Michael D. Seidman

The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage.

Several studies have demonstrated that noise exposure may result in local vasoconstriction of cochlear vessels. The subsequent decrease in cochlear blood flow may lead to hypoxia and predispose to the formation of free oxygen radicals (FORs). If hypoxia occurs in response to noise exposure, then drugs that scavenge or block the formation of FORs should protect the cochlea from damage resulting from hypoxic or ischemic events as well as noise trauma. Rats were exposed to 60 hours of continuous broad-band noise (90 dB SPL) and treated with superoxide dismutase — Polyethylene glycol (SOD-PEG), allopurinol, or a control vehicle. Exposure to noise resulted in significant threshold shifts at each frequency tested (3, 8, 12, and 18 kHz) as measured by tone burst-evoked compound action potentials and cochlear microphonics recorded from the round window. Both of these thresholds In drug-treated animals were attenuated compared with animals exposed to noise alone. These findings show that SOD-PEG and allopurinol may preserve cochlear sensitivity associated with noise exposure. This suggests that noise-induced damage to the cochlea may be related to the activity of FORs.

Clinical Practice Guideline Polysomnography for Sleep-Disordered Breathing Prior to Tonsillectomy in Children

Objective. This guideline provides otolaryngologists with evidence-based recommendations for using polysomnography in assessing children, aged 2 to 18 years, with sleep-disordered breathing and are candidates for tonsillectomy, with or without adenoidectomy. Polysomnography is the electrographic recording of simultaneous physiologic variables during sleep and is currently considered the gold standard for objectively assessing sleep disorders. Purpose. There is no current consensus or guideline on when children 2 to 18 years of age, who are candidates for tonsillectomy, are recommended to have polysomnography. The primary purpose of this guideline is to improve referral patterns for polysomnography among these patients. In creating this guideline, the American Academy of Otolaryngology—Head and Neck Surgery Foundation selected a panel representing the fields of anesthesiology, pulmonology medicine, otolaryngology–head and neck surgery, pediatrics, and sleep medicine. Results. The committee made the following recommendations: (1) before determining the need for tonsillectomy, the clinician should refer children with sleep-disordered breathing for polysomnography if they exhibit certain complex medical conditions such as obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (2) The clinician should advocate for polysomnography prior to tonsillectomy for sleep-disordered breathing in children without any of the comorbidities listed in statement 1 for whom the need for surgery is uncertain or when there is discordance between tonsillar size on physical examination and the reported severity of sleep-disordered breathing. (3) Clinicians should communicate polysomnography results to the anesthesiologist prior to the induction of anesthesia for tonsillectomy in a child with sleep-disordered breathing. (4) Clinicians should admit children with obstructive sleep apnea documented on polysomnography for inpatient, overnight monitoring after tonsillectomy if they are younger than age 3 or have severe obstructive sleep apnea (apnea-hypopnea index of 10 or more obstructive events/hour, oxygen saturation nadir less than 80%, or both). (5) In children for whom polysomnography is indicated to assess sleep-disordered breathing prior to tonsillectomy, clinicians should obtain laboratory-based polysomnography, when available.

Effects of Dietary Restriction and Antioxidants on Presbyacusis

Objectives/Hypothesis The premise of this study is that the membrane hypothesis of aging, also known as the mitochondrial clock theory of aging, is the basis for presbyacusis. Furthermore, it is proposed that treatment with antioxidants or dietary restriction can attenuate age‐related hearing loss. Many studies have demonstrated a reduction in blood flow to specific tissues, including the cochlea, with aging. Hypoperfusion leads to the formation of reactive oxygen metabolites (ROM). ROM are highly toxic molecules that directly affect tissues including inner ear structures. In addition, ROM can damage mitochondrial DNA (mtDNA), resulting in the production of specific mtDNA deletions (mtDNA del4977 [human] or mtDNA del4834 [rat]; also known as the common aging deletion]. Previous corroborating data suggest that the common aging deletion mtDNA4834 may be associated not only with aging but also with presbyacusis, thus further strengthening the basis of the current studies. In this study, experiments provide compelling evidence that long‐term treatment with compounds that block or scavenge reactive oxygen metabolites attenuate age‐related hearing loss and reduce the impact of associated deleterious changes at the molecular level.

Clinical Practice Guideline: Improving Voice Outcomes after Thyroid Surgery

Objective Thyroidectomy may be performed for clinical indications that include malignancy, benign nodules or cysts, suspicious findings on fine needle aspiration biopsy, dysphagia from cervical esophageal compression, or dyspnea from airway compression. About 1 in 10 patients experience temporary laryngeal nerve injury after surgery, with longer lasting voice problems in up to 1 in 25. Reduced quality of life after thyroid surgery is multifactorial and may include the need for lifelong medication, thyroid suppression, radioactive scanning/treatment, temporary and permanent hypoparathyroidism, temporary or permanent dysphonia postoperatively, and dysphagia. This clinical practice guideline provides evidence-based recommendations for management of the patient’s voice when undergoing thyroid surgery during the preoperative, intraoperative, and postoperative period. Purpose The purpose of this guideline is to optimize voice outcomes for adult patients aged 18 years or older after thyroid surgery. The target audience is any clinician involved in managing such patients, which includes but may not be limited to otolaryngologists, general surgeons, endocrinologists, internists, speech-language pathologists, family physicians and other primary care providers, anesthesiologists, nurses, and others who manage patients with thyroid/voice issues. The guideline applies to any setting in which clinicians may interact with patients before, during, or after thyroid surgery. Children under age 18 years are specifically excluded from the target population; however, the panel understands that many of the findings may be applicable to this population. Also excluded are patients undergoing concurrent laryngectomy. Although this guideline is limited to thyroidectomy, some of the recommendations may extrapolate to parathyroidectomy as well. Results The guideline development group made a strong recommendation that the surgeon should identify the recurrent laryngeal nerve(s) during thyroid surgery. The group made recommendations that the clinician or surgeon should (1) document assessment of the patient’s voice once a decision has been made to proceed with thyroid surgery; (2) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, if the patient’s voice is impaired and a decision has been made to proceed with thyroid surgery; (3) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, once a decision has been made to proceed with thyroid surgery if the patient’s voice is normal and the patient has (a) thyroid cancer with suspected extrathyroidal extension, or (b) prior neck surgery that increases the risk of laryngeal nerve injury (carotid endarterectomy, anterior approach to the cervical spine, cervical esophagectomy, and prior thyroid or parathyroid surgery), or (c) both; (4) educate the patient about the potential impact of thyroid surgery on voice once a decision has been made to proceed with thyroid surgery; (5) inform the anesthesiologist of the results of abnormal preoperative laryngeal assessment in patients who have had laryngoscopy prior to thyroid surgery; (6) take steps to preserve the external branch of the surperior laryngeal nerve(s) when performing thyroid surgery; (7) document whether there has been a change in voice between 2 weeks and 2 months following thyroid surgery; (8) examine vocal fold mobility or refer the patient for examination of vocal fold mobility in patients with a change in voice following thyroid surgery; (9) refer a patient to an otolaryngologist when abnormal vocal fold mobility is identified after thyroid surgery; (10) counsel patients with voice change or abnormal vocal fold mobility after thyroid surgery on options for voice rehabilitation. The group made an option that the surgeon or his or her designee may monitor laryngeal electromyography during thyroid surgery. The group made no recommendation regarding the impact of a single intraoperative dose of intravenous corticosteroid on voice outcomes in patients undergoing thyroid surgery.

Molecular mechanisms of age-related hearing loss.

Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with aging and is the most common cause of adult auditory deficiency in the United States. Presbyacusis is defined as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. This condition affects approximately 23% of the population between 65 and 75 years of age and 40% of the population older than 75 years of age. In 1980, it was estimated that 11% of the population was 76 years or older and this number is expected to nearly double by the year 2030 [, Otolaryngol. Head Neck Surg. 100, 262]. When coupled with the fact that the population over 65 years of age is experiencing the most rapid progression of hearing loss, the potential socioeconomic ramifications are staggering. Interestingly, presbyacusis varies in its frequency across differing societies. This discrepancy has been attributed to many factors such as genetics, diet, socioeconomic factors, and environmental variables [, Otolaryngol. Head Neck Surg. 100, 266;. Scand. Audiol. 26 (1997) 133]. The purpose of this discussion is to illuminate the various molecular mechanisms underlying this age-related hearing loss and to offer insights into potential ways to mitigate the effects of aging on hearing impairment.

Resveratrol-induced apoptotic death in human U251 glioma cells

Resveratrol (trans-3,4′,5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G0/G1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.

Biologic activity of mitochondrial metabolites on aging and age-related hearing loss.

HYPOTHESIS Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS Twenty-one Fischer rats, aged 24 months, were divided into three groups: acetyl-l-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities.

Tinnitus in the older adult: epidemiology, pathophysiology and treatment options.

Tinnitus is the perception of sound in the absence of an apparent acoustic stimulus. More than 35 million Americans experience tinnitus, with 2–3 million severely debilitated by this distressing symptom. The prevalence increases with age and there is a high incidence associated with both noise-induced and age-related hearing loss. Although there are several theories regarding the pathophysiology of tinnitus, the precise mechanism remains to be elucidated. The most compelling of these is the hypothesis that tinnitus occurs as a result of spontaneous and aberrant neural activity at any level along the auditory axis, even after cochlear nerve transection or labyrinthine ablation.There are numerous aetiologies associated with tinnitus. Tinnitus, in clinical practice, is characterised as either objective or subjective. The distinction is relevant in terms of both aetiology and treatment. Despite a large number of therapeutic interventions and studies claiming success in treating tinnitus, a cure remains elusive. However, there are several potential treatment options that offer patients varying degrees of symptomatic improvement and enhanced quality of life.It is imperative to formulate a rational and systematic approach in evaluating an older adult with tinnitus. An individualised treatment regimen and the creation of a strong therapeutic relationship are the hallmarks of successful management of the patient with tinnitus.

Mechanisms of Alterations in the Microcirculation of the Cochlea

ABSTRACT: Labyrinthine function is tightly coupled to proper homeostasis. This includes appropriate blood flow that is under strict autoregulatory control. Perturbations in labyrinthine microcirculation can lead to significant cochlear and vestibular dysfunction. The etiology of many otologic disorders, including sudden sensorineural hearing loss, presbyacusis, noise‐induced hearing loss, and certain vestibulopathies, are suspected of being related to alterations in blood flow. Some of the mechanisms responsible for hypoperfusion and possibly ischemia, within the cochlea, are addressed, with emphasis on the possibility that both noise and age contribute to localized low blood‐flow states and stasis. This reduction in blood supply to the cochlea is likely, in part, responsible for reduced auditory sensitivity associated with chronic noise exposure and aging.

Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts

The purpose of this study was to investigate the protective effects of U74389F (Upjohn Co. Kalamazoo, MI), a 21-aminosteroid/lipid peroxidation inhibitor, and a member of the lazaroid drug class, on temporary threshold shifts in animals exposed to prolonged noise stimulation. Animals treated with U74389F and exposed to noise showed attenuated cochlear action potential threshold (CAP) shifts and cochlear microphonic (CM) when compared to non-drug treated noise-exposed subjects. These data suggest that inhibition of FOR induced lipid peroxidation is an important mechanism in noise-induced asymptotic temporary threshold shifts.