Genetic architecture distinguishes tinnitus from hearing loss.

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties.

Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.

PURPOSE: Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. METHODS: The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. RESULTS: Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. CONCLUSION: Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Sex differences in the polygenic architecture of hearing problems in adults.

BACKGROUND: Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies. METHODS: Leveraging the UK Biobank, the Nurses' Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors. RESULTS: We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes. CONCLUSIONS: The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.

The Interrelationship of Tinnitus and Hearing Loss Secondary to Age, Noise Exposure, and Traumatic Brain Injury.

OBJECTIVE: Tinnitus has been the No. 1 disability at the Veteran Administration for the last 15 years, yet its interaction with hearing loss secondary to etiologies such as age, noise trauma, and traumatic brain injuries remains poorly characterized. Our objective was to analyze hearing loss and tinnitus, including audiogram data, of the Million Veteran Program within the context of military exposures in an aging population. DESIGN: Health records, questionnaires, audiograms, and military data were aggregated for 758,005 Veteran participants in the Million Veteran Program 2011 to 2020, with relative risks (RR) calculated for ancestries, sex, hearing loss and military exposures such as combat, blast, and military era served. A multivariate model with significant demographic measures and exposures was then analyzed. Next, audiogram data stratified by sex were compared for those with and without tinnitus by two methods: first, mean thresholds at standard frequencies were compared to thresholds adjusted per ISO 7029:2000E age and sex formulae. Second, levels for those ≤40 years of age were compared with those 41 and older. Finally, a proportional hazards model was examined to ascertain the timing between the onset of tinnitus and hearing loss, calculated separately for electronic health record diagnoses (ICD) and self-report. RESULTS: Tinnitus was either self-reported, diagnosed, or both in 37.5% (95% CI, 37.4 to 37.6), mean age 61.5 (95% CI, 61.4 to 61.5), range 18 to 112 years. Those with hearing loss were 4.15 times (95% CI, 4.12 to 4.15) as likely to have tinnitus. Americans of African descent were less likely to manifest tinnitus (RR 0.61, 95% CI, 0.60 to 0.61), as were women (RR 0.65, 95% CI, 0.64 to 0.65). A multivariate model indicated a higher RR of 1.73 for traumatic brain injury (95% CI, 1.71 to 1.73) and daily combat noise exposure (1.17, 95% CI, 1.14 to 1.17) than age (0.998, 95% CI, 0.997 to 0.998). Subjects ≤40 years of age had small but significantly elevated hearing thresholds through all standard frequencies compared to Veterans without tinnitus, and the effect of tinnitus on hearing thresholds diminished with age. In the hazard model, those >40 with new onset of tinnitus were at risk for hearing loss sooner and with greater incidence than those who were younger. The rate of hearing loss following tinnitus approached 100%. In contrast, only approximately 50% of those who self-reported hearing loss initially were at risk for later hearing loss, in contrast to ICD comparison, where those with ICD of hearing loss were more likely to sustain an ICD of tinnitus subsequently. CONCLUSIONS: Evidence suggests that the occurrence of tinnitus in the military is more closely related to environmental exposures than to aging. The finding that tinnitus affects hearing frequencies across the audiogram spectrum suggests an acoustic injury independent of tonotopicity. Particularly for males >40, tinnitus may be a harbinger of audiologic damage predictive of later hearing loss.

Hearing loss and tinnitus: association studies for complex-hearing disorders in mouse and man.

Genome-wide association studies (GWAS) provide an unbiased first look at genetic loci involved in aging and noise-induced sensorineural hearing loss and tinnitus. The hearing phenotype, whether audiogram-based or self-report, is regressed against genotyped information at representative single nucleotide polymorphisms (SNPs) across the genome. Findings include the fact that both hearing loss and tinnitus are polygenic disorders, with up to thousands of genes, each of effect size of < 0.02. Smaller human GWAS' were able to use objective measures and identified a few loci; however, hundreds of thousands of participants have been required for the statistical power to identify significant variants, and GWAS is unable to assess rare variants with mean allele frequency < 1%. Animal studies are required as well because of inability to access the human cochlea. Mouse GWAS builds on linkage techniques and the known phenotypic differences in auditory function between inbred strains. With the advantage that the laboratory environment can be controlled for noise and aging, the Hybrid Mouse Diversity Panel (HDMP) combines 100 strains sequenced at high resolution. Lift-over regions between mice and humans have identified over 17,000 homologous genes. Since most significant SNPs are either intergenic or in introns, and binding sites between species are poorly preserved between species, expression quantitative trait locus information is required to bring humans and mice into agreement. Transcriptome-wide analysis studies (TWAS) can prioritize putative causal genes and tissues. Diverse species, each making a distinct contribution, carry a synergistic advantage in the quest for treatment and ultimate cure of sensorineural hearing difficulties.

Memantine effects on auditory discrimination and training in schizophrenia patients.

The uncompetitive low-affinity NMDA receptor antagonist, memantine, acutely increases electrophysiological measures of auditory information processing in both healthy subjects (HS) and patients with schizophrenia. Memantine effects on functional measures of auditory discrimination performance and learning are not known; conceivably, beneficial effects on these measures might suggest a role for memantine in augmenting the cognitive and functional impact of auditory targeted cognitive training (TCT). Here, carefully characterized HS (n = 20) and schizophrenia patients (n = 22) were tested in measures of auditory discrimination performance (words-in-noise (WIN), quick speech-in-noise (QuickSIN), gaps-in-noise) and auditory frequency modulation learning (a component of TCT) on 2 days about a week apart, after ingesting either placebo or 20 mg memantine po, in a double-blind, within-subject cross-over random order design. Memantine modestly enhanced functional measures of auditory discrimination in both schizophrenia patients (WIN) and HS (WIN and QuickSIN), as well as auditory frequency modulation learning in schizophrenia patients. These findings converge with a growing literature showing that memantine can enhance a range of metrics of auditory function. These properties could contribute to the apparent benefits of memantine as an adjunctive treatment in schizophrenia, and suggest that memantine might augment learning and potentially clinical gains from auditory-based TCT.

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry.

Importance: Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished. Objective: To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits. Design, Setting, and Participants: A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020. Main Outcomes and Measures: Estimates of single nucleotide variation (SNV)-based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed. Results: Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (ß = 0.133; P = .003) and years of education had a protective effect (ß = -0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (ß = 0.072, P = .001 and ß = 1.546, P = <.001, respectively). Conclusions and Relevance: This large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disorder.

Marked Increases in Resting-State MEG Gamma-Band Activity in Combat-Related Mild Traumatic Brain Injury.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members and veterans. Recent animal studies show that GABA-ergic parvalbumin-positive interneurons are susceptible to brain injury, with damage causing abnormal increases in spontaneous gamma-band (30-80 Hz) activity. We investigated spontaneous gamma activity in individuals with mTBI using high-resolution resting-state magnetoencephalography source imaging. Participants included 25 symptomatic individuals with chronic combat-related blast mTBI and 35 healthy controls with similar combat experiences. Compared with controls, gamma activity was markedly elevated in mTBI participants throughout frontal, parietal, temporal, and occipital cortices, whereas gamma activity was reduced in ventromedial prefrontal cortex. Across groups, greater gamma activity correlated with poorer performances on tests of executive functioning and visuospatial processing. Many neurocognitive associations, however, were partly driven by the higher incidence of mTBI participants with both higher gamma activity and poorer cognition, suggesting that expansive upregulation of gamma has negative repercussions for cognition particularly in mTBI. This is the first human study to demonstrate abnormal resting-state gamma activity in mTBI. These novel findings suggest the possibility that abnormal gamma activities may be a proxy for GABA-ergic interneuron dysfunction and a promising neuroimaging marker of insidious mild head injuries.

Untangling the genomics of noise-induced hearing loss and tinnitus: Contributions of Mus musculus and Homo sapiens.

Acoustic trauma is a feature of the industrial age, in general, and mechanized warfare, in particular. Noise-induced hearing loss (NIHL) and tinnitus have been the number 1 and number 2 disabilities at U.S. Veterans hospitals since 2006. In a reversal of original protocols to identify candidate genes associated with monogenic deafness disorders, unbiased genome-wide association studies now direct animal experiments in order to explore genetic variants common in Homo sapiens. However, even these approaches must utilize animal studies for validation of function and understanding of mechanisms. Animal research currently focuses on genetic expression profiles since the majority of variants occur in non-coding regions, implying regulatory divergences. Moving forward, it will be important in both human and animal research to define the phenotypes of hearing loss and tinnitus, as well as exposure parameters, in order to extricate genes related to acoustic trauma versus those related to aging. It has become clear that common disorders like acoustic trauma are influenced by large numbers of genes, each with small effects, which cumulatively lead to susceptibility to a disorder. A polygenic risk score, which aggregates these small effect sizes of multiple genes, may offer a more accurate description of risk for NIHL and/or tinnitus.

Impact of TBI, PTSD, and Hearing Loss on Tinnitus Progression in a US Marine Cohort.

INTRODUCTION: Mild TBI (TBI) is associated with up to a 75.7% incidence of tinnitus, and 33.0% of tinnitus patients at the US Veterans Administration carry a diagnosis of post-traumatic stress syndrome (PTSD). Yet factors contributing to new onset or exacerbation of tinnitus remain unclear. MATERIALS AND METHODS: Here we measure intermittent and constant tinnitus at two time points to ascertain whether pre-existing or co-occurring traumatic brain injury (TBI), hearing loss, or post-traumatic stress disorder (PTSD) predicts new onset, lack of recovery and/or worsening of tinnitus in 2,600 United States Marines who were assessed before and after a combat deployment. RESULTS: Ordinal regression revealed that constant tinnitus before deployment was likely to continue after deployment (odds ratio [OR] = 28.62, 95% confidence interval [CI]: 9.84,83.26). Prior intermittent tinnitus increased risk of post-deployment constant tinnitus (OR = 4.95, CI: 2.97,8.27). Likelihood of tinnitus progression increased with partial PTSD (OR = 2.39, CI: 1.50,3.80) and TBI (OR = 1.59, CI: 1.13,2.23), particularly for blast TBI (OR = 2.01, CI: 1.27,3.12) and moderate to severe TBI (OR = 2.57, CI: 1.46,4.51). Tinnitus progression also increased with low frequency hearing loss (OR = 1.94, CI: 1.05,3.59), high frequency loss (OR = 3.01, CI: 1.91,4.76) and loss across both low and high frequency ranges (OR = 5.73, CI: 2.67,12.30). CONCLUSIONS: Screening for pre-existing or individual symptoms of PTSD, TBI, and hearing loss may allow for more focused treatment programs of comorbid disorders. Identification of those personnel vulnerable to tinnitus or its progression may direct increased acoustic protection for those at risk.

MEG Working Memory N-Back Task Reveals Functional Deficits in Combat-Related Mild Traumatic Brain Injury.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained cognitive impairment in military service members and Veterans. However, the mechanism of persistent cognitive deficits including working memory (WM) dysfunction is not fully understood in mTBI. Few studies of WM deficits in mTBI have taken advantage of the temporal and frequency resolution afforded by electromagnetic measurements. Using magnetoencephalography (MEG) and an N-back WM task, we investigated functional abnormalities in combat-related mTBI. Study participants included 25 symptomatic active-duty service members or Veterans with combat-related mTBI and 20 healthy controls with similar combat experiences. MEG source-magnitude images were obtained for alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and low-frequency (1-7 Hz) bands. Compared with healthy combat controls, mTBI participants showed increased MEG signals across frequency bands in frontal pole (FP), ventromedial prefrontal cortex, orbitofrontal cortex (OFC), and anterior dorsolateral prefrontal cortex (dlPFC), but decreased MEG signals in anterior cingulate cortex. Hyperactivations in FP, OFC, and anterior dlPFC were associated with slower reaction times. MEG activations in lateral FP also negatively correlated with performance on tests of letter sequencing, verbal fluency, and digit symbol coding. The profound hyperactivations from FP suggest that FP is particularly vulnerable to combat-related mTBI.

The Genomic Basis of Noise-induced Hearing Loss: A Literature Review Organized by Cellular Pathways.

OBJECTIVE: Using Reactome, a curated Internet database, noise-induced hearing loss studies were aggregated into cellular pathways for organization of the emerging genomic and epigenetic data in the literature. DATA SOURCES: PubMed and Reactome.org, a relational data base program systematizing biological processes into interactive pathways and subpathways based on ontology, cellular constituents, gene expression, and molecular components. STUDY SELECTION: Peer-reviewed population and laboratory studies for the previous 15 years relating genomics and noise and hearing loss were identified in PubMed. Criteria included p values <0.05 with correction for multiple genes, a fold change of >1.5, or duplicated studies. DATA EXTRACTION AND SYNTHESIS: One-hundred fifty-eight unique HGNC identifiers from 77 articles met the selection criteria, and were uploaded into the analysis program at http://reactome.org. These genes participated in a total of 621 cellular interactions in 21 of 23 pathways. Cellular response to stress with its attenuation phase, particularly in response to heat stress, detoxification of ROS, and specific areas of the immune system are predominant pathways identified as significantly 'overrepresented' (p values <0.1e-5 and false discovery rates <0.01). CONCLUSION: Twenty-one of 23 of the designated pathways in Reactome have significant influence on noise-induced hearing loss, signifying a confluence of molecular pathways in reaction to acoustic trauma; however, cellular response to stress, including heat shock response, and other small areas of immune response were highly overrepresented. Yet-to-be-explored genomics areas include miRNA, lncRNA, copy number variations, RNA sequencing, and human genome-wide association study.

Prospective Associations Between Traumatic Brain Injury and Postdeployment Tinnitus in Active-Duty Marines.

OBJECTIVE: To examine whether cause, severity, and frequency of traumatic brain injury (TBI) increase risk of postdeployment tinnitus when accounting for comorbid posttraumatic stress disorder. DESIGN: Self-report and clinical assessments were done before and after an "index" deployment to Iraq or Afghanistan. SETTING, PARTICIPANTS, AND MEASURES: Assessments took place on Marine Corps bases in southern California and the VA San Diego Medical Center. Participants were 1647 active-duty enlisted Marine and Navy servicemen who completed pre- and postdeployment assessments of the Marine Resiliency Study. The main outcome was the presence of tinnitus at 3 months postdeployment. RESULTS: Predeployment TBI increased the likelihood of new-onset postdeployment tinnitus (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.28-2.70). Deployment-related TBIs increased the likelihood of postdeployment tinnitus (OR = 2.65; 95% CI, 1.19-5.89). Likelihood of new-onset postdeployment tinnitus was highest for those who were blast-exposed (OR = 2.93; 95% CI, 1.82-6.17), who reported moderate-severe TBI symptoms (OR = 2.22; 95% CI, 1.22-3.40), and who sustained multiple TBIs across study visits (OR = 2.27; 95% CI, 1.44-4.24). Posttraumatic stress disorder had no effect on tinnitus outcome. CONCLUSIONS: Participants who were blast-exposed, sustained multiple TBIs, and reported moderate-severe TBI symptoms were most at risk for new-onset tinnitus.

Genetic Polymorphisms Associated with Hearing Threshold Shift in Subjects during First Encounter with Occupational Impulse Noise.

Noise-induced hearing loss (NIHL) is the most significant occupational health issue worldwide. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with hearing threshold shift in young males undergoing their first encounter with occupational impulse noise. We report a significant association of SNP rs7598759 (p < 5 x 10(-7); p = 0.01 after permutation and correction; Odds Ratio = 12.75) in the gene coding for nucleolin, a multifunctional phosphoprotein involved in the control of senescence and protection against apoptosis. Interestingly, nucleolin has been shown to mediate the anti-apoptotic effect of HSP70, a protein found to prevent ototoxicity and whose polymorphisms have been associated with susceptibility to NIHL. Increase in nucleolin expression has also been associated with the prevention of apoptosis in cells undergoing oxidative stress, a well-known metabolic sequela of noise exposure. To assess the potential role of nucleolin in hearing loss, we tested down-regulation of nucleolin in cochlear sensory cells HEI-OC1 under oxidative stress conditions and report increased sensitivity to cisplatin, a chemotherapeutic drug with ototoxic side effects. Additional SNPs were found with suggestive association (p < 5 x 10(-4)), of which 7 SNPs were located in genes previously reported to be related to NIHL and 43 of them were observed in 36 other genes previously not reported to be associated with NIHL. Taken together, our GWAS data and in vitro studies reported herein suggest that nucleolin is a potential candidate associated with NIHL in this population.

Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids.

In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [(14)C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [(14)C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.

Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas.

OBJECTIVE: Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. STUDY DESIGN: Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. SETTING: Laboratory. SUBJECTS AND METHODS: All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. RESULTS: Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05). CONCLUSION: Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.

The nonhealing scar.

Pyogenic granulomas are common benign skin growths often present at sites of trauma. They can be difficult to treat in austere environments. A case report of a pyogenic granuloma in an austere environment has not previously been published. We submit this work to describe a case of a pyogenic granuloma arising from a properly treated laceration in an austere environment and to review current treatment options. Multiple treatment modalities are available to providers with limited resources to include topical Imiquimod, ethanol injection, silver nitrate application, and oral steroids.

Impulse noise: theoretical solutions to the quandary of cochlear protection.

Workers in industries with impact noise, as well as soldiers exposed to supersonic blasts from armament and explosive devices, appear to be more at risk for hearing loss than are their counterparts exposed to continuous noise. Alternative considerations for hearing protection are dictated because of a disproportionately increased biophysical response in comparison to continuous noise. Impulse noise is a significant and distinct problem that requires a new strategy for hearing protection. A review of current clinical and occupational literature suggests that impulse noise may be more damaging than continuous sound. Statistical measurements such as kurtosis hold promise for the quantitative prediction of hearing loss. As sound energy to the cell increases, the mechanism of cochlear damage shifts from biochemical injury to mechanical injury. Outer hair cells appear to be more sensitive than inner hair cells to impulse noise because of their energy requirements, which lead to increased production of reactive oxygen and nitrogen species and self-destruction by apoptosis. Hearing protective devices currently in use for impulse noise include hunters' hearing devices, active noise-reduction headsets, and various in-ear plugs, including nonlinear reacting inserts. Existing equipment is hampered by the materials used and by present-day electronic technology. Antioxidants administered before sound exposure show promise in mitigating hearing loss in industrial and combat situations. New materials with improved damping, reflective, and absorption characteristics are required. Hearing protective devices that allow passage of ambient sound while blocking harmful noise might improve the compliance and safety of those exposed. Sensing devices that instantaneously and selectively hyperpolarize outer hair cells are discussed as alternate protection.