Serum Prestin After Ototoxin Exposure Is Not Dependent on Outer Hair Cell Loss.

HYPOTHESIS: Cyclodextrin (CDX)-induced serum prestin burst is not dependent on outer hair cell (OHC) loss. BACKGROUND: Serum prestin has been proposed as a biomarker for ototoxicity. We recently used an automated Western approach to quantify serum prestin changes in a newly introduced model of CDX ototoxicity. To gain insights into prestin as a biomarker, here we further characterize serum prestin in the CDX model. METHODS: Guinea pigs were treated with 750, 3,000, or 4,000 mg/kg CDX, and serum samples were obtained through up to 15 weeks after exposure. Serum prestin levels were quantified using automated Western, and hair cell counts were obtained. RESULTS: All three doses induced an N -glycosylated ~134-kDa prestin burst; however, only the 3,000 and 4,000 mg/kg resulted in robust OHC loss. Prestin levels returned to baseline where they remained up to 15 weeks in the absence of OHCs. CONCLUSION: The ~134-kDa prestin burst induced after CDX administration is N -glycosylated, representing a posttranslational modification of prestin. Serum prestin seems to be a promising biomarker when using therapeutics with ototoxic properties because it is not dependent on OHC loss as a necessary event, thus affording the opportunity for early detection and intervention.

Relationship of Serum Prestin Levels to the Severity of Sensorineural Hearing Loss.

OBJECTIVE: Prestin is an outer hair cell (OHC) protein responsible for increasing cochlear sensitivity and has been proposed as a biomarker. We aimed to evaluate whether the serum prestin level is related to the severity of chronic sensorineural hearing loss (SNHL). METHODS: Ninety subjects were recruited from the patient base at Samarra public hospitals and clinics in Iraq from January to October of 2022. They were divided into three groups equally: a group of healthy people without hearing loss (G0), a group with moderate SNHL (G1), and a group with severe SNHL (G2). The subjects ranged from 20 to 80 years of age and included 51 males and 39 females. Blood samples were collected, then serum was separated, and enzyme-linked immunosorbent assays were performed to quantify the levels of prestin. RESULTS: Hearing thresholds were sequentially statistically higher across the three groups. While prestin levels were significantly higher in G1 and G2 than that in G0, there were no differences between the G1 and G2 levels. Serum prestin levels were positively correlated with hearing thresholds in G1, but not G2. CONCLUSION: Our results suggest that in the clinical setting, prestin is sensitive to chronic mild to moderate SNHL (i.e., up to 40-60 dB), not more severe loss. This range is consistent with the added sensitivity provided by OHCs in the cochlea and provides support for prestin as a biomarker of OHC-mediated SNHL.

Unilateral Tonsillar Enlargement as Initial Presentation of Bilateral Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Unilateral tonsillar enlargement is a common indication for tonsillectomy, but there are varying rates of malignancy among tonsils removed for asymmetry and a lack of clear guidelines for management within the literature. Lymphoma of the palatine tonsils is among the concerns leading to tonsillectomy, but chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) of the tonsil is rare. We report a case of primary CLL/SLL of the palatine tonsil in a 51-year-old gentleman who presented with tonsillar asymmetry and obstructive sleep apnea (OSA) but lacked signs and symptoms suspicious for malignancy, including lymphadenopathy and "B-symptoms." To our knowledge, only 7 cases of CLL/SLL of the palatine tonsil have been reported in the English literature, with the tonsil being the primary site of involvement in only 4 of those cases. Our unique case highlights the importance of thorough physical exam, family history, and tissue biopsy in patients presenting to the otolaryngologist with OSA and asymmetric tonsils.

Automated Western Blot Analysis of Ototoxin-Induced Prestin Burst in the Blood after Cyclodextrin Exposure.

HYPOTHESIS: Ototoxin cyclodextrin (CDX) will induce a burst in serum prestin when quantified with automated Western blot analysis. BACKGROUND: In the clinical realm, we primarily rely on audiological measures for diagnosis and surveillance of sensorineural hearing loss (SNHL) and have limited therapeutic options. We have proposed a blood-based biomarker approach to overcome this challenge by measuring the outer hair cell's (OHC) electromotile protein, prestin, in the blood. Previously, we demonstrated a burst in serum prestin after cisplatin exposure using enzyme-linked immunosorbent assayELISA. METHODS: Guinea pigs were treated with either 3,000 or 4,000 mg/kg CDX, and serum samples were obtained through 3 days after exposure. Serum prestin levels were quantified using automated blot analysis, western and hair cell counts were obtained. RESULTS: Both 3,000 and 4,000 mg/kg resulted in robust OHC loss, although more variability was seen at the lower dose. Automated Western blot analysis demonstrated that the prestin profile after CDX exposure is different than baseline. Specifically, a new ~134- kDa band accounted for the prestin burst after ototoxin ablation of OHCs at both doses. CONCLUSIONS: We reproduced the prestin burst seen after cisplatin administration using CDX. Automated Western blot western analysis revealed that a ~a ~ 134- kDa species of prestin is responsible for the burst. We suggest that the induced band may be a prestin dimer, which could serve as a biomarker for early detection of ototoxicity in the clinical setting. These results add further promise to the potential of serum prestin to serve as an ototoxicity biomarker when using therapeutics with ototoxic properties.

Head & Neck Trauma in the Geriatric Population.

Craniofacial trauma in the geriatric population is increasing as our population ages. Due to loss of bone quality and medical comorbidities, injuries for minor trauma can be severe. A more extensive medical evaluation is usually warranted in this population before proceeding with surgery. In addition, unique surgical considerations exist in the repair of atrophic and edentulous bony fractures. Some quality improvement measures have already been undertaken but more is needed to help standardize care in this vulnerable population.

An Analysis of Otolaryngology in Avicenna's Canon of Medicine: Utilizing the Original Arabic Text.

Avicenna authored The Canon of Medicine, a principal medical textbook for over 600 years. Our primary goal is to systematically review and translate relevant portions of The Canon in its original Arabic and correlate to Sardo's 2014 translation, focusing on otolaryngology, to present an accurate representation of Avicenna's impact and highlight notable discrepancies. Secondarily, we aim to review the literature for citations discussing Avicenna's contributions to otolaryngology and identify misinterpretations. Notably, Avicenna may have described the shape of the cochlea 500 years before its believed discovery in humans by Eustachius (1552) and Falloppius (1561). There are also obscurities in Avicenna's descriptions of the etiology of epistaxis and airway management. It is essential to remain critical of historical texts and safeguard the accurate propagation of information to preserve the integrity of historical context and timelines of scientific advancement.

Giant Parathyroid Adenoma Associated With Aberrant Subclavian Artery and Nonrecurrent Laryngeal Nerve.

Parathyroid adenomas are responsible for 80% to 85% of cases of primary hyperparathyroidism. Giant parathyroid adenomas are a rare type of parathyroid adenoma defined as weighing >3.5 grams. Although giant parathyroid adenomas are rare entities whose clinical presentation may not be atypical, their surgical management can be challenging, especially in the setting of anatomical variants. We present here a case of a 29-year-old female with a 37-gram giant adenoma which was diagnosed after presentation with recurrent severe headaches. The presentation was also unique in that it was associated with a right aberrant subclavian artery and nonrecurrent laryngeal nerve.

Vertebral Artery Compression by the Greater Cornu of the Thyroid Cartilage.

A case of symptomatic unilateral vertebral artery compression by the greater cornu of the thyroid cartilage is described. Imaging shows ossification of the greater cornu of the thyroid cartilage with compression of an aberrant vertebral artery that enters the transverse foramen at the level of C4. Diagnostic workup and surgical treatment are described. Laryngoplasty with a transverse cervical approach and resection of the greater cornu of the thyroid cartilage resulted in resolution of symptoms.

Age-related declines to serum prestin levels in humans.

Measurement of the motor protein prestin offers a novel approach to assessing outer hair cell (OHC) status using serological techniques. Motivated by our prior work showing reduced serum prestin levels in healthy young adults at-risk for noise damage, the current study examined serum prestin levels, measured from circulating blood, across the age span from 18 to 82 years old. Results suggest that serum prestin levels negatively correlate with age, with young adults having higher levels of circulating serum in the blood than older adults. Group-level analyses showed minimal differences in prestin levels between 18 and 29, 30-39, and 40-49 year olds, but significant reductions in the 50+ years-old age group compared to the three younger groups, even though all groups significantly differed from each other in audiometric thresholds and distortion product otoacoustic emissions signal-to-noise ratio. Serum prestin levels declined with increasing levels of hearing loss, with a statistically significant relationship emerging between prestin and low-frequency hearing thresholds (0.25-2 kHz) but a weaker non-significant relationship for high-frequency hearing thresholds (3-8 kHz). This differential pattern between low- and high- frequency thresholds is consistent with the basal-to-apical progression of OHC loss with age. Findings support the idea that serum prestin is the product of residual OHCs in the less age-affected apical regions. Moreover, when entered in a regression model with audiometric thresholds, age was a stronger predictor than pure tone hearing threshold level for predicting serum prestin levels.

Intrathyroidal Parathyroid Cyst in a Middle-aged Woman.

Parathyroid cyst is a rare entity that can closely mimic thyroid and brachial cleft cysts, particularly when located within the thyroid gland. Most commonly, the cysts are non-functional but can produce compressive symptoms. The cyst contains watery content with elevated PTH levels, specifying parathyroid origin1. Parathyroid cysts should be considered in the differential in patients with a neck mass. This study describes a rare case of a middle-aged woman with a history of a symptomatic intrathyroidal parathyroid cyst discovered intraoperatively.

Noise exposure levels predict blood levels of the inner ear protein prestin.

Serological biomarkers of inner ear proteins are a promising new approach for studying human hearing. Here, we focus on the serological measurement of prestin, a protein integral to a human's highly sensitive hearing, expressed in cochlear outer hair cells (OHCs). Building from recent nonhuman studies that associated noise-induced OHC trauma with reduced serum prestin levels, and studies suggesting subclinical hearing damage in humans regularly engaging in noisy activities, we investigated the relation between serum prestin levels and environmental noise levels in young adults with normal clinical audiograms. We measured prestin protein levels from circulating blood and collected noise level data multiple times over the course of the experiment using body-worn sound recorders. Results indicate that serum prestin levels have a negative relation with noise exposure: individuals with higher routine noise exposure levels tended to have lower prestin levels. Moreover, when grouping participants based on their risk for a clinically-significant noise-induced hearing loss, we found that prestin levels differed significantly between groups, even though behavioral hearing thresholds were similar. We discuss possible interpretations for our findings including whether lower serum levels may reflect subclinical levels of OHC damage, or possibly an adaptive, protective mechanism in which prestin expression is downregulated in response to loud environments.

Evaluating the Role of Otologic Biomarkers to Differentiate Meniere's Disease and Vestibular Migraine.

OBJECTIVE: To evaluate the role for prestin and otolin-1 as biomarkers for differentiating Meniere's disease (MD) from vestibular migraine (VM). STUDY DESIGN: It is a cross-sectional, cohort study. RESULTS: There were 19 MD and 11 VM patients. In the 19 MD patients, the mean prestin level was 2.33 ng/ml compared to 0.64 ng/ml in VM patients (p = 0.238). Otolin-1 levels in MD patients were 109.67 pg/ml, while in VM patients, otolin-1 levels were 30.9 pg/ml (p = 0.102). In MD patients, prestin levels were correlated with word recognition scores, being strongest when prestin >2 ng/ml (rho = 0.9; p = 0.019). CONCLUSIONS: Prestin and otolin-1 levels differed between MD patients relative to VM patients. The relationship between prestin and word recognition scores in MD suggests that there may be a role for prestin as a marker for inner ear function, but its role in differentiating MD from VM remains to be elucidated.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

Clinical Biomarkers in Otolaryngology-Head and Neck Surgery.

OBJECTIVE: The purpose of this paper is to review the literature and compile promising and clinically relevant biomarkers in otolaryngology-head & neck surgery not related to autoimmune disorders. STUDY DESIGN: Narrative review. METHODS: PubMed and Google Scholar were queried using combined key words such as "biomarkers" and "otolaryngology." Additional queries were made with combined key words such as "biomarkers" and a particular subspecialty such as "rhinology" or "otology" to maximize yield of relevant titles. Subsequently, specific biomarkers identified, such as "beta-2 transferrin," were used as key words. Relevant titles were reviewed and selected for abstract review. Applicable abstracts were then selected for review of the full text. RESULTS: Biomarkers currently in clinical use within the field of otolaryngology were included in this review. The compiled biomarkers were then detailed individually regarding their molecular characteristics, function, and clinical significance. CONCLUSIONS: The number of biomarkers in use in otolaryngology is rapidly expanding representing a new diagnostic modality for our field. This review defines the key biomarkers that are currently or likely to be soon translated into clinical use within the field of otolaryngology. The majority of these biomarkers are in the form of proteins such as beta-2 transferrin, thyroglobulin, and P16. Given their growing impact on diagnosis, management and surveillance of otolaryngologic disorders periodic surveys are needed for education and to guide further advances and applications of otolaryngologic biomarkers.

Clinical Biomarkers in Otolaryngology-Head and Neck Surgery: Autoimmune Diseases.

OBJECTIVE: The purpose of this article is to review the literature and compile promising and clinically relevant biomarkers in autoimmune disease related to otolaryngology-head and neck surgery. STUDY DESIGN: Narrative review. METHODS: Pubmed and Google Scholar were queried using combined key words such as "biomarkers" and "otolaryngology." Additional queries were made with combined key words such as "biomarkers" and a particular subspecialty such as "autoimmune" or "Meniere's" to maximize yield of relevant titles. Subsequently, specific biomarkers identified, such as "anti-TPO-antibodies," were used as key words. Relevant titles were reviewed and selected for abstract review. Applicable abstracts were then selected for review of the full text. RESULTS: Biomarkers that are currently in clinical use for the management of autoimmune diseases within the field of otolaryngology were included in this review. The compiled biomarkers were then detailed individually regarding their molecular characteristics, function, and clinical significance. CONCLUSIONS: Based on this literature review, there are several biomarkers currently in clinical use within the field of otolaryngology relating to autoimmune diseases. The majority of these biomarkers are in the form of proteins such as Cogan peptide and c-ANCA. This survey may serve as a comprehensive resource on biomarkers for autoimmune diseases in clinical otolaryngology.

Reliability of Serological Prestin Levels in Humans and its Relation to Otoacoustic Emissions, a Functional Measure of Outer Hair Cells.

OBJECTIVES: Serological biomarkers, common to many areas of medicine, have the potential to inform on the health of the human body and to give early warning of risk of compromised function or illness before symptoms are experienced. Serological measurement of prestin, a motor protein uniquely produced and expressed in outer hair cells, has recently been identified as a potential biomarker to inform on the health of the cochlea. Before any test can be introduced into the clinical toolkit, the reproducibility of the measurement when repeated in the same subject must be considered. The primary objective of this study is to outline the test-retest reliability estimates and normative ranges for serological prestin in healthy young adults with normal hearing. In addition, we examine the relation between serum prestin levels and otoacoustic emissions (OAEs) to compare this OHC-specific protein to the most common measure of OHC function currently used in hearing assessments. DESIGN: We measured prestin levels serologically from circulating blood in 34 young adults (18 to 24 years old) with clinically normal pure-tone audiometric averages at five different timepoints up to six months apart (average intervals between measurements ranged from <1 week to 7 weeks apart). To guide future studies of clinical populations, we present the standard error of the measurement, reference normative values, and multiple measures of reliability. Additionally, we measured transient evoked OAEs at the same five timepoints and used correlation coefficients to examine the relation between OAEs and prestin levels (pg/mL). RESULTS: Serum prestin levels demonstrated good to excellent reliability between and across the five different time points, with correlation coefficients and intraclass correlations >0.8. Across sessions, the average serum prestin level was 250.20 pg/mL, with a standard error of measurement of 7.28 pg/mL. Moreover, positive correlations (generally weak to moderate) were found between prestin levels and OAE magnitudes and signal-to-noise ratios. CONCLUSIONS: Findings characterize serum prestin in healthy young adults with normal hearing and provide initial normative data that may be critical to interpreting results from individuals with sensorineural hearing loss. Our results demonstrate reliability of serum prestin levels in a sample of normal-hearing young adults across five test sessions up to 6 months apart, paving the way for testing larger samples to more accurately estimate test-retest standards for clinical protocols, including those involving serial monitoring. The positive correlations between serum prestin and OAE levels, although weak to moderate, reinforce that the source of serum prestin is likely the outer hair cells in the inner ear, but also that serum prestin and OAEs each may also index aspects of biologic function not common to the other.

Why is primary hyperparathyroidism more severe in children?

The disease presentation of primary hyperparathyroidism (PHPT) is more severe in children. We hypothesize that this difference in disease presentation is a result of several factors including a delay in diagnosis, age-related differences in calcium metabolism and bone turnover, and the influence of the growth hormone (GH)/insulin growth factor-1 (IGF-1) axis. Only the first two explanations for the heightened disease severity of PHPT in children have been previously discussed in the literature. In regards to the potential role GH and IGF-1 may play in this disparity, previous studies have documented decreases in GH and IGF-1 secretion in symptomatic adult PHPT patients potentially influencing the severity of the patients' disease presentation. While these studies have yet to be replicated in the pediatric population, given that both GH and IGF-1 are important for the achievement of peak bone mass in young individuals, it is logical to infer that the GH/IGF-1 axis may be partly responsible for the severe presentation of PHPT in children.

PIK3CA Mutational Analysis of Parathyroid Adenomas.

Benign parathyroid adenoma is the most common cause of primary hyperparathyroidism, whereas malignant parathyroid carcinoma is exceedingly rare. Distinguishing parathyroid carcinoma from benign adenoma is often difficult, and may be considerably delayed even after surgical resection until the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases may potentially aid in earlier diagnostic discrimination between the two, as well as informing new directions for treatment. In two recent studies, gain-of-function mutations in PIK3CA, a recognized driver oncogene in many human malignancies, have been newly identified in parathyroid carcinoma. To assess the potential specificity for malignant, as opposed to benign parathyroid disease, of PIK3CA hotspot mutations, we PCR-amplified and Sanger sequenced codons 111, 542/545, and 1047 and the immediate flanking regions in genomic DNA from 391 typical, sporadic parathyroid adenomas. Four parathyroid adenomas (1%) had subclonal, somatic, heterozygous, activating PIK3CA mutations. The rarity of PIK3CA activating mutations in benign parathyroid adenomas suggests that tumorigenic activation of PIK3CA is strongly associated with malignant parathyroid neoplasia. However, it does not appear that such mutations, at least in isolation, can be relied upon for definitive molecular diagnosis of parathyroid carcinoma. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.