Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies.

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.

Safety of ofloxacin otic and other ototopical treatments in animal models and in humans.

To assess the safety of topical agents in the middle ear, animal studies were reviewed. Compared with aminoglycoside-containing preparations, which caused significant loss of hair cells in the basal turn of the cochlea, ofloxacin caused no loss of hair cells, even at concentrations higher than used clinically. Moreover auditory brainstem testing revealed no change in auditory thresholds in the ofloxacin-treated animals, whereas neomycin-treated animals showed substantial threshold shifts. In human studies, use of topical ofloxacin 0.3% was not associated with any change in hearing. Topical ofloxacin has no demonstrable adverse effects on middle ear or cochlear function.

Measuring quality of life in children with obstructive sleep disorders.

OBJECTIVE: To validate a disease-specific health-related quality of life (HRQOL) instrument for children with obstructive sleep disorders (OSDs). DESIGN: Prospective cohort study using a 6-item health-related instrument (OSD-6). SUBJECTS: One hundred caregivers of patients with OSDs secondary to adenotonsillar hypertrophy (age range, 2-12 years) from 2 tertiary care, pediatric otolaryngology practices. INTERVENTION: The OSD-6 was administered on initial presentation and 4 to 5 weeks after adenotonsillectomy. A subset of patients repeated the OSD-6 within 3 weeks after presentation to assess test-retest reliability. MAIN OUTCOME MEASURES: Test-retest reliability, internal consistency, construct validity, and responsiveness to clinical change of the OSD-6 score. RESULTS: Test-retest reliability was good (intraclass correlation coefficient = 0.74). Median OSD-6 score was 4.5 (0- to 6-point scale) with higher scores indicating poorer quality of life (QOL). Construct validity was demonstrated by the moderate correlation between OSD-6 score and global adenoid and tonsil-related QOL (R = -0.62), strong correlation between the OSD-6 change score and change in global adenoid and tonsil-related QOL (R = -0.63), and the moderate correlation between the change score and parent estimate of clinical change (R = 0.40). The mean change in OSD-6 score after adenotonsillectomy was 3.0 (95% confidence interval, 2.7-3.4). The mean standardized response was 2.3 (95% confidence interval, 1.9-2.7) indicating the instrument's large responsiveness to clinical change. The change score was very reliable (R = 0.85). CONCLUSIONS: The OSD-6 is a reliable, responsive, easily administered instrument. It is valid for detecting change after adenotonsillectomy in children with OSDs. Arch Otolaryngol Head Neck Surg. 2000;126:1423-1429

Clinimetrics of Meniere's disease.

Two clinically useful measures to quantify the morbidity of Meniere's disease are the daily vertigo diary card and the Meniere's Disease Patient-Oriented Severity Index (MD POSI). The development and application of these outcomes instruments for patients with vertigo are discussed.

Longitudinal threshold changes in older men with audiometric notches.

Age-related hearing loss (presbycusis) is a multifactorial process that results chiefly from the accumulating effects of noise damage and aging on the cochlea. Noise damage is typically evidenced clinically by a discrete elevation (notch) of the auditory thresholds in the 3-6 kHz region of the audiogram whereas aging affects the highest frequencies first. To determine whether the presence of such high-frequency notches influences auditory aging, we examined the 15 year change in audiometric thresholds in 203 men from the Framingham Heart Study cohort. The mean age at the first hearing test was 64 years (range 58-80). Occupational and recreational noise exposure over the 15 years was assumed to be minimal due to the age of the subjects. The presence or absence of a notch was determined using a piecewise linear/parabolic curve fitting strategy. A discrete elevation of the pure-tone thresholds of 15-34 dB in the 3-6 kHz region was deemed a small notch (N1), and elevations of 35 dB or greater were deemed large notches (N2). Absence of a notch (N0) was encoded those ears with <15 dB elevation in the 3-6 kHz region. The presence and absence of notches correlated with the subjects' history of noise exposure. The 15 year pattern of change in age-adjusted pure-tone thresholds varied significantly by notch category. There was less change over time in the notch frequencies (3-6 kHz) and significantly greater change in the adjacent frequency of 2 kHz in the N2 group as compared to the N0 and N1 groups. The adjacent frequency of 8 kHz showed a significant, but smaller, change in the N1 group as compared to the N0 and N2 groups. The change at 2 kHz was independent of the starting hearing level at E15, whereas the changes at 4-8 kHz were influenced by the hearing level at E15. These data suggest that the noise-damaged ear does not 'age' at the same rate as the non-noise damaged ear. The finding of increased loss at 2 kHz suggests that the effects of noise damage may continue long after the noise exposure has stopped. The mechanism for this finding is unknown but presumably results from prior noise-induced damage to the cochlea.

Genetic associations in age-related hearing thresholds.

OBJECTIVE: To determine the inheritance of age-related hearing loss. DESIGN: Cohort study comparing aggregation of hearing levels in genetically unrelated people (spouse pairs) and in genetically related people (sibling pairs, parent-child pairs). SETTING: Framingham Heart Study biennial Examination 15 (1973-1975) and Framingham Offspring Study Examination 6 (1995-1998). SUBJECTS: Members of the Framingham cohorts with hearing tests and with a relative in the Framingham hearing study. MAIN OUTCOME MEASURES: Audiometric pure-tone thresholds at 250 to 8000 Hz were obtained and pure-tone average (PTA) hearing thresholds were calculated for the middle (0.5-2 kHz), high (4-8 kHz), and low (0.25-1 kHz) frequencies for each ear. The shape of the audiogram was categorized as either normal, abrupt high-frequency loss (sensory phenotype) or flat loss (strial phenotype). Correlations were made using the Familial Correlations program of the Statistical Analysis for Genetic Epidemiology software system. The level of significance was P = .01. RESULTS: Hearing threshold levels did not aggregate in spouses. Significant aggregation was noted in siblings and parent-child pairings for PTA at low, middle, and high frequencies. Sisters but not brothers had significant aggregation of each PTA measure. Mother-daughter and mother-son pairs but not father-son pairs had significant aggregation of hearing levels. For the sensory phenotype, there was significant aggregation in all related pairs except for father-child pairs. For the strial phenotype, there was significant aggregation of hearing levels in the related female pairs but not in the related male pairs. CONCLUSIONS: A clear familial aggregation occurs for age-related hearing levels, sensory presbycusis phenotypes, and strial presbycusis phenotypes. The aggregations are stronger in women than in men. The heritability estimate was greater for the strial phenotypes than for the sensory phenotypes. The data support a genetic effect on the inheritance of presbycusis in women and a mixed, genetically acquired cause in men.

Innovar treatment for Meniere's disease.

Patients with intractable vertigo due to clinical Meniere's disease were offered treatment with Innovar, a neurolept analgesic. The patients were from a single clinical practice, had failed conventional dietary and medical treatment and were eligible on clinical grounds for endolymphatic sac surgery. After a follow-up of 2-8 years, 58% of patients had long-lasting relief of vertigo. Hearing was not affected. Risk factors for a favorable response were male gender, fluctuating hearing, and early stage of the disorder. Innovar is a safe, cost-effective second-line therapy for patients with Meniere's disease who have failed conventional first-line medical therapy.

Measuring the effects of Meniere's disease: results of the Patient-Oriented Severity Index (MD POSI) version 1.

We describe the development and initial psychometric testing of a new self-report instrument for quantifying the impact of Meniere's disease (MD) on patients' lives: the Meniere's Disease Patient-Oriented Severity Index (MD POSI). Eighty-five volunteers with chronic MD took a self-administered MD POSI. The internal consistency form of reliability was determined by calculating Cronbach's alpha. The relationship between total MD POSI problem severity scores and responses to a global question concerning the degree to which his or her MD had changed the patient's life assessed construct-related validity. The total problem severity score yielded excellent reliability (Cronbach's alpha = .928). No significant age or gender effects were seen. A highly statistically significant association was noted between total problem severity scores and the degree to which the patient's life had been changed by his or her MD (Spearman rank correlation = .526, p < .0001), indicating excellent construct-related validity. The material included in the initial questionnaire provides important information that can be used clinically to quantify the impact of MD on patients' health status. A beta version of the instrument is in the process of validation and determination of its sensitivity to change in health status.

Measuring the indirect and direct costs of acute otitis media.

OBJECTIVES: To test a method of measuring the related cost of acute otitis media (AOM) and to provide a preliminary calculation of the indirect and directs costs associated with a single, medically treated episode of AOM. DESIGN: The Otitis Media Diary was used to measure indirect and direct costs associated with AOM in a prospective cohort study. Measured values included the parental time spent in otitis-specific child care and the number and type of medications used. A previously developed economic model was used to calculate the monetary costs associated with the value of caregiver time and the total opportunity cost of AOM. SETTING: The pediatric clinic of Madigan Army Medical Center, Tacoma, Wash. PATIENTS: A cohort of 25 children (12 with AOM and 13 controls) aged 1 to 3 years. MAIN OUTCOME MEASURES: Caregiver time and medication use. RESULTS: The total cost attributable to AOM in the 3-month period following diagnosis was $1330.58 (95% confidence interval, $1008.75-$1652.43), with the majority of that cost stemming from the indirect, rather than direct, costs of illness. After conservative estimates of unmeasured expenses, such as clinic visits and transportation, were accounted for, indirect costs, accrued primarily by parental time, accounted for nearly 90% (95% confidence interval, 87.1%-92.3%) of the total 3-month cost associated with AOM and its medical treatment. The cost items of the Otitis Media Diary were also highly correlated with each other and with other measures of clinical and functional health status. CONCLUSIONS: Otitis Media Diary measures of parental time and medication use appear to provide a more accurate means of calculating the real social costs attributable to the AOM disease process in this cost-effectiveness analysis.

Noise-induced hearing loss in young adults: the role of personal listening devices and other sources of leisure noise.

CONCEPT: No consensus exists regarding the magnitude of the risk of noise-induced hearing loss (NIHL) associated with leisure noise, in particular, personal listening devices in young adults. OBJECTIVE: Examine the magnitude of hearing loss associated with personal listening devices and other sources of leisure noise in causing NIHL in young adults. STUDY DESIGN: Prospective auditory testing of college student volunteers with retrospective history exposure to home stereos, personal listening devices, firearms, and other sources of recreational noise. METHODS: Subjects underwent audiologic examination consisting of estimation of pure-tone thresholds, speech reception thresholds, and word recognition at 45 dB HL. RESULTS: Fifty subjects aged 18 to 30 years were tested. All hearing thresholds of all subjects (save one-a unilateral 30 dB HL threshold at 6 kHz) were normal, (i.e., 25 dB HL or better). A 10 dB threshold elevation (notch) in either ear at 3 to 6 kHz as compared with neighboring frequencies was noted in 11 (22%) subjects and an unequivocal notch (15 dB or greater) in either ear was noted in 14 (28%) of subjects. The presence or absence of any notch (small or large) did not correlate with any single or cumulative source of noise exposure. No difference in pure-tone threshold, speech reception threshold, or speech discrimination was found among subjects when segregated by noise exposure level. CONCLUSION: The majority of young users of personal listening devices are at low risk for substantive NIHL. Interpretation of the significance of these findings in relation to noise exposure must be made with caution. NIHL is an additive process and even subtle deficits may contribute to unequivocal hearing loss with continued exposure. The low prevalence of measurable deficits in this study group may not exclude more substantive deficits in other populations with greater exposures. Continued education of young people about the risk to hearing from recreational noise exposure is warranted.

In vivo measures of cochlear length and insertion depth of nucleus cochlear implant electrode arrays.

Three-dimensional cochlear canal lengths, electrode array intracochlear insertion depths, and characteristic frequency ranges were estimated for 20 Nucleus implant recipients on the basis of in vivo computed tomography (CT) scans. Ultra-high resolution images were reconstructed from spiral CT data with 0.1-mm slicing and expanded attenuation scales. Canal length estimates (mean 33.01 mm; SD 2.31) were consistent with previous findings for normal human temporal bones. Intracochlear array insertion depths estimated by 3-dimensional (3-D) spiral calculations (mean 20.19 mm; SD 2.86) and by a computerized array tracking algorithm (mean 20.36 mm; SD 2.66) were not significantly different. Estimates from surgical observations were significantly longer (mean 21.03 mm; SD 2.31) because array compressions were not detectable. Characteristic frequencies at apical electrodes estimated from Greenwood's equations ranged from 387 Hz to 2,596 Hz. The results show that significant variations in cochlear anatomy and array distribution among implant patients that may impact implant performance can be reliably detected and quantified by using in vivo high-resolution CT and 3-D reconstructions.

Obstructive sleep apnea treatment outcomes pilot study.

Approximately 40 million Americans have chronic sleep disorders, the most serious of which is obstructive sleep apnea. The goals of this research were to serve as a demonstration project for a multicenter treatment outcomes research project for patients with obstructive sleep apnea. A clinical-severity staging system was created to control for important differences in the severity of sleep apnea among the enrolled patients. A disease-specific quality-of-life measure was used in this project to measure, from the patient's perspective, important pretreatment and posttreatment physical, functional, and emotional aspects of obstructive sleep apnea. Adults with apnea indexes greater than 5 who had not previously undergone uvulopalatoplasty were eligible. In total 142 patients were enrolled from eight otolaryngology practices. The mean age was 48 years, 112 were men, and 114 were white. The mean pretreatment apnea index was 40.0, and the mean respiratory distress index was 60.5. Seventy-one patients received continuous positive airway pressure, and 48 patients received surgery. Outcomes were assessed from scores on patient-based general and disease-specific health status measures 4 months after enrollment. The short duration of follow-up and limited number of patients undergoing posttreatment polysomnograms prohibit any analysis of treatment effectiveness. Nevertheless, this research represents a step forward for the support of future outcomes research projects by organized otolaryngology.

Otitis media health status evaluation: a pilot study for the investigation of cost-effective outcomes of recurrent acute otitis media treatment.

There are no reliable and valid instruments that measure otitis media clinical or functional health status in children ages 1 to 3 years. This study develops and tests three new instruments of clinical and functional otitis health status: the Otitis Media Clinical Severity Index (OM-CSI), the Otitis Media Functional Status Questionnaire (OM-FSQ), and the Otitis Media Diary (OMD). The OM-CSI was found to be a reliable measure of clinical acute otitis media (AOM) severity, with high internal consistency (Cronbach's alpha) scores, as well as an accurate indicator of AOM severity. The OM-FSQ and OMD were demonstrated to be reliable and valid measures of otitis-specific functional health status, with reproducible scores over time, high internal consistency alpha scores, and high correlation with measures of AOM clinical severity and other functional health status instruments. These three new instruments were also sensitive and specific indicators of AOM episodes.

Hear ye? Hear ye! Successful auditory aging.

Age-related hearing loss (presbycusis) is a multifactorial process that affects nearly all people in their senior years. Most cases are due to a loss of cochlear hair cell function and are well mediated by communication courtesy and modern amplification technology. Severe hearing loss is generally due to cochlear problems or age-related diseases and may require speech reading, assistive listening devices, and cochlear implants, depending on the degree of loss. Presbycusis may seriously impair communication and contribute to isolation, depression, and possibly dementia. Accurate diagnosis and prompt remediation are widely available but are frequently underused. Geriatric health care and well-being is enhanced by the detection and remediation of communication disorders.