Hearing molecules: contributions from genetic deafness.

Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As functional studies of these molecular elements become available, we can put together the pieces of the puzzle and begin to reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies over the past decade that address the function of the proteins implicated in genetic deafness and to place them in the context of basic molecular mechanisms in hearing. The first part of this review highlights structural and functional features of the cochlea and auditory nerve. This background will provide a context for the second part, which addresses the molecular mechanisms underlying cochlear function as elucidated by genetic causes of deafness.

Chick cochlear hair cell exocytosis mediated by dihydropyridine-sensitive calcium channels.

1. A semi-intact preparation of the chick basilar papilla was developed to study calcium-dependent neurotransmitter release by tall hair cells (avian equivalent of cochlear inner hair cells). 2. Tall hair cell depolarization resulted in changes in cell membrane capacitance (DeltaC(m)) that reflected cell surface area increases following synaptic vesicle exocytosis and provided a surrogate measure of neurotransmitter release. Both calcium current (I(Ca)) and DeltaC(m) were reversibly blocked by cobalt, and exhibited a similar bell-shaped dependency on voltage with a peak response around -10 mV. 3. Pharmacological agents selective for L-type calcium channels were employed to assess the role of this channel type in neurotransmitter exocytosis. Nimodipine, a dihydropyridine (DHP) antagonist, suppressed I(Ca) and blocked DeltaC(m). Conversely, the DHP agonist Bay K 8644 increased both I(Ca) and DeltaC(m) amplitude nearly 3-fold. These findings suggest that chick tall hair cell neurotransmitter release is mediated by calcium influx through L-type calcium channels.

Morbidity after midline mandibulotomy and radiation therapy.

PURPOSE: To assess the morbidity of mandibulotomy in patients treated for neoplasms of the oropharynx and oral cavity, and to determine if postoperative radiation therapy to the mandibulotomy site carries an increased risk of complications. PATIENTS AND METHODS: The medical charts of 30 patients treated between 1992 and 1996 undergoing midline mandibulotomy for tumors of the oral cavity (7 patients) and oropharynx (23 patients) were retrospectively reviewed. Three patients presented with recurrent disease, 1 of whom was previously irradiated. Twenty-five patients received postoperative radiation after mandibulotomy to a median dose of 60 Gy to the primary tumor bed, whereas 5 patients were treated with surgery alone. The patients were separated into those whose mandibulotomy site was within the radiation treatment field (n = 9), and those whose site was shielded (n = 10). Median follow-up was 27.8 months (range 5-81 months). End points included significant pain involving the mandibulotomy site, trismus, malocclusion, wound infection, osteoradionecrosis, and time to oral intake. RESULTS: There were no postoperative deaths. Minor wound infection or breakdown occurred in 4/30 patients (13%). All of these resolved with local care and parenteral antibiotics. More serious complications involving the mandibulotomy occurred in 2 patients (7%). One patient had chronic wound drainage at the mandibular osteotomy site, which healed after plate removal. Another patient developed osteoradionecrosis. No patient developed trismus or malocclusion. With a median follow-up of 27.8 months, 4 patients have recurred locally. The complication rate was 11% for patients whose mandibulotomy site was irradiated, and 30% for those whose site was shielded. CONCLUSION: Mandibulotomy can be safely performed in patients who are likely to require postoperative external radiation.

Preoperative imaging to predict orbital invasion by tumor.

BACKGROUND: Our purpose was to examine the accuracy of preoperative imaging in assessing tumor invasion of the orbit and nasolacrimal system. METHODS: Nineteen preoperative CT and 17 preoperative MR images from patients at risk for orbital invasion were retrospectively reviewed. Invasion was corroborated by pathologic and intraoperative assessment. RESULTS: Tumor adjacent to the periorbita was the most sensitive predictor of orbital invasion (90%) for both CT and MRI. Extraocular muscle involvement on MRI (100%) and orbital fat obliteration (80% MRI, 86% CT) had the highest positive predictive values of the criteria evaluated. Extraocular muscle displacement and enhancement were less accurate (<65%) predictors. No one criterion was >79% accurate in predicting orbital invasion. Six or more positive criteria predicted invasion with 67% sensitivity and 80% specificity (accuracy, 72%). CT was more accurate than MRI in seven of nine criteria. Invasion of the nasolacrimal system was predicted accurately (89%). CONCLUSIONS: Although preoperative imaging can aid in surgical planning, it should not replace intraoperative assessment in ambiguous cases of orbital invasion.

Current imaging modalities for the diagnosis of breast cancer.

Although mammography still remains the gold standard for breast cancer screening and diagnosis, it typically cannot differentiate benign from malignant disease and is less accurate in patients with dense glandular breasts. This article is an overview of imaging modalities that have emerged to augment mammography and improve the accuracy of non-invasive breast cancer diagnosis. Ultrasound is currently used to differentiate breast masses and guide aspirations and biopsies. Magnetic resonance imaging has excellent sensitivity in demonstrating breast cancer but a low specificity. Nuclear medicine studies have recently emerged that detect the increased metabolic rate and vascularity of breast cancers. Other modalities, such as thermography and computed tomography, have a more limited utility for breast cancer diagnosis. Digital mammography is among other emerging technological advancements that will continue to develop and improve the accuracy of breast cancer diagnosis in the future.

The tip link's role in asymmetric stereocilia motion of chick cochlear hair cells.

The symmetry of chick cochlear hair bundle motion was examined in this study. Isolated segments from the basilar papilla were incubated in vitro in either normal or low calcium medium, which is known to disrupt tip links. Stereociliary bundles, stimulated with an oscillating water microjet, were oriented in profile and viewed in slow motion at high magnification with stroboscopic illumination. The displacement of the tallest hair in the bundle was fixed to 20 degrees peak-to-peak (P-P) motion. The angular deflections of the shortest and tallest hairs were then measured in both the positive (towards the tallest hair) and negative (towards the shortest) directions with respect to the non-stimulated position of the hair. The tallest hairs exhibited nearly symmetric motion in medium containing normal and low calcium. The shortest hairs, in normal calcium, displayed considerable asymmetry with angular deflections in the positive direction significantly larger than in the negative direction. This asymmetric motion disappeared after incubation in low calcium. The shortest hair angular displacement in the negative direction, however, was the same in both normal and low calcium conditions. These results indicated that the tallest and shortest hairs moved with equal angular deflection in the negative direction, while in the positive direction the shortest hair moved through a significantly greater angular deflection than the tallest hair. The implication of this finding is that the tip links contributed significantly to hair bundle motion in the positive direction only.

Distal separation of chick cochlear hair cell stereocilia: analysis of contact-constraint models.

One model often used in the study of hair bundle micromechanics assumes simple geometric relationships between hair displacements, constrained by contact between neighboring hairs at their distal tips. Recent observations of hair bundle motion provided the opportunity to evaluate the contact-constraint model against measured displacements for the tallest and shortest sensory hairs. A contact-constraint model was developed based on the geometry of a single column of stereocilia. The model used morphological data from chick hair bundles for which displacement data in the excitatory and inhibitory directions were also available. For each hair bundle, a unique sensory hair radius was determined so that the calculated resting bundle morphology matched the measured values. The model was then evaluated against the displacement data for each hair bundle. In each case, the model underestimated the excitatory displacement of the shortest hairs. Failure of the model to accurately predict bundle motion raises the possibility of a distal separation between the hairs at rest. It is suggested that tip links pull the hairs through this separation during excitatory deflections. Perhaps at damaging levels of displacement, the hairs suddenly come into contact, tip-link tension dramatically increases, and the tip-links are fractured.

Lipomas of the internal auditory canal and cerebellopontine angle.

OBJECTIVE: To evaluate lipomas of the internal auditory canal (IAC) and cerebellopontine angle (CPA). STUDY DESIGN: Retrospective review. METHODS: Review of a multi-institutional series of 17 lipomas of the IAC/CPA, combined with a Medline review of the 67 cases reported in the world literature. RESULTS: This series of 17 IAC/CPA lipomas is the largest reported series to date, bringing the total number of documented cases to 84. There appears to be a nearly 2:1 male to female predominance. Sixty percent were left-sided lesions, and three were bilateral. Hearing loss, dizziness, and tinnitus were the most common presenting symptoms. Surgical resection was performed in 52 (62%) of these lesions; however, total tumor removal was accomplished in only 17 (33%), which is most likely because of the fact that these tumors tend to have a poorly defined matrix and a dense adherence to neurovascular structures. Sixty-eight percent of patients experienced a new deficit postoperatively, 11% were unchanged, and only 19% improved with no new deficit. Only one documented case of tumor growth was identified; however, the reported follow-up was short (average, less than 3 years). CONCLUSION: With the magnetic resonance imaging techniques now available, lipomas can be reliably differentiated from other masses within the CPA and IAC, so histopathologic diagnosis is rarely necessary. Because of the potential for significant morbidity with resection of these lesions, we believe that conservative follow-up is the best treatment option for patients with these rare lesions. Surgery is indicated only when significant progressive or disabling symptoms are present.

Otolaryngological manifestations of Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is one of the uniformly fatal spongiform encephalopathies that is characterized clinically by an unrelenting progression of myoclonus, dementia, and ataxia. Since many of these patients will develop cerebellar abnormalities, some may present to the otolaryngologist with dizziness. Hearing loss, however, to our knowledge, has not been reported. We describe a patient with CJD who presented with hearing loss and vague symptoms of imbalance, and whose disease progressed rapidly and fatally despite an extensive initial workup that was otherwise unrevealing. A review and discussion of the otolaryngological manifestations of CJD is presented. The otolaryngologist should be aware that CJD can present with otolaryngological manifestations, and with proper diagnosis extensive workups may be avoided.

Use of preoperative MR to predict dural, perineural, and venous sinus invasion of skull base tumors.

PURPOSE: To assess the accuracy of MR imaging in predicting dural, venous sinus, and perineural invasion by skull base tumors. METHODS: The preoperative MR images of 22 patients who had resection of skull base neoplasms were evaluated for the following characteristics: dural enhancement, pial enhancement, local perineural invasion by adjacent tumor, and venous sinus invasion by tumor. The greatest width of dural enhancement was measured, and the character of dural enhancement was noted. The pathologic and surgical reports were reviewed retrospectively with specific attention to dural, venous, and local perineural invasion. RESULTS: Of the 22 patients studied, dural invasion by tumor was confirmed in eight patients, vascular invasion in six patients, and perineural invasion in four patients. The sensitivity of dural enhancement in predicting invasion was 88%, the specificity 50%, and the accuracy 64%. When enhancement and focal nodularity were present, the sensitivity remained at 88%; however, specificity was 100% and accuracy 95%. If the dural enhancement was more than 5 mm thick, sensitivity, specificity, and accuracy were 75%, 100%, and 91%, respectively. Predicting tumor invasion of the dura by the presence of pial enhancement was 50% sensitive and 100% specific. Venous sinus/jugular vein invasion was predicted with 100% sensitivity, 94% specificity, and 95% accuracy. Local perineural invasion was predicted with 100% sensitivity, 50% specificity, and 59% accuracy. CONCLUSIONS: The presence of pial enhancement, focal dural nodules, or dural thickening of more than 5 mm is highly accurate in predicting the presence of neoplastic dural invasion. Linear enhancement of dura does not imply dural infiltration by tumor. Venous invasion by tumor can be predicted accurately with preoperative MR imaging.