Carla V. Valenzuela

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 GABAA receptors (GABAARs). 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 Ca2+ 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 Ca2+ influx induced by GABAAR 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.

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

To investigate the effects of increasing time and magnitude doses of vibration exposure on transcription of the vocal folds junctional proteins, structural alterations, and functional tissue outcomes.

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.

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.

Nonstimulated rabbit phonation model: Cricothyroid approximation

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.

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

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. Laryngoscope, 126:945–948, 2016

Proliferative laryngitis with airway obstruction in an adult

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. Laryngoscope, 126:945–948, 2016

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 1β and transforming growth factor β1 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.

Characterizing the Vocal Fold Epithelial Response to Recovery following Phonation-Induced Trauma at the Transcriptional Level

Objectives: It is unknown how acute episodes of phonotrauma affect the recovery of the vocal fold epithelial barrier. The epithelial barrier is characterized by specialized adhesive structures. Our objective was to evaluate the gene expression of junctional complex proteins and inflammatory mediators following phonation-induced trauma in an in vivo rabbit model. Methods: Sixty-five New Zealand white breeder rabbits were randomized to normal (n = 5), modal intensity (n = 30), or raised intensity (n = 30) phonation for 120 minutes. Larynges were harvested at 0 hours, 4 hours, 8 hours, 1 day, 3 days, or 7 days following phonation and compared with normal. Real-time polymerase chain reaction was used to evaluate mRNA expression of occludin, zonula occluden-1 (ZO-1), E-cadherin, β-catenin, interleukin 1β (IL-1β), cyclooxygenase-2 (COX-2), and transforming growth factor β-1 (TGFβ1). Results: Both phonation groups demonstrated a down-regulation of occludin between 8 hours and 1 day (P < .016), and ZO-1 levels at 3 days (P = .08). β-catenin and E-cadherin demonstrated an inverse relationship at 8 hours in the modal phonation group (P = .08). IL-1β, COX-2, and TGFβ1 levels peaked at 8 hours in the modal intensity group (P = .08), with TGFβ1 peaking at day 1 in the raised intensity group (P = .08). Conclusions: Results revealed a critical time point at 8 hours and 1 day in which most junctional complex and inflammatory markers decreased or peaked. Given the mechanical stresses that the vocal folds must withstand on a regular basis, time-dependent changes in barrier and inflammatory gene regulation are critical to understanding vocal fold homeostasis and tissue recovery.

Tight Subperiosteal Pocket during Cochlear Implant Surgery: Results in a Large Cohort of Patients

Objectives: (1) Investigate the results of cochlear implant receiver-stimulator (RS) placement using the tight postauricular subperiosteal pocket technique. (2) Compare the efficiency of solely using a tight subperiosteal pocket compared to the conventional bone-recess technique. Methods: Retrospective series from a tertiary academic referral center. All primary and revision cochlear implant patients in whom the RS was placed into a tight subperiosteal pocket without additional fixation were included. Primary outcome measures included RS migration, prevalence of flap complications requiring revision surgery, and time difference comparing the conventional bony well and trough technique to use of a tight subperiosteal pocket. Results: Two hundred consecutive cochlear implants (average age 46.9 years) were analyzed. At a mean follow-up of 12.8 months, only 1 patient experienced device migration; however, none have required revision to date for complications related to RS placement. One patient experienced a hematoma that was managed with observation, and no other soft-tissue flap complications occurred. The subperiosteal pocket technique resulted in a 20% reduction in total operative time compared to conventional RS placement methods (P < .01). Conclusions: The tight subperiosteal pocket is a safe, durable, and time saving technique for RS placement during cochlear implantation. Notably, the prevalence of device migration was exceedingly low, and none have required revision surgery for device drift or flap complications to date.