Nestin-expressing cells are mitotically active in the mammalian inner ear.

Nestin expression is associated with pluripotency. Growing evidence suggests nestin is involved in hair cell development. The objective of this study was to investigate the morphology and role of nestin-expressing cells residing in the early postnatal murine inner ear. A lineage-tracing nestin reporter mouse line was used to further characterize these cells. Their cochleae and vestibular organs were immunostained and whole-mounted for cell counting. We found Nestin-expressing cells present in low numbers throughout the inner ear. Three morphotypes were observed: bipolar, unipolar, and globular. Mitotic activity was noted in nestin-expressing cells in the cochlea, utricle, saccule, and crista. Nestin-expressing cell characteristics were then observed after hair cell ablation in two mouse models. First, a reporter model demonstrated nestin expression in a significantly higher proportion of hair cells after hair cell ablation than in control cochleae. However, in a lineage tracing nestin reporter mouse, none of the new hair cells which repopulated the organ of Corti after hair cell ablation expressed nestin, nor did the nestin-expressing cells change in morphotype. In conclusion, Nestin-expressing cells were identified in the cochlea and vestibular organs. After hair cell ablation, nestin-expressing cells did not react to the insult. However, a small number of nestin-expressing cells in all inner ear tissues exhibited mitotic activity, supporting progenitor cell potential, though perhaps not involved in hair cell regeneration.

Pediatric cholesteatoma associated with congenital aural atresia and stenosis.

OBJECTIVE: Investigate presenting features, associated surgical treatment, and outcomes in patients with cholesteatoma associated with congenital aural atresia (CAA) or stenosis (CAS). METHODS: Colorado Multiple Institution Review Board approval was obtained. A retrospective chart review was performed at a single tertiary care children's hospital of all pediatric patients with congenital aural atresia or stenosis with associated cholesteatoma from January 1, 2003, to October 15, 2018. RESULTS: Of the 278 patients identified with CAA or CAS, twelve (4.3 %) were found to have a canal cholesteatoma. There was a male predominance (8:4). Nine patients (75 %) had conductive loss and three (25 %) had mixed loss. Four patients (33.3 %) exhibited canal cholesteatomas extending into the middle ear or mastoid cavity. All patients underwent surgery, and 25 % of patients required revision canalplasty while 58 % of patients required revision surgery for cholesteatoma recidivism. The average age at the time of surgery was 11.3 ± 3.7 years. CONCLUSION: Fewer than 5 % of pediatric patients with congenital aural atresia or stenosis were diagnosed with an acquired canal cholesteatoma. The need for revision surgery was common, occurring in >50 % of cases. Screening patients with CAA/CAS for cholesteatoma with imaging is recommended to avoid the morbidity of delayed identification.

Debilitating Gentamicin Ototoxicity: Case Report and Recommendations Against Routine Use in Surgical Prophylaxis.

INTRODUCTION: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including Staphylococcus aureus. However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent. OBJECTIVE: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery. CASE SUMMARY: We present a case of a woman with preexisting Meniere's Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient's medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior. DISCUSSION: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin.

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere's disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere's disease, and 38 European-American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere's disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.

Cupulolithiasis: A Critical Reappraisal.

Objective: To review the history and pathophysiologic theories for cupulolithiasis and canalith jam in benign paroxysmal positional vertigo. Data Sources: PubMed, Google Scholar. Review Methods: Three PubMed and Google Scholar searches were performed, keywords: "cupulolithiasis," "apogeotropic [and] benign," and "canalith jam," resulting in 187 unique full-text articles in English or with English translation. Figures-Labyrinthine photographs were obtained of fresh utricles, ampullae, and cupulae of a 37-day-old mouse. Conclusions: Freely moving otoconial masses explain most cases (>98%) of benign paroxysmal positional vertigo. Evidence that otoconia adhere strongly or persistently to the cupula is lacking. Apogeotropic nystagmus in the horizontal canal form is often attributed to cupulolithiasis; however, periampullary canalithiasis explains self-limited nystagmus, and reversible canalith jam explains prolonged apogeotropic nystagmus. Treatment-resistant cases can be explained by entrapment of particles in the canals or ampullae, but persistent adherence to the cupula remains theoretical. Implications for Practice: Apogeotropic nystagmus is usually due to freely moving particles and should not be used in studies of horizontal canal benign paroxysmal positional vertigo as the sole method to define entrapment or cupulolithiasis. Caloric testing and imaging may help differentiate jam from cupulolithiasis. Treatment for apogeotropic benign paroxysmal positional vertigo should include maneuvers that rotate the head through 270° to fully clear the canal of mobile particles, using mastoid vibration or head shaking if entrapment is suspected. Canal plugging can be used for treatment failures.

Effect of Head Position and Magnetic Resonance Sequence on Cochlear Implant-Related Artifact Size and Internal Auditory Canal Visibility.

HYPOTHESIS: To assess whether cochlear implant (CI)-related magnetic resonance imaging (MRI) artifact and visibility of the internal auditory canal (IAC) can be improved with head positioning and select MRI sequences. BACKGROUND: CI-related MRI artifact limits the use of CIs in otherwise good candidates because of the need for serial MRIs for monitoring of pathology. This most notably impacts patients with tumors of the cerebellopontine angle and IAC. METHODS: Two cadaver heads were implanted with either a Med-El CONCERT (fixed magnet) or SYNCHRONY (rotating magnet) device. Each head was imaged in a 1.5T scanner in 11 different positions. The SYNCHRONY-implanted head was also imaged in a 3.0T scanner in seven positions. Artifact size and IAC visibility (graded on a Likert scale) were measured for each head position by a neuroradiologist. RESULTS: The CONCERT CI produced significantly smaller artifact than the SYNCHRONY CI (effect size, 14.65 mm; p < 0.001). There was no significant difference between CI models in regard to IAC visibility. No head positions were statistically significantly better than neutral position for minimizing artifact size or IAC visibility, although some positions resulted in significantly larger artifact (effect sizes, 2.1-14.3 mm; p < 0.05) or significantly poorer IAC visibility (effect size, 1.4; p < 0.01). The T2 three-dimensional (CISS/FIESTA) sequence demonstrated significantly smaller artifact than T1 sequences, whereas T1 sequences demonstrated significantly better IAC visibility than T2 sequences. CONCLUSION: Head positioning and magnetic resonance sequence selection impact CI-related artifact size and IAC visibility.

Hyaluronic acid fillers may be longer-lasting than previously described: A case report of delayed filler-associated facial cellulitis.

Hyaluronic acid-based filler is the most popular injectable augmentation preparation due to its efficacy and safety compared to other injection fillers. The complication of infected filler is known, but it is unknown exactly how long filler persists prior to reabsorption. A case was presented of filler-exacerbated facial cellulitis that occurred 2.5 years after hyaluronic acid-based filler administration. The presence of residual filler was confirmed with magnetic resonance imaging, suggesting that hyaluronic acid-based fillers may persist longer than previously thought and act as a reservoir for regional bacterial infections refractory to antibiotics.

Pediatric Primary Tympanoplasty Outcomes With Autologous and Non-autologous Grafts.

OBJECTIVE: To compare rates of successful tympanic membrane (TM) closure in primary pediatric tympanoplasty between various autologous and non-autologous tissues. METHODS: A retrospective chart review was performed examining all primary pediatric tympanoplasties over a 20-year period at a single institution. RESULTS: In 564 pediatric tympanoplasties, no statistically significant difference existed between success rates of autologous and non-autologous grafts (p = 0.083). Compared with fascia, the hazard ratios (and 95% confidence intervals [CI]) for failure for each graft were as follows: human pericardial collagen (HR 0.90, CI 0.54-1.50, p = 0.680), porcine submucosal collagen (HR 1.07, CI 0.56-2.05, p = 0.830), human acellular dermal collagen (HR 1.66, CI 0.95-2.87, p = 0.073), and "multiple grafts" (HR 0.72, CI 0.26-1.98, p = 0.520). Survival curves demonstrated that 75% of graft failures occurred by 6 months after surgery, the rest occurring between 6 and 12 months postoperatively. Larger perforations encompassing more than or equal to 50% of the TM had lower success rates (HR 1.50, CI 1.02-2.21, p = 0.041) than smaller perforations encompassing less than 50% of the TM. Age was not correlated with success (HR 0.98, CI 0.93-1.03, p = 0.390). CONCLUSION: This study found that non-autologous collagen grafts provide equivalent rates of healing when compared with autologous tissue in primary pediatric tympanoplasty. In addition to the potential for reduced operative time and donor site morbidity, these materials provide a viable graft alternative in fascia-depleted ears.Level of Evidence: Level 4.

Tonsillectomy and hematologic malignancy: Should routine pediatric tonsillectomy specimens be sent to pathology?

OBJECTIVES: Routine pediatric tonsillectomy ± adenoidectomy (T ± A) is one of the most common procedures for children worldwide, accounting for approximately 2000 procedures per year at our institution. To determine the utility of pathologic analysis of routine, nonsuspicious pediatric tonsil specimens, we investigated the incidence of hematologic and lymphoid malignancy diagnosed at the time of or following T ± A. METHODS: Retrospective review of patients 0-18 years undergoing T ± A between 2012 and 2020 with or without pathologic analysis. RESULTS: Included were 14,141 patients who underwent routine T ± A (mean age 11 ± 4.6 years, 48% female). Of these, tonsils of 2464 patients were sent to pathology, where zero were found to harbor malignancy. Seven patients (0.050%) developed malignancy after T ± A. Of these, 4 had unremarkable tonsils per pathology, and 3 did not have tonsils analyzed. There were 5 cases of Acute Lymphocytic Leukemia (ALL, 0.035%), 1 case of Acute Myeloid Leukemia (0.007%), and 1 case of Lymphoma (0.007%). The average length of time from T ± A to diagnosis was 2.4 ± 1.8 years. CONCLUSION: No cases of occult malignancy were identified in specimens from routine T ± A with pathologic analysis, even among patients who later developed malignancy. This study suggests that sending routine pediatric T ± A specimens for formal pathologic analysis is an inefficient use of resources without appreciably improving the quality and safety of patient care.

Reversible Canalith Jam of the Horizontal Semicircular Canal Mimicking Cupulolithiasis.

OBJECTIVE: To describe a case of benign paroxysmal positional vertigo (BPPV) resulting in reversible horizontal semicircular canalith jam successfully treated with horizontal canal occlusion. A brief literature review of similar cases was performed. METHODS: Case report and literature review. RESULTS: A 68-year-old female presented with apogeotropic positional nystagmus, attributed to reversible horizontal canalith jam mimicking cupulolithiasis that was refractory to tailored repositioning maneuvers across months. She was unable to work due to the severity of her symptoms. She underwent surgical occlusion of the affected canal with immediate resolution of her symptoms. A literature review revealed similar cases of canalith jam mimicking cupulolithiasis. CONCLUSIONS: Reversible canalith jam, in which particles moving with horizontal head position alternate between obstructing the semicircular canal and resting on the cupula, can mimic signs of cupulolithiasis. This variant of BPPV can be effectively managed with surgical canal occlusion should symptoms fail to resolve after tailored repositioning maneuvers.

Anatomic considerations in headaches associated with cervical sagittal imbalance: A cadaveric biomechanical study.

Chronic Forward Head Posture is associated with headaches, neck pain, and disability, though few studies have investigated the effects it has on the suboccipital triangle. The objective of this study was to quantitatively assess whether the biomechanical changes in the suboccipital triangle help explain the clinical manifestations of Forward Head Posture. Specifically, this study aimed to identify whether the Greater Occipital Nerve or C2 nerve root may be compressed in Forward Head Posture. Three-dimensional, specimen-specific computer models were rendered from thirteen cadaveric cervical spine specimens. The spines transitioned from neutral to Forward head posture while motion data was collected. This data was synced with the computer models to make precise measurements. In Forward Head Posture, occiput-C1, C1-C2, and occiput-C2 segments extended by 10.7 ±â€¯4.6 deg, 4.6 ±â€¯4.3 deg, and 15.3 ±â€¯2.3 deg, respectively. The Rectus Capitis Posterior Major and Minor and Obliquus Capitis Superior muscles shortened by 20.0 ±â€¯4.6%, 15.0 ±â€¯7.6%, and 6.6 ±â€¯3.3%, respectively. The Obliquus Capitis muscle inferior length did not change. The suboccipital triangle area decreased by 18.7 ±â€¯6.4%, but the protective gaps surrounding the C2 nerve root and the Greater Occipital Nerve did not reveal clinically significant impingement. The C2 nerve root gap decreased by 1.0 ±â€¯1.3 mm and the Greater Occipital Nerve gap by 0.2 ±â€¯0.18 mm. These results demonstrate that the C2 nerve root and the Greater Occipital Nerve are protected by the bony landscape of the cervical spine. However, there is likely persistent contraction of the rectus muscles in Forward Head Posture, which suggests a secondary tension-type etiology of the associated headache.

Cervical sagittal balance: a biomechanical perspective can help clinical practice.

PURPOSE: In this article, we summarize our work on understanding the influence of cervical sagittal malalignment on the mechanics of the cervical spine. METHODS: Biomechanical studies were performed using an ex vivo laboratory model to study the kinematic and kinetic response of human cervical spine specimens in the setting of cervical sagittal imbalance. The model allowed controlled variations of C2-C7 Sagittal Vertical Alignment (C2-C7 SVA) and T1-Slope so that clinically relevant sagittally malaligned profiles could be prescribed, while maintaining horizontal gaze, and their biomechanical consequences studied. RESULTS: Our results demonstrated that increasing C2-C7 SVA caused flexion of lower cervical (C2-C7) segments and hyperextension of suboccipital (C0-C1-C2) segments to maintain horizontal gaze. An increase in C2-C7 SVA increased the lower cervical neural foraminal areas. Conversely, increasing T1-slope predominantly influenced subaxial cervical lordosis and, as a result, decreased cervical neural foraminal areas. Therefore, we believe patients with increased upper thoracic kyphosis and radicular symptoms may respond with increased forward head posture (FHP) as a compensatory mechanism to increase their lower cervical neural foraminal area and alleviate nerve root compression as well as reduce the burden on posterior muscles and soft and bony structures of the cervical spine. Increasing FHP (i.e., increased C2-C7 SVA) was associated with shortening of the cervical flexors and occipital extensors and lengthening of the cervical extensors and occipital flexors, which corresponds to C2-C7 flexion and C0-C2 extension. The greatest shortening occurred in the suboccipital muscles, suggesting considerable load bearing of these muscles during chronic FHP. Regardless, there was no evidence of nerve compression within the suboccipital triangle. Finally, cervical sagittal imbalance may play a role in exacerbating adjacent segment pathomechanics after multilevel cervical fusion and should be considered during surgical planning. CONCLUSIONS: The results of our biomechanical studies have improved our understanding of the impact of cervical sagittal malalignment on pathomechanics of the cervical spine. We believe this improved understanding will assist in clinical decision-making.

Cervical Spine Muscle-Tendon Unit Length Differences Between Neutral and Forward Head Postures: Biomechanical Study Using Human Cadaveric Specimens.

BACKGROUND: Forward head posture (FHP) may be associated with neck pain and poor health-related quality of life. Literature describes only qualitative muscle length changes associated with FHP. OBJECTIVE: The purpose of this study was to quantify how muscle-tendon unit lengths are altered when human cadaveric specimens are placed in alignments representing different severities of FHP. DESIGN: This biomechanical study used 13 fresh-frozen cadaveric cervical spine specimens (Occiput-T1, 54±15 y). METHODS: Specimens' postural changes simulating increasing FHP severity while maintaining horizontal gaze were assessed. Specimen-specific anatomic models derived from computed tomography-based anatomic data were combined with postural data and specimen-specific anatomy of muscle attachment points to estimate the muscle length changes associated with FHP. RESULTS: Forward head posture was associated with flexion of the mid-lower cervical spine and extension of the upper cervical (sub-occipital) spine. Muscles that insert on the cervical spine and function as flexors (termed "cervical flexors") as well as muscles that insert on the cranium and function as extensors ("occipital extensors") shortened in FHP when compared to neutral posture. In contrast, muscles that insert on the cervical spine and function as extensors ("cervical extensors") as well as muscles that insert on the cranium and function as flexors ("occipital flexors") lengthened. The greatest shortening was seen in the major and minor rectus capitis posterior muscles. These muscles cross the Occiput-C2 segments, which exhibited extension to maintain horizontal gaze. The greatest lengthening was seen in posterior muscles crossing the C4-C6 segments, which exhibited the most flexion. LIMITATIONS: This cadaver study did not incorporate the biomechanical influence of active musculature. CONCLUSIONS: This study offers a novel way to quantify postural alignment and muscle length changes associated with FHP. Model predictions are consistent with qualitative descriptions in the literature.

Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy.

Up-regulation and activation of PYK2, a member of the FAK family of protein tyrosine kinases, is involved in the pathogenesis of left ventricular (LV) remodeling and heart failure (HF). PYK2 activation can be prevented by CRNK, the C-terminal domain of PYK2. We previously demonstrated that adenoviral-mediated CRNK gene transfer improved survival and LV function, and slowed LV remodeling in a rat model of coronary artery ligation-induced HF. We now interrogate whether cardiomyocyte-specific, transgenic CRNK expression prevents LV remodeling and HF in a mouse model of dilated cardiomyopathy (DCM) caused by constitutively active Protein Kinase Cε (caPKCε). Transgenic (TG; FVB/N background) mice were engineered to express rat CRNK under control of the α-myosin heavy chain promoter, and crossed with FVB/N mice with cardiomyocyte-specific expression of caPKCε to create double TG mice. LV structure, function, and gene expression were evaluated in all 4 groups (nonTG FVB/N; caPKCε(+/-); CRNK(+/-); and caPKCε×CRNK (PXC) double TG mice) at 1, 3, 6, 9 and 12mo of age. CRNK expression followed a Mendelian distribution, and CRNK mice developed and survived normally through 12mo. Cardiac structure, function and selected gene expression of CRNK mice were similar to nonTG littermates. CRNK had no effect on caPKCε expression and vice versa. PYK2 was up-regulated ~6-fold in caPKCε mice, who developed a non-hypertrophic, progressive DCM with reduced systolic (Contractility Index=151±5 vs. 90±4s(-1)) and diastolic (Tau=7.5±0.5 vs. 14.7±1.3ms) function, and LV dilatation (LV Remodeling Index (LVRI)=4.2±0.1 vs. 6.0±0.3 for FVB/N vs. caPKCε mice, respectively; P<0.05 for each at 12mo). In double TG PXC mice, CRNK expression significantly prolonged survival, improved contractile function (Contractile Index=115±8s(-1); Tau=9.5±1.0ms), and reduced LV remodeling (LVRI=4.9±0.1). Cardiomyocyte-specific expression of CRNK improves contractile function and slows LV remodeling in a mouse model of DCM.