoma.

Vinca alkaloids are known to cause bilateral jaw pain that occurs once during the chemotherapy course. We report a patient with first bite syndrome (FBS) during active treatment with chemotherapy. A patient with Hodgkin lymphoma presented with unilateral jaw pain after beginning his chemotherapy regimen. Pain was worse with the first bite of each meal and dissipated over subsequent bites. Workup was negative for any lesions in the parotid, parapharyngeal space, or infratemporal fossa. Pain was timed closely with chemotherapy administration and would improve prior to next cycle. A trial of botulinum chemodenervation failed to completely relieve symptoms. The patient noted resolution of symptoms after the completion of chemotherapy. We report a case of FBS, which may represent the jaw pain seen commonly with administration of vinca alkaloids. There appears to be a correlation between onset and duration of first bite symptoms with chemotherapy administration.

Intranasal Corticosteroids Do Not Lead to Ocular Changes: A Systematic Review and Meta-analysis.

OBJECTIVES: The safety and efficacy of intranasal corticosteroids (INCS) are well established, but there remains apprehension that INCS could lead to systemic side effects, as with oral steroids. The objective of this systematic review was to assess whether the use of INCS lead to increased intraocular pressure (IOP) above 20 mm Hg, glaucoma, or formation of posterior subcapsular cataracts in adult patients with rhinitis. METHODS: Two medical librarians searched the published literature for records discussing the use of "nasal steroids" in "rhinitis" and their effect on "intraocular pressure," "cataracts," or "glaucoma." RESULTS: A total of 484 studies were identified, and 10 randomized controlled trials met our inclusion criteria. Meta-analysis of 2,226 patients revealed that the relative risk of elevated IOP in those who received INCS was 2.24 (95% confidence interval [CI]: 0.68 to 7.34) compared to placebo. The absolute increased incidence of elevated IOP in patients using INCS compared to placebo was 0.8% (95% CI: 0% to 1.6%). There were zero cases of glaucoma in both placebo and INCS groups at 12 months. The absolute increased incidence of developing a posterior subcapsular cataract was 0.02% (95% CI: -0.3% to 0.4%). CONCLUSIONS: Use of INCS is not associated with a significant risk of elevating IOP or developing a posterior subcapsular cataract in patients with allergic rhinitis. Presence of glaucoma, however, is the real clinical adverse event of concern. There were zero reported cases of glaucoma at 12 months. Future studies should formally evaluate for glaucoma rather than use IOP measures as a surrogate. Laryngoscope, 129:6-12, 2019.

Intra-Cochlear Electrocochleography During Cochear Implant Electrode Insertion Is Predictive of Final Scalar Location.

HYPOTHESIS: Electrocochleography (ECochG) patterns observed during cochlear implant (CI) electrode insertion may provide information about scalar location of the electrode array. BACKGROUND: Conventional CI surgery is performed without actively monitoring auditory function and potential damage to intracochlear structures. The central hypothesis of this study was that ECochG obtained directly through the CI may be used to estimate intracochlear electrode position and, ultimately, residual hearing preservation. METHODS: Intracochlear ECochG was performed on 32 patients across 3 different implant centers. During electrode insertion, a 50-ms tone burst stimulus (500 Hz) was delivered at 110 dB SPL. The ECochG response was monitored from the apical-most electrode. The amplitude and phase changes of the first harmonic were imported into an algorithm in an attempt to predict the intracochlear electrode location (scala tympani [ST], translocation from ST to scala vestibuli [SV], or interaction with basilar membrane). Anatomic electrode position was verified using postoperative computed tomography (CT) with image processing. RESULTS: CT analysis confirmed 25 electrodes with ST position and 7 electrode arrays translocating from ST into SV. The ECochG algorithm correctly estimated electrode position in 26 (82%) of 32 subjects while 6 (18%) electrodes were wrongly identified as translocated (sensitivity = 100%, specificity = 77%, positive predictive value = 54%, and a negative predictive value = 100%). Greater hearing loss was observed postoperatively in participants with translocated electrode arrays (36 ±â€Š15 dB) when compared with isolated ST insertions (28 ±â€Š20 dB HL). This result, however, was not significant (p = 0.789). CONCLUSION: Intracochlear ECochG may provide information about CI electrode location and hearing preservation.

Recovery of Vocal Fold Epithelium after Acute Phonotrauma.

We investigated the timeline of tissue repair of vocal fold epithelium after acute vibration exposure using an in vivo rabbit model. Sixty-five New Zealand white breeder rabbits were randomized to 120 min of modal- or raised-intensity phonation. After the larynges were harvested at 0, 4, 8, and 24 h, and at 3 and 7 days, the vocal fold tissue was evaluated using electron microscopy and quantitative real-time polymerase chain reaction. There was an immediate decrease in the microprojection depth and height following raised-intensity phonation, paired with upregulation of cyclooxygenase-2. This initial 24-h period was also characterized by the significant downregulation of junction proteins. Interleukin 1ß and transforming growth factor ß1 were upregulated for 3 and 7 days, respectively, followed by an increase in epithelial cell surface depth at 3 and 7 days. These data appear to demonstrate a shift from inflammatory response to the initiation of a restorative process in the vocal fold epithelium between 24 h and 3 days. Despite the initial damage from raised-intensity phonation, the vocal fold epithelium demonstrates a remarkable capacity for the expeditious recovery of structural changes from transient episodes of acute phonotrauma. While structurally intact, the return of functional barrier integrity may be delayed by repeated episodes of phonotrauma and may also play an important role in the pathophysiology of vocal fold lesions.

Nonstimulated rabbit phonation model: Cricothyroid approximation.

OBJECTIVES/HYPOTHESIS: To describe a nonstimulated in vivo rabbit phonation model using an Isshiki type IV thyroplasty and uninterrupted humidified glottal airflow to produce sustained audible phonation. STUDY DESIGN: Prospective animal study. METHODS: Six New Zealand white breeder rabbits underwent a surgical procedure involving an Isshiki type IV thyroplasty and continuous airflow delivered to the glottis. Phonatory parameters were examined using high-speed laryngeal imaging and acoustic and aerodynamic analysis. Following the procedure, airflow was discontinued, and sutures remained in place to maintain the phonatory glottal configuration for microimaging using a 9.4 Tesla imaging system. RESULTS: High-speed laryngeal imaging revealed sustained vocal fold oscillation throughout the experimental procedure. Analysis of acoustic signals revealed a mean vocal intensity of 61 dB and fundamental frequency of 590 Hz. Aerodynamic analysis revealed a mean airflow rate of 85.91 mL/s and subglottal pressure of 9 cm H2 O. Following the procedure, microimaging revealed that the in vivo phonatory glottal configuration was maintained, providing consistency between the experimental and postexperimental laryngeal geometry. The latter provides a significant milestone that is necessary for geometric reconstruction and to allow for validation of computational simulations against the in vivo rabbit preparation. CONCLUSION: We demonstrate a nonstimulated in vivo phonation preparation using an Isshiki type IV thyroplasty and continuous humidified glottal airflow in a rabbit animal model. This preparation elicits sustained vocal fold vibration and phonatory measures that are consistent with our laboratory's prior work using direct neuromuscular stimulation for evoked phonation. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1589-1594, 2016.

Proliferative laryngitis with airway obstruction in an adult: Consider herpes.

OBJECTIVES/HYPOTHESIS: Few cases of herpes simplex virus (HSV) affecting the larynx have been reported in the literature. Although HSV laryngitis appears to present with nonspecific symptoms, this is a potentially serious condition that can rapidly progress to unnecessary morbidity and mortality if not identified and treated accordingly. We report a case of HSV laryngitis in an individual with well controlled human immunodeficiency virus infection and perform a comprehensive literature review of HSV laryngitis in adults. From this case report and review of the literature, we advocate early diagnostic biopsy of unusual or poorly responsive laryngeal lesions for pathology, culture, and virology studies.

The Natural History and Management of Petrous Apex Cholesterol Granulomas.

OBJECTIVE: To evaluate the clinical and radiographic characteristics of cholesterol granulomas of the petrous apex, as well as the outcomes of operative and conservative management. STUDY DESIGN: Retrospective chart review. SETTING: Two independent tertiary academic referral centers. PATIENTS: Adult and pediatric patients with cholesterol granulomas of the petrous apex were identified from the experience of two separate centers. Patients were included after radiographic diagnosis and clinical evaluation. All patients with less than 6 months of follow-up and those with iatrogenic postoperative cholesterol granulomas were excluded. INTERVENTION: Demographic information, presenting symptoms, imaging characteristics, treatment strategies, and outcomes were recorded. MAIN OUTCOME MEASURES: Patients were evaluated on the basis of symptom and radiographic evolution during time, with or without operative intervention. RESULTS: Ninety petrous apex cholesterol granulomas were analyzed (57.8% females, 55.6% right-sided). The average age at presentation was 43.1 years (median 42.0, range 8.0-77.0 years). The most common presenting symptom was headache (56.7%), and the average lesion size in the greatest dimension was 2.1 cm (median 1.7, range 0.7-5.0 cm). During a mean follow-up of 46.0 months, no cases of spontaneous rupture or carotid injury occurred. Twenty-three patients (25.6%) ultimately underwent surgical management, most commonly for intractable headache, and only 47.8% of these patients experienced durable symptom improvement by their last postoperative follow-up. CONCLUSION: Many cholesterol granulomas of the petrous apex remain stable during time and can be safely managed with primary observation. Surgery should be reserved for lesions that are causing, or threatening, neurologic dysfunction because of mass effect or erosion of critical structures such as the otic capsule. Cranial neuropathy associated with cholesterol granuloma may improve after operative management; however, symptoms such as headache and dizziness are less likely to benefit from surgery. As a general guideline, in the presence of a radiologically stable cholesterol granuloma in the petrous apex, alternative etiologies for headache and dizziness should be considered and treated before offering surgical intervention.

228 cases of cochlear implant receiver-stimulator placement in a tight subperiosteal pocket without fixation.

OBJECTIVES: (1) To investigate the outcomes of cochlear implant receiver-stimulator (RS) placement using a tight subperiosteal pocket technique without device fixation and (2) to compare the efficiency of this approach with the traditional bony well and trough technique. STUDY DESIGN: Case series with planned chart review. SETTING: Single tertiary academic referral center. SUBJECTS AND METHODS: All cochlear implant surgeries utilizing a tight subperiosteal pocket without additional fixation or use of a bone well were identified retrospectively. Revision cases were only included if the tight subperiosteal pocket technique was used during the initial surgery. Patients with less than 6 months of postoperative follow-up were excluded. Primary outcome measures included RS migration, flap complications, device failure, and percentage reduction in operative time. RESULTS: Two hundred twenty-eight cases (average age 45.3 years) met inclusion criterion and were analyzed. At a mean follow-up of 18.1 months, no patient experienced RS migration. One patient experienced a postoperative hematoma that was managed with observation. One patient developed a surgical site infection that resolved following exploration and intravenous antibiotics. The subperiosteal pocket technique resulted in an 18.9% reduction in total operative time compared to a more conventional RS placement method (P < .01). CONCLUSIONS: The tight subperiosteal pocket without fixation is a safe, durable, and time-saving technique for RS placement during cochlear implantation. Notably, device migration and flap complications are very uncommon.

Effects of phonation time and magnitude dose on vocal fold epithelial genes, barrier integrity, and function.

OBJECTIVES/HYPOTHESIS: To investigate the effects of increasing time and magnitude doses of vibration exposure on transcription of the vocal fold's junctional proteins, structural alterations, and functional tissue outcomes. STUDY DESIGN: Animal study. METHODS: 100 New Zealand White breeder rabbits were studied. Dependent variables were measured in response to increasing time doses (30, 60, or 120 minutes) and magnitude doses (control, modal intensity, and raised intensity) of vibration exposure. Messenger RNA expression of occludin, zonula occluden-1 (ZO-1), E-cadherin, ß-catenin, interleukin 1ß, cyclooxygenase-2, transforming growth factor ß-1, and fibronectin were measured. Tissue structural alterations were assessed using transmission electron microscopy (TEM). Transepithelial resistance was used to measure functional tissue outcomes. RESULTS: Occludin gene expression was downregulated in vocal folds exposed to 120-minute time doses of raised-intensity phonation, relative to control, and modal-intensity phonation. ZO-1 gene expression was upregulated following a 120-minute time dose of modal-intensity phonation, compared to control, and downregulated after a 120-minute time dose of raised-intensity phonation, compared to modal-intensity phonation. E-cadherin gene expression was downregulated after a 120-minute time dose of raised-intensity phonation, compared to control and modal-intensity phonation. TEM revealed extensive desquamation of the stratified squamous epithelial cells with increasing time and magnitude doses of vibration exposure. A general observation of lower transepithelial resistance measures was made in tissues exposed to raised-intensity phonation compared to all other groups. CONCLUSIONS: This study provides evidence of vocal fold tissue responses to varying time and magnitude doses of vibration exposure. LEVEL OF EVIDENCE: NA.

Kinases SPAK and OSR1 are upregulated by estradiol and activate NKCC1 in the developing hypothalamus.

In immature neurons the amino acid neurotransmitter, GABA provides the dominant mode for neuronal excitation by inducing membrane depolarization due to Cl(-) efflux through GABA(A) receptors (GABA(A)Rs). The driving force for Cl(-) is outward because the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) elevates the Cl(-) concentration in these cells. GABA-induced membrane depolarization and the resulting activation of voltage-gated Ca(2+) channels is fundamental to normal brain development, yet the mechanisms that regulate depolarizing GABA are not well understood. The neurosteroid estradiol potently augments depolarizing GABA action in the immature hypothalamus by enhancing the activity of the NKCC1 cotransporter. Understanding how estradiol controls NKCC1 activity will be essential for a complete understanding of brain development. We now report that estradiol treatment of newborn rat pups significantly increases protein levels of two kinases upstream of the NKCC1 cotransporter, SPAK (STE20/SPS1-related proline alanine rich kinase) and OSR1 (oxidative stress response kinase). The estradiol-induced increase is transcription dependent, and its time course parallels that of estradiol-enhanced phosphorylation of NKCC1. Antisense oligonucleotide-mediated knockdown of SPAK, and to a lesser degree of OSR1, precludes estradiol-mediated enhancement of NKCC1 phosphorylation. Functionally, knockdown of SPAK or OSR1 in embryonic hypothalamic cultures diminishes estradiol-enhanced Ca(2+) influx induced by GABA(A)R activation. Our data suggest that SPAK and OSR1 may be critical factors in the regulation of depolarizing GABA-mediated processes in the developing brain. It will be important to examine these kinases with respect to sex differences and developmental brain anomalies in future studies.