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Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel do...

Objective Determine if D-methionine (D-met) rescue prevents temporary threshold shift (TTS) from steady-state or impulse noise and determine D-met's impact on serum and cochlear antioxidant levels. Design D-met at 50, 100 or 200 mg/kg/doses were administered 0, 6 and 18 hours-post noise. ABRs at baseline and 24 hours post-noise measured TTS. Serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels measured physiological influence. Three control groups, with impulse or steady-state or without noise, were saline-injected. Study sample Ten Chinchillas/group. Results D-met rescue did not significantly reduce TTS or impact serum CAT, SOD, GPx or GR levels vs. noise-exposed control groups, but TTS was greater in all groups relative to no-noise controls. D-met significantly elevated CAT at 50 mg/kg vs. steady-state controls and SOD at 200 mg/kg vs. impulse noise controls. D-met significantly reduced cochlear GSH/GSSG ratios in the 100 mg/kg D-met group vs. impulse noise controls. Conclusions While D-met rescue has reduced permanent threshold shift in previous studies, it did not reduce TTS in this study. However, D-met rescue did alter selective serum and cochlear oxidative state changes 24 hours post-noise relative to controls. Results demonstrate TTS studies do not always predict PTS protection in otoprotectant experimental designs.

Self-conjugate nuclei in the A ≈ 70 – 80 region have attracted a great deal of attention due to phenomena such as shape coexistence and increasing collectivity along the N = Z line. We investigate the structure of nuclei in this region through lifetime measurements using the GRETINA array. The first implementation of the Differential Recoil Distance Doppler Shift technique with fast radioactive beams is demonstrated and verified through a measurement of the well-known B ( E 2 ; 2 1 + → 0 1 + ) transition strength in 74Kr. The method is then applied to determine the B ( E 2 ; 2 1 + → 0 1 + ) transition strength in 74Rb, the heaviest odd–odd N = Z nucleus for which this quantity has been determined. This result and extended systematics along N = Z suggest the dominance of the isoscalar part of the quadrupole transition strengths in self-conjugate nuclei, as well as the possible presence of shape coexistence in 74Rb.

Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.

The purpose of this article is to provide guidelines for determining a Significant Noise-Induced Threshold Shift in clinical trials involving human populations. The article reviews recommendations for the standards to be referenced for human subjects, equipment, test environment, and personnel. Additional guidelines for military populations are provided. Guidelines for the calibration of audiometers, sound booth noise levels, and immitance equipment are provided. In addition the guidance provides specific suggestions for the subjects history before study onset, and otoscopy.Test frequencies for threshold determination and methods of threshold determination are reviewed for both air conduction and bone conduction for both baseline testing and later determination of either a temporary (TTS) or permanent threshold shift (PTS). Once a Significant Noise-Induced Threshold Shift has been determined, subjects should be retested, conductive component should be ruled out or addressed, and the subject should be counseled or referred for additional medical evaluation. Guidance for reporting procedures and the computerized study database are described. Finally, experimental designs suggested for noise-induced otoprotection clinical trials are described.

Test D-methionine (D-met) as an otoprotectant from kanamycin-induced ototoxicity and determine the lowest maximally protective D-met dose.Auditory brainstem responses (ABR) were measured at 4, 8, 14, and 20 kHz at baseline and two, four, and six weeks after kanamycin and D-met administration initiation. ABR threshold shifts assessed auditory function. Following six-week ABR testing, animals were decapitated and cochleae collected for outer hair cell (OHC) quantification.Eight groups of 10 male pigmented guinea pigs were administered a subcutaneous kanamycin (250 mg/kg/dose) injection once per day and an intraperitoneal D-met injection (0 (saline), 120, 180, 240, 300, 360, 420, or 480 mg/kg/day) twice per day for 23 days.Significant ABR threshold shift reductions and increased OHC counts (p ≤ 0.01) were measured at multiple D-met-dosed groups starting at two-week ABR assessments. A 300 mg/kg/day optimal otoprotective D-met dose provided 34-41 dB ABR threshold shift reductions and OHC protection. Lesser, but significant, D-met otoprotection was measured at lower and higher D-met doses.D-met significantly reduced ABR threshold shifts and increased OHC percentages compared to kanamycin-treated controls. Results may be clinically significant particularly for multidrug-resistant tuberculosis patients who frequently suffer from kanamycin-induced hearing loss in developing countries.

Background The purpose of this study was to test if oral D-methionine (D-met) reduced mucositis during chemoradiotherapy. Methods We conducted a placebo-controlled double-blind randomized phase II trial of D-met (100 mg/kg p.o. b.i.d.) testing the rate of severe (grades 3-4) mucositis. Results Sixty patients were randomized. Grade 2 + oral pain was higher with placebo (79% vs 45%; P = .0165), whereas grade 2 + body odor was greater with D-met (3% vs 41%; P = .0015). Mucositis was decreased with D-met by the physician (World Health Organization [WHO], P = .007; Radiation Therapy Oncology Group [RTOG], P = .009) and patient functional scales (RTOG, P = .0023). The primary end point of grades 3 to 4 mucositis on the composite scale demonstrated a decrease with D-met (48% vs 24%; P = .058), which was borderline in significance. A planned secondary analysis of a semiquantitative scoring system noted decreased oral ulceration (2.2 vs 1.5; P = .023) and erythema (1.6 vs 1.1; P = .048) with D-met. Conclusion Although not meeting the primary end point, results of multiple assessments suggest that D-met decreased mucositis.

This study tested multiple dosing epochs of pre-loaded D-methionine (D-met) for otoprotection from noise-induced hearing loss (NIHL).Auditory brainstem response (ABR) thresholds were measured at baseline, 1 day, and 21 days following a 6-hour 105 dB sound pressure level (SPL) octave band noise (OBN) exposure. Outer hair cell (OHC) counts were measured after day 21 sacrifice.Three groups of five Chinchillas laniger each were given a 2-day regimen comprising five doses of D-met (200 mg/kg/dose) intraperitoneally (IP) starting 2, 2.5, or 3 days prior to noise exposure. A control group (n = 5) received five doses of equivalent volume saline IP starting 2.5 days prior to noise exposure.ABR threshold shifts from baseline to day-21 post-noise exposure were reduced in all D-met groups versus controls, reaching significance (p0.05) in the 3-day group. D-met groups showed reduced OHC loss relative to controls at day-21 post-noise exposure, reaching significance (p0.05) at all frequency regions in the 3-day group and at the 2, 4, and 8 kHz frequency regions in the 2.5-day group.D-met administration in advance of noise-exposure, without further administration, significantly protects from noise-induced ABR threshold shift and OHC loss.

The neutron-rich nucleus $^{144}$Ba ($t_{1/2}$=11.5 s) is expected to exhibit some of the strongest octupole correlations among nuclei with mass numbers $A$ less than 200. Until now, indirect evidence for such strong correlations has been inferred from observations such as enhanced $E1$ transitions and interleaving positive- and negative-parity levels in the ground-state band. In this experiment, the octupole strength was measured directly by sub-barrier, multi-step Coulomb excitation of a post-accelerated 650-MeV $^{144}$Ba beam on a 1.0-mg/cm$^2$ $^{208}$Pb target. The measured value of the matrix element, $\langle 3_1^- \| \mathcal{M}(E3) \| 0_1^+ \rangle=0.65(^{+17}_{-23})$ $e$b$^{3/2}$, corresponds to a reduced $B(E3)$ transition probability of 48($^{+25}_{-34}$) W.u. This result represents an unambiguous determination of the octupole collectivity, is larger than any available theoretical prediction, and is consistent with octupole deformation., Comment: 5 pages, 2 figures, 1 table, Physical Review Letters 2016

For decades, cisplatin chemotherapy has significantly increased survival in numerous cancer patient populations. However, cisplatin treatment results in severe adverse side effects including nephrotoxicity, neurotoxicity, radiation-induced oral mucositis, ototoxicity, and permanent hearing loss. Protection from cisplatin’s adverse side effects has therefore been a translational research focus for many years. This chapter discusses cisplatin’s historical discovery, its clinical application, and cisplatin-induced ototoxicity mechanisms. The chapter then reviews current translational research to protect from cisplatin-induced hearing loss, including clinical behavioral and objective monitoring techniques; adult and pediatric grading scales implemented to measure and identify cisplatin-induced ototoxicity; and potential otoprotective mechanisms that are currently tested to prevent cisplatin-induced ototoxicity in animals and clinical trials. Finally, the chapter reviews potential clinical trial funding and the steps required by the FDA, including the extensive investigational new drug (IND) application, to test otoprotective agents for protection from cisplatin-induced hearing loss. At the chapter’s end, readers should acquire general knowledge underlying cisplatin’s intricate history and clinical cisplatin use and understand the steps required to design and perform translational otoprotection studies to prevent cisplatin-induced ototoxicity and permanent hearing loss.

The objective of this study was to determine if increased overjet (greater than 6 mm) influences the magnitude and reproducibility of natural smile and maximal smile in Caucasian adult females. Twenty adult females with an increased overjet (6–10 mm) and 20 control adult females (overjet 2–4 mm) with no history of orthodontic treatment volunteered to participate. The mean age in the control group was 30.1 ± 6.4 years and the mean age in the test group was 31.9 ± 10.8 years. Three-dimensional stereophotogrammetric images were captured of each subject for three expressions: at rest, natural smile, and maximal smile. The images were recorded twice on two separate occasions, 6 weeks apart. Images were landmarked and a partial ordinary Procrustes superimposition was used to adjust for the differences in head posture between the same expressions. The magnitude of movement relative to the rest position, averaged over all the landmarks, was calculated and compared between the groups using analysis of variance (linear mixed-effects model); the intra- and inter-session reproducibility of both expressions was assessed. There was greater mean movement, averaged over all the landmarks, in the control group than in the increased overjet group for both natural smile and maximal smile ( P = 0.0068). For these expressions, there were no statistically significant differences in reproducibility within sessions ( P = 0.5403) or between sessions ( P = 0.3665). Increased overjet had a statistically significant effect on the magnitude of smiling but did not influence the reproducibility of natural or maximal smile relative to controls.

Ototoxicity monitoring is particularly critical in patients receiving platinum-based chemotherapy or long-term aminoglycoside antibiotic administration. Furthermore, as new otoprotective agents are developed, audiologists need to not only be able to monitor for ototoxicity but know the various criteria for early detection of ototoxicity and how to grade ototoxic adverse events. The three primary methods for ototoxicity monitoring are conventional audiometry, high-frequency audiometry, and otoacoustic emissions. However, early detection and adverse event criteria depend primarily on conventional and high-frequency audiometry. No consensus exists on determining significant changes in otoacoustic emissions secondary to ototoxic drugs. Also, no consensus exists on how to monitor for tinnitus, although it is a common complication in these patients. Currently, tinnitus surveys can be helpful. A baseline evaluation is critical for accurate interpretation of auditory threshold results. Thus, a team approach is needed to ensure adequate care of these children. For clinical trials and in reading the literature, audiologists need to be aware of the American Speech Language Hearing Association's 1994 criteria for detection of ototoxic change, and the Common Terminology Criteria for Adverse Events, Brock, and the Change scales for classification of adverse events. These methods and scales are reviewed and discussed.

Summary Background Sprague-Dawley rats were used as an acute cisplatin ototoxicity model to compare the chemo-protective efficacy of 2 sulphur-containing antioxidants (D-methionine, N-L-acetylcysteine) and 1 seleno-organic compound (ebselen). Each putative chemo-protective agent was tested at 3 different dosages in order to assess the influence of dose on auditory preservation. Material/Methods A total of 40 Sprague-Dawley albino male rats were used in the study. Animals were divided into 10 groups, 3 groups of different doses for each protective agent and a cisplatin-treated control group. The animals were weight-matched before drug exposure to ensure similar weights in all groups. Auditory function was assessed with auditory brainstem responses and distortion product otoacoustic emissions at time zero and at 96 hours post-treatment. Results At the post-treatment follow-up no significant threshold change at 8 kHz was found in the D-Met- and NAC-treated groups. All ebselen-treated animals presented significant threshold elevations. At 12 and 16 kHz, only the groups treated with 300, 450 mg/kg of D-Met and 475 mg/kg of NAC presented thresholds comparable to the pre-treatment ABR data. The ebselen-treated animals presented significant threshold shifts and showed the highest threshold elevations. The DPOAE data analysis showed that only the animals from the 350 mg/kg D-met group presented lack of statistical differences between the pre and post recordings. Conclusions Considering the outcome from the ABR and DPOAE analyses together, only the 350 mg/kg D-met group presented a complete auditory preservation against the 14 mg/kg cisplatin administered i.v. Data from ebselen pre-treated Sprague-Dawley albino male rats demonstrate that ebselen dosages up to 12 mg/kg given by i.p. administration lack auditory preservation in this species.

The neutron-rich nucleus 74Ni was studied with inverse-kinematics inelastic proton scattering using a 74Ni radioactive beam incident on a liquid hydrogen target at a center-of-mass energy of 80 MeV. From the measured de-excitation γ rays, the population of the first 2+ state was quantified. The angle-integrated excitation cross section was determined to be 14(4) mb. A deformation length of δ = 1.04 ( 16 ) fm was extracted in comparison with distorted wave theory, which suggests that the enhancement of collectivity established for 70Ni continues up to 74Ni. A comparison with results of shell model and quasi-particle random phase approximation calculations indicates that the magic character of Z = 28 or N = 50 is weakened in 74Ni.

Background Tobramycin is a critical cystic fibrosis treatment however it causes ototoxicity. This study tested d-methionine protection from tobramycin-induced ototoxicity and potential antimicrobial interference. Methods Auditory brainstem responses (ABRs) and outer hair cell (OHC) quantifications measured protection in guinea pigs treated with tobramycin and a range of d-methionine doses. In vitro antimicrobial interference studies tested inhibition and post antibiotic effect assays. In vivo antimicrobial interference studies tested normal and neutropenic Escherichia coli murine survival and intraperitoneal lavage bacterial counts. Results d-Methionine conferred significant ABR threshold shift reductions. OHC protection was less robust but significant at 20kHz in the 420mg/kg/day group. In vitro studies did not detect d-methionine-induced antimicrobial interference. In vivo studies did not detect d-methionine-induced interference in normal or neutropenic mice. Conclusions d-Methionine protects from tobramycin-induced ototoxicity without antimicrobial interference. The study results suggest d-met as a potential otoprotectant from clinical tobramycin use in cystic fibrosis patients.

Drug-induced hearing loss can occur secondary to a variety of clinical therapeutics, including certain classes of antineoplastics, antimicrobials, diuretics, analgesics, and antimalarials. Unfortunately, not all patients receiving even highly ototoxic medications are routinely monitored for potential hearing loss. For patients receiving medications with a lower incidence of ototoxicity, the hearing loss, when it occurs may be attributed to other factors such as stress or malaise. New pharmacologic otoprotective agents are approaching or are already in clinical trials to prevent ototoxicity while retaining the primary drug’s therapeutic efficacy. This chapter reviews some of the common ototoxic drugs in clinical use, the potential otoprotective agents in clinical trials, methods for audiologic monitoring for ototoxicity and otoprotection, and the ototoxicity grading scales for use in clinical practice and in clinical trials.

For decades, it has been known that ingested potassium bromate and sodium bromate can induce hearing loss. Hearing loss onset, following high-dose ingestion, is generally rapid occurring within 4-16 h and of a severe to profound degree. Unlike the sensorineural hearing loss which is generally irreversible, bromate-induced tinnitus, which is less well-studied, may reportedly be permanent or temporary. It is not clear whether actual bromate-induced vestibulotoxicity occurs in clinical populations. The primary sites of lesion for bromate-induced ototoxicity appear to be in the cochlea. However, possible effects on the VIIIth nerve and central auditory system have not been fully investigated. Based on animal studies, in the cochlea, bromate damages the stria vascularis, Reissner's membrane, inner and outer hair cells, Claudius cells and inner sulcus cells. Physiologically, bromate reduces the endocochlear potential, cochlear microphonics, and electrophysiologic auditory thresholds. Possible mechanisms are discussed. The effects of long-term low-dose bromate exposure on hearing have not been studied. These effects, if they occur, may not be readily detected in many clinical populations, because idiopathic hearing loss occurs commonly in the population as a whole. Further it is unknown whether or not chronic bromate ingestion may exacerbate noise-induced hearing loss. Further study to determine the maximum safe exposure level for long-term administration and to develop possible antidotes is warranted.

Fifty-two healthy adult male and female volunteers were enrolled in this double-blind study to determine the maximum tolerated dose, characterize the pharmacokinetics, and obtain serum bactericidal activity (SBA) data for intravenous dalbavancin. Subjects were assigned to single- or multiple-dose groups and randomized to receive dalbavancin or placebo intravenously over 30 min. Doses started at 140 mg in the single-dose group and with a 300-mg loading dose (LD), followed by six daily 30-mg maintenance doses (MDs), in the multiple-dose cohort and escalated to a 1,120-mg single dose and a 1,000-mg LD and 100-mg MD regimen. Plasma, urine, and skin blister fluid aspirate drug concentrations were measured, and pharmacokinetic parameters were determined via noncompartmental methods. SBA against methicillin-resistant Staphylococcus aureus (MRSA) was determined at several time points. Adverse events and changes from the baseline for laboratory data, electrocardiograms, audiologic assessments, physical examinations, and vital signs were assessed. Concentrations increased in proportion to the dose. Steady-state concentrations were achieved by day 3 with the 10:1 LD-MD regimen. The half-life averaged 181 h, and the mean volume of distribution and clearance were 9.75 liters and 0.0473 liters/h, respectively. Mean values were similar in all groups and in males and females. The portion of the dose excreted renally averaged 33.5%. Bactericidal activity was demonstrated in serum at 7 days in all subjects receiving single doses of ≥500 mg. All doses were well tolerated. Dose-limiting toxicity was not encountered. No changes in auditory or vestibular function occurred. The long half-life and maintenance of SBA against MRSA for 1 week suggest that weekly dosing may be feasible.

This study describes audiologic methodology and results for evaluating potential ototoxicity in a phase I clinical trial of a new glycopeptide. This study was conducted under good clinical practices, which are regulated by the US Food and Drug Administration (FDA) (21 Code of Federal Regulations), and input from the FDA was sought prior to study implementation. Healthy, normal volunteers underwent extensive medical and audiologic assessments as part of this phase I dose- escalation study of dalbavancin, a new glycopeptide, to assess potential side effects. Audiologic monitoring included air-conduction thresholds in the conventional (0.25-8 kHz) and high-frequency (10-16 kHz) ranges. At baseline, subjects were also tested using word recognition, bone conduction testing if indicated, and tympanometry. Full testing was to be repeated if any subject met the American Speech-language-Hearing Association (ASHA) 1994 criteria for ototoxic change. However, no subjects demonstrated ototoxic change after receiving dalbavancin, nor were any false-positive results obtained.

Glutathione (GSH) provides an important antioxidant and detoxification pathway. We tested to determine if direct administration of GSH or GSH ester could reduce cisplatin- (CDDP) induced ototoxicity. We tested eight groups of five rats each: a control group, a group receiving 16 mg/kg ip CDDP infused over 30 minutes, and six groups receiving either GSH or GSH ester at 500, 1000, or 1500 mg/kg intraperitoneally 30 minutes prior to 16 mg/kg CDDP. Auditory brainstem response thresholds were measured for click and tone-burst stimuli at baseline and 3 days later. Outer hair cell (OHC) loss was measured for the apical, middle and basal turns. The 500 mg/kg GSH ester reduced hearing loss and OHC loss, but protection decreased as dosage increased, suggesting possible toxicity. GSH was not significantly protective. The best GSH ester protection was less than we have previously reported with D-methionine. El glutatión (GSH) brinda una importante vía antioxidante y de cetoxificación. Realizamos una prueba para determinar si la administración directa de GSH o del éster de GSH podía reducir la ototoxicidad inducida por cisplatino (CDDP). Hicimos una evaluación en ocho grupos de cinco ratas cada uno: un grupo control, un grupo que recibió CDDP intraperitoneal a 16 mg/kg en una ínfusión durante 30 minutos y seis grupos que recibieron intraperitonealmente GSH o el éster de GSH a 500, 1000 o 1500 mg/kg, 30 minutos antes del CDDP a 16 mg/kg. Se midieron umbrales de respuestas auditivas del tallo cerebral tanto para clicks como para bursts tonales, al inicio y 3 días después. La pérdida de células ciliadas externas (OHC) fue establecida a nivel de las vueltas apical, media y basal. La dosis de 500 mg/kg de éster de GSH redujo la hipoacusia y la pérdida de OHC, pero la protección disminuyó conforme la dosis se incrementó, sugiriendo una posible toxicidad. EL GSH no resultó significativamente protector. El mejor efecto protector del éster de GSH fue menor que el previamente reportado con D-Metionina.

D-methionine (D-met) protects against cisplatin (CDDP) ototoxicity, but the mechanisms are not well understood. This study investigated D-met protection of cochlear oxidative state as measured by superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and malondiadehyde (MDA) levels. The design comprised four groups of five rats each: (1) a saline control group, (2) a CDDP-only-treated group, (3) a CDDP group pretreated with D-met, and (4) a group receiving only D-met. Auditory brainstem response testing (ABR) was performed before and 3 days after injection. CDDP alone caused marked hearing loss; significantly reduced SOD, CAT, and GR levels; and increased MDA levels, but D-met pretreatment protected against these changes. These studies suggest that D-met protects cochlear antioxidant enzyme levels from CDDP-induced decrements. The excellent correlation of enzyme levels with hearing loss and weight loss suggests that antioxidant enzyme level protection may underlie, at least in part, D-met's otoprotective action.

Objectives To summarize the findings relevant to otolaryngology from the annual meeting of the Blood–Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001. Study Design Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included. Results Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity. Conclusions The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.

Objectives/Hypothesis Oxidative stress plays a substantial role in the genesis of noise-induced cochlear injury that causes permanent hearing loss. We present the results of three different approaches to enhance intrinsic cochlear defense mechanisms against oxidative stress. This article explores, through the following set of hypotheses, some of the postulated causes of noise-induced cochlear oxidative stress (NICOS) and how noise-induced cochlear damage may be reduced pharmacologically. 1) NICOS is in part related to defects in mitochondrial bioenergetics and biogenesis. Therefore, NICOS can be reduced by acetyl-L carnitine (ALCAR), an endogenous mitochondrial membrane compound that helps maintain mitochondrial bioenergetics and biogenesis in the face of oxidative stress. 2) A contributing factor in NICOS injury is glutamate excitotoxicity, which can be reduced by antagonizing the action of cochlear N-methyl-D-aspartate (NMDA) receptors using carbamathione, which acts as a glutamate antagonist. 3) Noise-induced hearing loss (NIHL) may be characterized as a cochlear-reduced glutathione (GSH) deficiency state; therefore, strategies to enhance cochlear GSH levels may reduce noise-induced cochlear injury. The objective of this study was to document the reduction in noise-induced hearing and hair cell loss, following application of ALCAR, carbamathione, and a GSH repletion drug D-methionine (MET), to a model of noise-induced hearing loss. Study Design This was a prospective, blinded observer study using the above-listed agents as modulators of the noise-induced cochlear injury response in the species chinchilla laniger. Methods Adult chinchilla laniger had baseline-hearing thresholds determined by auditory brainstem response (ABR) recording. The animals then received injections of saline or saline plus active experimental compound starting before and continuing after a 6-hour 105 dB SPL continuous 4-kHz octave band noise exposure. ABRs were obtained immediately after noise exposure and weekly for 3 weeks. After euthanization, cochlear hair cell counts were obtained and analyzed. Results ALCAR administration reduced noise-induced threshold shifts. Three weeks after noise exposure, no threshold shift at 2 to 4 kHz and

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84-member four-generation central Illinois family with autosomal dominant Charcot-Marie-Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2-p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family.

The present study has evaluated the use of distortion product otoacoustic emission (DPOAE) responses in the detection of cisplatin-induced ototoxicity in a Sprague Dawley rat animal model. The cisplatin was administered as a 16 mg/kg, dose introduced by a slow 30-min intraperitoneal infusion. Data from three DP-gram protocols, DPOAE input-output responses at 8 kHz, and auditory brainstem responses (ABRs) at 8, 12 and 16 kHz were collected before and 72 h after treatment. The post-treatment ABRs at 16 kHz showed the greatest mean threshold shift of 33.6 dB. The post-treatment DP-gram data showed significant reduction of the signal to noise ratios in the majority of the frequencies tested, across all tested protocols. The data suggest that the most sensitive DPOAE procedure for the early detection of the cisplatin-induced ototoxic damage is the DPOAE I/O protocol. Morphological analyses indicated that the inner hair cells remained intact, while several types of alterations were observed in the arrangement o...

Two electrode voltage clamp and single channel recordings were used to investigate the actions of various ATP-sensitive K+ (KATP) channel inhibitors on cloned KATP channels, expressed in Xenopus oocytes and HEK 293 cells. Oocytes expressing Kir6.2 and SUR1 gave rise to inwardly rectifying K+ currents following bath application of 3 mM sodium azide. Inside-out recordings from non-azide treated oocytes demonstrated the presence of KATP channels which were activated by direct application of 3 mM azide and 0.1 mM Mg-ATP. Tolbutamide inhibited azide-induced macroscopic Kir6.2-SUR1 currents, recorded from Xenopus oocytes, with an IC50 value similar to native KATP channels. Ciclazindol and englitazone also inhibited these currents in a concentration-dependent manner, but with relative potencies substantially less than for native KATP channels. Single channel currents recorded from inside-out patches excised from oocytes expressing Kir6.2-SUR1 currents were inhibited by tolbutamide, Mg-ATP, englitazone and ciclazindol, in the absence of azide, with potencies similar to native KATP channels. In the presence of azide, Kir6.2-SUR1 currents were inhibited by englitazone and tolbutamide but not ciclazindol. Single channel currents derived from Kir6.2Δ26, expressed in HEK 293 cells, were inhibited by ciclazindol and englitazone irrespective of the absence or presence of SUR1. In conclusion, heterologously expressed Kir6.2 and SUR1 recapitulate the pharmacological profile of native pancreatic β-cell KATP channels. However, currents induced by azide exhibit a substantially reduced sensitivity to ciclazindol. It is likely that ciclazindol and englitazone inhibit KATP currents by interaction with the Kir6.2 subunit. British Journal of Pharmacology (2000) 130, 857–866; doi:10.1038/sj.bjp.0703395

The metabolic effects during myocardial ischemia and sustained reperfusion of the antianginal agents diltiazem (n = 10) and propranolol (n = 10) were monitored with noninvasive phosphorus nuclear m...

We have developed a closed chest animal model that allows noninvasive monitoring of cardiac high energy phosphate metabolism before, during, and for at least 3 weeks after a myocardial infarction. Ten beagles underwent 2 h of coronary occlusion followed by 3 weeks of reperfusion. Myocardial high energy phosphates from 12-ml voxels were noninvasively tracked using 31P two-dimensional chemical shift imaging. Gadolinium enhanced 1H MRI identified the zone at risk, and radioactive microspheres assessed regional blood flow and partition coefficients. Occlusion of the left anterior descending coronary artery produced infarcts that were 13.7+/-8.8% (mean+/-SD) of the left ventricular volume. Rapid changes in the phosphocreatine and inorganic phosphate levels were observed during occlusion, whereas adenosine triphosphate levels decreased more slowly. All metabolites recovered to base-line levels 2 weeks after occluder release. Multiple inorganic phosphate peaks in the infarct voxel spectra indicated that more than one metabolically compromised tissue zone developed during occlusion and reperfusion. Microsphere data indicating three distinct blood flow zones during ischemia and reperfusion (0.3, 0.3-0.75, and0.75 ml/min/g) supported the grouping of pH values into three distinct metabolic distributions.

Phosphorus 31 magnetic resonance spectroscopy at 2 T was used to monitor high-energy phosphate metabolism over a 3-week period in a canine model of myocardial infarction and reperfusion. Twenty animals were divided into two groups: group 1 (n = 11) received intravenous nitroglycerin beginning at the onset of coronary occlusion; group 2 (n = 9) received a 105-minute infusion of superoxide dismutase (SOD) beginning at the onset of reperfusion. A metabolic protective effect was observed (vs controls) with both agents, manifested by a reduction in the degree of pH decline from baseline values and preservation of the adenosine triphosphate/total phosphate ratio during occlusion and reperfusion. Further, both treatments, compared with controls, produced a lower infarct/zone at risk ratio: controls, 1.5 +/- 1.2; nitroglycerin, 0.52 +/- 0.50; and SOD, 0.64 +/- 0.40. The technique of 31P magnetic resonance spectroscopy demonstrated its use for the noninvasive assessment of myocardial metabolism in response to therapeutic intervention.

One-neutron knockout at intermediate beam energies, an experimental approach sensitive to the single-particle structure of exotic nuclei, has been applied to the well-bound N = 16 isotones 34Ar, 33Cl and 32S as well as to the N = 14 nucleus 32Ar where the knockout residue 31Ar is located at the proton drip line. The reduction of single-particle strength compared to USD shell-model calculations is discussed in the framework of correlation effects beyond the effective-interaction theory employed in the shell-model approach.

Thirty perinatal solid tissue samples were used in a pilot study to test the efficacy of collagenase disaggregation onto coverslips, open system culture under low O 2 conditions, pre-harvest incubation in bromodeoxyuridine (BrdU) and colcemid, and in situ automated harvesting. Following the success of the pilot study, the new method was applied to a further 126 consecutive diagnostic samples making a total of 156. The method reduced average tissue culture times from 17 to 8.7 days (range 2-17), improved success rates from 76 to 88 per cent, and simultaneously increased the resolution of cytogenetic analysis.

tice and research.Through understanding the underlying mechanisms of ototoxic hearing loss, we have the very real possibility of developing new drugs in the near future that either do not have ototoxicity as a side effect or work specifically to prevent ototoxicity as a side effect of other drugs. The mechanisms of ototoxic damage and protection can be complex but some general concepts apply. In virtually all scientific journals and even in the popular press, we read about “oxidative damage” and “oxidative stress” as a factor in many degenerative processes. Although oxidative processes are part of normal metabolic activity, they also play a major role in many disease processes and in aging. Oxidative damage is also a common factor in cisplatin-induced, aminoglycoside-induced, and noise-induced hearing loss. Therefore audiologists and others working in hearing loss prevention should have a working knowledge of oxidative mechanisms. The following is a list of terms and concepts that may be helpful in reading the articles on ototoxicity in this issue of JAAA.

Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. d-Methionine (d-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of d-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with d-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75 mM cisplatin. l-Methionine, the optical isomer, showed lower potency and less efficacy than d-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin. Pre-exposure time of d-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that d-Met protects central nervous system tissue from acute cisplatin toxicity.

We report pure-tone hearing threshold findings in 56 college students. All subjects reported normal hearing during telephone interviews, yet not all subjects had normal sensitivity as defined by well-accepted criteria. At one or more test frequencies (0.25–8 kHz), 7% of ears had thresholds ≥25 dB HL and 12% had thresholds ≥20 dB HL. The proportion of ears with abnormal findings decreased when three-frequency pure-tone-averages were used. Low-frequency PTA hearing loss was detected in 2.7% of ears and high-frequency PTA hearing loss was detected in 7.1% of ears; however, there was little evidence for “notched” audiograms. There was a statistically reliable relationship in which personal music player use was correlated with decreased hearing status in male subjects. Routine screening and education regarding hearing loss risk factors are critical as college students do not always self-identify early changes in hearing. Large-scale systematic investigations of college students’ hearing status appear to be warranted; the current sample size was not adequate to precisely measure potential contributions of different sound sources to the elevated thresholds measured in some subjects.

Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue. The development of novel therapeutic agents to reduce NIHL will potentially benefit multiple very large noise-exposed populations. Oxidative stress has been identified as a significant contributor to noise-induced sensory cell death and noise-induced hearing loss, and several antioxidant strategies have now been suggested for potential translation to human subjects. One such strategy is a combination of beta-carotene, vitamins C and E, and magnesium, which has shown promise for protection against NIHL in rodent models, and is being evaluated in a series of international human clinical trials using temporary (military gunfire, audio player use) and permanent (stamping factory, military airbase) threshold shift models (NCT00808470). The noise exposures used in the recently completed Swedish military gunfire study described in this report did not, on average, result in measurable changes in auditory function using conventional pure-tone thresholds and distortion product otoacoustic emission (DPOAE) amplitudes as metrics. However, analysis of the plasma samples confirmed significant elevations in the bloodstream 2 hours after oral consumption of active clinical supplies, indicating the dose is realistic. The plasma outcomes are encouraging, but clinical acceptance of any novel therapeutic critically depends on demonstration that the agent reduces noise-induced threshold shift in randomized, placebo-controlled, prospective human clinical trials. Although this noise insult did not induce hearing loss, the trial design and study protocol can be applied to other populations exposed to different noise insults.

In summary, the clinician has a variety of protocols available for monitoring ototoxicity. Depending on the patient's risk factors and ability to be tested, the protocol for a given patient may vary. A flow chart reflecting some of the possible decisions and options is presented in Figure 1. Certainly, as we learn more about ototoxicity and the advantages and disadvantages of the various test methods, further refinements of patient and test selection will ensue. Ototoxicity is a rapidly expanding and interesting area. Hopefully, the care of patients receiving ototoxic medications will continue to improve and will ultimately prevent, or at least ameliorate, ototoxic hearing loss.

• This study compares noninvasive vs invasive electrodes for electrocochleography in chinchillas. Summating potential (SP) amplitude, action potential (AP) amplitude, and AP threshold, recorded with five types of noninvasive electrodes, were compared with simultaneous bulla recordings. Noninvasive electrodes included a needle electrode over the bulla, gold Tiptrode (Etymotic Research, Elk Grove Village, Ill), Enhancer I (Nicolet Instrument Corp, Madison, Wis), Coats (Lifetech Inc, Austin, Tex) electrode, and a locally constructed tympanic membrane (TM) electrode. Stimuli included 100-microsecond clicks and 6000-Hz tone bursts (with a 1 millisecond rise/fall time and a 5 millisecond plateau). Stimuli were initially presented at 110 dB peak equivalent sound pressure level for the clicks and 100 dB peak equivalent sound pressure level for the tone bursts. Intensity was then decreased in 10-dB decrements until no replicable AP activity was observed. The TM damping for the TM electrode was measured with 0.5,1,2,4, and 6 kHz and click stimuli. The AP was clear and replicable for all electrodes used in the study, although the amplitude was substantially less for the noninvasive electrodes as opposed to the invasive electrode. The invasive electrode provided the largest amplitude SP recording, but SP could generally be clearly recorded with the needle electrode, Enhancer I, and the Coats electrode. The TM electrode and gold Tiptrode provided SP recordings less consistently. The AP threshold could be recorded with all the electrodes in the study and was generally within 10 dB of threshold recorded invasively. Electrode variables, including ease of electrode placement and potential injury, were examined. The Tiptrode and Enhancer I electrodes posed relatively few problems during placement. The needle electrode placed over the bulla occasionally caused some subdermal bleeding at the placement site. The Coats electrode was more difficult to place because of the marked bend in the chinchilla ear canal. The TM electrode occasionally perforated the TM. Tympanic membrane damping with this electrode ranged from 0 to 50 dB. Consequently, this electrode would not be recommended for use in the chinchilla unless further improved. (Arch Otolaryngol Head Neck Surg.1993;119:767-771)

Electrocochleographic recordings were obtained from 20 subjects with normal hearing and 10 subjects with Meniere's disease by using an eardrum electrode. Stimuli included clicks and 6,000-Hz tone bursts. Results were not significantly different between the two groups for summating potential (SP) amplitude, action potential (AP) amplitude, or the SP/AP amplitude ratio. Interpreting the results in light of symptoms on the date of assessment or hearing threshold did not appear to improve separation between the two groups. Various SP/AP amplitude ratio criteria have been proposed in order to separate normal patients from those with Meniere's disease. Applying these proposed criteria to our data did not successfully separate the two groups.

The purpose of the present study was to evaluate the effect of an acute perilymphatic fistula on the amplitude ratio (SP/AP) of the summating potential (SP) and action potential (AP). The effect of the acute fistula on AP threshold was also addressed. Electrocochleo-graphic recordings were obtained before and immediately after surgical laceration of the round window membrane in 19 guinea pigs. Stimuli comprised clicks and 2,000-Hz and 8,000-Hz tone bursts, presented initially at 100 dB peak equivalent sound pressure level and in descending 10-dB steps. After fistula induction the SP/AP significantly increased for the click and 8,000-Hz tone burst stimuli but not for the 2,000-Hz tone burst stimuli. No significant change in AP threshold occurred. These findings suggest that the SP/AP may be sensitive to perilymphatic fistula, at least in guinea pigs. The changes in the SP/AP do not appear to be related to changes in threshold.