Alterations in Evoked Otoacoustic Emissions by the Use of Meglumine Antimoniate in American Tegumentary Leishmaniasis Patients

by Débora Cristina de Oliveira Bezerra, Renata Oliveira de Barcelos, Ellen Carvalho de Castro, Claudia Cristina Jardim Duarte, Raquel de Vasconcellos Carvalhaes Oliveira, Tania Salgado de Sousa Torraca, Maria Helena de Araújo-Melo, Frederico Pereira Bom Braga, Benivaldo Ramos Ferreira Terceiro, Lúcia Regina do Nascimento Brahim Paes, Armando de Oliveira Schubach, Cláudia Maria Valete-Rosalino

Introduction

Tegumentary Leishmaniasis (TL) is a neglected, non-contagious, infectious disease, caused by different protozoa species of the Leishmania genus that affects skin and mucous membranes. Meglumine Antimoniate (MA), the first drug of choice for TL treatment in Brazil, has already been associated with cochlear toxicity, which is defined as damages of the cochlea caused by exposure to chemical substances, resulting in reversible or irreversible hearing loss. Auditory monitoring for cochlear toxicity aims at the early detection of auditory disorders, enabling, when possible, hearing to be preserved or an early auditory rehabilitation. Although otoacoustic emissions (OAEs) are used in this monitoring, there is no consensus on the criteria that define cochlear toxicity by this examination. The objective of this study was to describe the characteristics of the OAEs in cochlear toxicity monitoring in TL patients using MA.

Methods

Prospective and longitudinal study of auditory monitoring of 35 patients with parasitological diagnosis of TL, with liminal tonal audiometry, high frequency audiometry, immitanciometry, distortion product evoked otoacoustic emissions (DPEOAEs) and transient evoked otoacoustic emissions (TEOAEs) before treatment, at the end of treatment, one month after the end of treatment and two months after the end of treatment.

Results

80% male, with median age of 44 years (IIQ: 22–59). In the pre-treatment evaluation: 11.4% complained of hearing loss and 20% of tinnitus, 48.6% presented auditory alterations in liminal tonal audiometry (LTA, 65.2% in high frequency audiometry (HFA), 26.6% in DPEOAE and 51.4% in TEOAE. No association was verified between genre and alterations in the EOAE examinations. We observed that patients that presented disorders in DPEOAE examinations were 17 years older than those without alterations and that patients that showed disorders in TEOAEO examinations were 34 years older than those without disorders. The presence of alterations in DPEOAE and TEOAE before beginning treatment was associated with each other and with the presence of alterations in LTA and HFA, and only DPEOAE was associated with hearing loss. We observed a significantly higher number of alterations of DPEOAE at the end of treatment than during pre-treatment and values of the ratio signal/noise significantly smaller at the end of treatment than during pre-treatment in the frequencies of 2 kHz (difference of 1.7dB; p = 0.016) and 4 kHz (difference of 2.45dB; p = 0.016) in DPEOAE and in the range 1.75/2.5 kHz in TEOAE (difference of 2.9dB; p = 0.039).

Conclusion

The ototoxic signals observed in our study using EOAE indicated that both, DPEOAE and TEOAE are adequate and sensitive techniques for clinical monitoring of ototoxicity by MA. Their application is very simple, and their results help the physician to take the most adequate steps for each patient, thus avoiding permanent hearing damage.

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Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity.

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Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity.

Clin Cancer Res. 2016 Dec 30;:

Authors: Wheeler HE, Gamazon ER, Frisina R, Perez-Cervantes C, El Charif O, Mapes B, Fossa SD, Feldman D, Hamilton R, Vaughn DJ, Beard C, Fung C, Kollmannsberger C, Kim J, Mushiroda T, Kubo M, Ardeshir-Rouhani-Fard S, Einhorn LH, Cox N, Dolan ME, Travis L

Abstract
PURPOSE: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).
EXPERIMENTAL DESIGN: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.
RESULTS: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4x10(-8)). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n=18,620 patients, Bonferroni adjusted P<0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048).
CONCLUSIONS: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.

PMID: 28039263 [PubMed - as supplied by publisher]

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Global Analysis of Protein Expression of Inner Ear Hair Cells.

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Global Analysis of Protein Expression of Inner Ear Hair Cells.

J Neurosci. 2016 Dec 30;:

Authors: Hickox AE, Wong AC, Pak K, Strojny C, Ramirez M, Yates JR, Ryan AF, Savas JN

Abstract
The mammalian inner ear subserves auditory and vestibular sensations via highly specialized cells and proteins. Sensory receptor hair cells (HCs) are necessary for transducing mechanical inputs and stimulating sensory neurons by employing a host of known and yet unknown protein machinery. To understand the protein composition of these unique post-mitotic cells, in which irreversible protein degradation or damage can lead to impaired hearing and balance, we analyzed inner ear samples by tandem mass spectrometry to generate an unbiased, shotgun-proteomics view of protein identities and abundances. By using Pou4f3/eGFP transgenic mice, in which HCs express GFP driven by Pou4f3, we FACS-purified a population of HCs to analyze and compare the HC proteome with other inner ear sub-proteomes from sensory epithelia and whole inner ear. We show that the mammalian HC proteome comprises hundreds of uniquely or highly expressed proteins. Our global proteomic analysis of purified HCs extends the existing HC transcriptome, revealing previously undetected gene products and isoform-specific protein expression. Comparison of our proteomic data with mouse and human databases of genetic auditory/vestibular impairments confirms the critical role of the HC proteome for normal inner ear function, providing a cell-specific pool of candidates for novel, important HC genes. Several proteins identified exclusively in HCs by proteomics and verified by immunohistochemistry map to human genetic deafness loci, potentially representing new deafness genes.
SIGNIFICANCE STATEMENT: Hearing and balance rely on specialized sensory hair cells (HCs) in the inner ear to convey information about sound, acceleration and orientation to the brain. Genetically and environmentally induced perturbations to HC proteins can result in deafness and severe imbalance. We used transgenic mice with GFP-expressing HCs, coupled with FACS-sorting and tandem mass spectrometry, to define the most complete HC-, and inner ear-, proteome to-date. We show that hundreds of proteins are uniquely identified or enriched in HCs, extending previous gene expression analyses to reveal novel HC proteins and isoforms. Importantly, deafness-linked proteins were significantly enriched in HCs, suggesting that this in-depth proteomic analysis of inner ear sensory cells may hold potential for deafness gene discovery.

PMID: 28039372 [PubMed - as supplied by publisher]

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Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

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Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

Neuro Oncol. 2016 Dec 29;:

Authors: King AA, Seidel K, Di C, Leisenring WM, Perkins SM, Krull KR, Sklar CA, Green DM, Armstrong GT, Zeltzer LK, Wells E, Stovall M, Ullrich NJ, Oeffinger KC, Robison LL, Packer RJ

Abstract
BACKGROUND: Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized.
METHODS: The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models.
RESULTS: Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66).
CONCLUSIONS: Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.

PMID: 28039368 [PubMed - as supplied by publisher]

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Global Analysis of Protein Expression of Inner Ear Hair Cells.

Related Articles

Global Analysis of Protein Expression of Inner Ear Hair Cells.

J Neurosci. 2016 Dec 30;:

Authors: Hickox AE, Wong AC, Pak K, Strojny C, Ramirez M, Yates JR, Ryan AF, Savas JN

Abstract
The mammalian inner ear subserves auditory and vestibular sensations via highly specialized cells and proteins. Sensory receptor hair cells (HCs) are necessary for transducing mechanical inputs and stimulating sensory neurons by employing a host of known and yet unknown protein machinery. To understand the protein composition of these unique post-mitotic cells, in which irreversible protein degradation or damage can lead to impaired hearing and balance, we analyzed inner ear samples by tandem mass spectrometry to generate an unbiased, shotgun-proteomics view of protein identities and abundances. By using Pou4f3/eGFP transgenic mice, in which HCs express GFP driven by Pou4f3, we FACS-purified a population of HCs to analyze and compare the HC proteome with other inner ear sub-proteomes from sensory epithelia and whole inner ear. We show that the mammalian HC proteome comprises hundreds of uniquely or highly expressed proteins. Our global proteomic analysis of purified HCs extends the existing HC transcriptome, revealing previously undetected gene products and isoform-specific protein expression. Comparison of our proteomic data with mouse and human databases of genetic auditory/vestibular impairments confirms the critical role of the HC proteome for normal inner ear function, providing a cell-specific pool of candidates for novel, important HC genes. Several proteins identified exclusively in HCs by proteomics and verified by immunohistochemistry map to human genetic deafness loci, potentially representing new deafness genes.
SIGNIFICANCE STATEMENT: Hearing and balance rely on specialized sensory hair cells (HCs) in the inner ear to convey information about sound, acceleration and orientation to the brain. Genetically and environmentally induced perturbations to HC proteins can result in deafness and severe imbalance. We used transgenic mice with GFP-expressing HCs, coupled with FACS-sorting and tandem mass spectrometry, to define the most complete HC-, and inner ear-, proteome to-date. We show that hundreds of proteins are uniquely identified or enriched in HCs, extending previous gene expression analyses to reveal novel HC proteins and isoforms. Importantly, deafness-linked proteins were significantly enriched in HCs, suggesting that this in-depth proteomic analysis of inner ear sensory cells may hold potential for deafness gene discovery.

PMID: 28039372 [PubMed - as supplied by publisher]

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Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

Related Articles

Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

Neuro Oncol. 2016 Dec 29;:

Authors: King AA, Seidel K, Di C, Leisenring WM, Perkins SM, Krull KR, Sklar CA, Green DM, Armstrong GT, Zeltzer LK, Wells E, Stovall M, Ullrich NJ, Oeffinger KC, Robison LL, Packer RJ

Abstract
BACKGROUND: Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized.
METHODS: The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models.
RESULTS: Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66).
CONCLUSIONS: Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.

PMID: 28039368 [PubMed - as supplied by publisher]

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Simultaneously-evoked Auditory Potentials (SEAP): a new method for concurrent measurement of cortical and subcortical auditory-evoked activity

Publication date: Available online 31 December 2016
Source:Hearing Research
Author(s): Christopher Slugocki, Daniel Bosnyak, Laurel J. Trainor
Recent electrophysiological work has evinced a capacity for plasticity in subcortical auditory nuclei in human listeners. Similar plastic effects have been measured in cortically-generated auditory potentials but it is unclear how the two interact. Here we present Simultaneously-Evoked Auditory Potentials (SEAP), a method designed to concurrently elicit electrophysiological brain potentials from inferior colliculus, thalamus, and primary and secondary auditory cortices. Twenty-six normal-hearing adult subjects (mean 19.26 years, 9 male) were exposed to 2400 monaural (right-ear) presentations of a specially-designed stimulus which consisted of a pure-tone carrier (500 or 600 Hz) that had been amplitude-modulated at the sum of 37 and 81 Hz (depth 100%). Presentation followed an oddball paradigm wherein the pure-tone carrier was set to 500 Hz for 85% of presentations and pseudo-randomly changed to 600 Hz for the remaining 15% of presentations. Single-channel electroencephalographic data were recorded from each subject using a vertical montage referenced to the right earlobe. We show that SEAP elicits a 500 Hz frequency-following response (FFR; generated in inferior colliculus), 80 (subcortical) and 40 (primary auditory cortex) Hz auditory steady-state responses (ASSRs), mismatch negativity (MMN) and P3a (when there is an occasional change in carrier frequency; secondary auditory cortex) in addition to the obligatory N1-P2 complex (secondary auditory cortex). Analyses showed that subcortical and cortical processes are linked as (i) the latency of the FFR predicts the phase delay of the 40 Hz steady-state response, (ii) the phase delays of the 40 and 80 Hz steady-state responses are correlated, and (iii) the fidelity of the FFR predicts the latency of the N1 component. The SEAP method offers a new approach for measuring the dynamic encoding of acoustic features at multiple levels of the auditory pathway. As such, SEAP is a promising tool with which to study how relationships between subcortical and cortical processes change through early development and auditory learning as well as by hearing loss and aging.



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