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Ototoxic effects of mefloquine in cochlear organotypic cultures

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Journal of Otology 2009年第2期4卷 76-85页

作者： Richard Salvi center for hearing and Deafness State University of New York at Buffalo

Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate the ototoxic and neurotoxic potential of mefloquine, we treated cochlear organotypic cultures and spiral ganglion cultures with various concentrations of mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01 mM. Hair cell loss progressed from base to apex and from outer to inner hair cells with increasing dose. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. To investigate the mechanisms underlying mefloquine-induced cell death, cochlear cultures were stained with TO-Pro-3 to identify morphological changes in the nucleus, and with carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3 to determine caspase-mediated cell death. TO-Pro-3-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine treatment. These three caspases were also expressed in support cells, although labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat cochlea by initially activating cell death signaling pathways on the cell membrane and in mitochondria.

关键词： Mefloquine ototoxicity neuropathology outer hair cell inner hair cell spiral ganglion neurons axon degeneration

Cell proliferation during hair cell regeneration induced by Math1 in vestibular epithelia in vitro

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Neural Regeneration Research 2018年第3期13卷 497-501页

作者： Yi-bo Huang Rui Ma Juan-mei Yang Zhao Han Ning Cong Zhen Gao Dongdong Ren Jing Wang Fang-lu Chi Department of Otology and Skull Base Surgery EYE & ENT Hospital of Fudan University Shanghai China Shanghai Clinical Medical center of hearing Medicine Shanghai China Key Laboratory of hearing Medicine Ministry of Health Shanghai China

Hair cell regeneration is the fundamental method of correcting hearing loss and balance disorders caused by hair cell damage or loss. How to promote hair cell regeneration is a hot focus in current research. In mammals, cochlear hair cells cannot be regenerated and few vestibular hair cells can be renewed through spontaneous regeneration. However, Math1 gene transfer allows a few inner ear cells to be transformed into hair cells in vitro or in vivo. Hair cells can be renewed through two possible means in birds： supporting cell differentiation and transdifferentiation with or without cell division. Hair cell regeneration is strongly associated with cell proliferation. Therefore, this study explored the relationship between Math1-induced vestibular hair cell regeneration and cell division in mammals. The mouse vestibule was isolated to harvest vestibular epithelial cells. Ad-Math1-enhanced green fluorescent protein （EGFP） was used to track cell division during hair cell transformation.5-Bromo-2′-deoxyuridine （BrdU） was added to track cell proliferation at various time points. Immunocytochemistry was utilized to determine cell differentiation and proliferation. Results demonstrated that when epithelial cells were in a higher proliferative stage, more of these cells differentiated into hair cells by Math1 gene transfer. However, in the low proliferation stage, no BrdU-positive cells were seen after Math1 gene transfer. Cell division always occurred before Math1 transfection but not during or after Math1 transfection, when cells were labeled with BrdU before and after Ad-Math1-EGFP transfection. These results confirm that vestibular epithelial cells with high proliferative potential can differentiate into new hair cells by Math1 gene transfer, but this process is independent of cell proliferation.

关键词： erve regeneration cell proliferation cell division Math1 hair cells hair cell renewal supporting cell differentiation vestibular cells neural regeneration

Spontaneous Proliferation in Organotypic Cultures of Mouse Cochleae

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Journal of Otology 2008年第2期3卷 76-83页

作者： Richard Salvi center for hearing and Deafness State University of New York at BuffaloNY USA

Cells in mammalian cochleae virtually stop proliferation and exit cellular circle before birth. Consequently, hair cells and spiral ganglion neurons destroyed by ototoxic factors cannot be replaced through proliferative regeneration. However, substantial proliferation occurs in organotypic cultures of cochleae from postnatal mice. In the present study, we studied the time course of proliferative growth in cultures of mouse cochlea explants obtained from up to 12 postnatal days. The mitotic nature of this growth was confirmed by bromodeoxyuridine (BrdU) staining and expression of proliferation cell nuclear antigen (PCNA) evaluated with real-time quantitative poly-merase chain reaction(RT-PCR). Similar growth time course was found in the cochlear explants of different postnatal ages. The new growth reached its maximum at around 2 days in culture followed by a slow-down, and virtually stopped after 5 days of culture. The possible mechanisms and the significance of this proliferation are discussed.

关键词： organotypic culture cochlea proliferation bromodeoxyuridine (BrdU) proliferation cell nuclear antigen(PCNA) real-time quantitative polymerase chain reaction(RT-PCR)

CONTRALATERAL SUPPRESSION OF DISTORTION PRODUCT OTOACOUSTIC EMISSION IN CHILDREN WITH AUDITORY PROCESSING DISORDERS

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Journal of Otology 2014年第1期9卷 21-26页

作者： Jessica Oppee SUN Wei Nancy Stecker center for hearing & Deafness Department of Communicative Disorders and Sciences State University of New York at Buffalo

Previous research has demonstrated that the amplitude of evoked emissions decreases in human sub-jects when the contralateral ear is stimulated by noise. The medial olivocochlear bundle (MOCB) is be-lieved to control this phenomenon. Recent research has examined this effect in individuals with auditory pro-cessing disorders (APD), specifically with difficulty understanding speech in noise. Results showed tran-sient evoked otoacoustic emissions (TEOAEs) were not affected by contralateral stimulation in these sub-jects. Much clinical research has measured the function of the MOCB through *** study will use an alternative technique, distortion product otoacoustic emissions (DPOAEs), to examine this phenomenon and evaluate the function of the MOCB. DPOAEs of individuals in a control group with normal hearing and no significant auditory processing difficulties were compared to the DPOAEs of children with signifi-cant auditory processing *** showed that the suppression effect was observed in the control group at 2 kHz with 3 kHz of narrowband noise. For the auditory processing disorders group, no significant suppression was ***, DPOAEs showed suppression with contralateral noise, while the APD group levels increased *** results provide further evidence that the MOCB may have reduced function in children with APD.

关键词： Auditory processing disorder Otoacoutic emissions Medial olivocochlear bundle

Lead neurotoxicity in rat cochlear organotypic cultures

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Journal of Otology 2011年第2期6卷 43-50页

作者： Richard Salvi center for hearing and Deafness State University of New York at BuffaloBuffaloNew YorkUSA

Lead is a major environmental toxicant throughout the *** can induce severe neurotoxicity including irreversible hearing *** in vivo studies have shown that lead damages the auditory nervous system,but has little or no effect on cochlear sensory hair *** gain insights on lead ototoxic and neurotoxic effects in vitro,lead acetate (LA) was applied to postnatal day 3-4 rat cochlear organotypic cultures for 24 or 72 h with doses of 0.1,0.5,1,2 or 4 *** 24 or 72 h treatment with lead acetate,nearly all of cochlear sensory hair cells were ***,after 72 h treatment,the peripheral auditory nerve fibers projecting to the hair cells and the spiral ganglion neurons (SGN) were damaged when lead concentration exceeded 2 *** results indicated that 72 h treatment with only the high doses (> 2 mM) of lead actate damaged SGNs and peripheral nerve fibers;hair cells remained structurally intact even after 4 mM *** results show that lead primarily damages cochlear nerve fibers andSGNratherthanhaircells.

关键词： lead cochlea organotypic culture spiral ganglion neurons hair cells.

Current trends in outcome studies for children with hearing loss and the need to establish a comprehensive framework of measuring outcomes in children with hearing loss in China

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Journal of Otology 2016年第2期11卷 43-56页

作者： Xueman Liu University of Texas at Dallas Communication Sciences and Disorders Bethel Hearing and Speaking Training Center Research and DevelopmentUnited States

Since the 1970s, outcome studies for children with hearing loss expanded from focusing on assessing auditory awareness and speech perception skills to evaluating language and speech development. Since the early 2000s, the multi-center large scale research systematically studied outcomes in the areas of auditory awareness, speech-perception, language development, speech development, educational achievements, cognitive development, and psychosocial development. These studies advocated the establishment of baseline and regular follow-up evaluations with a comprehensive framework centered on language development. Recent research interests also include understanding the vast differences in outcomes for children with hearing loss, understanding the relationships between neurocognitive development and language acquisition in children with hearing loss, and using outcome studies to guide evidence-based clinical practice. After the establishment of standardized Mandarin language assessments, outcomes research in China's Mainland has the potential to expand beyond auditory awareness and speech perception studies.

关键词： Outcome assessment Language assessment Mandarin Standardized assessment hearing impaired children

Early diagnosis and management of neonatal sepsis:a perspective

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World Journal of Pediatrics 2024年第4期20卷 303-306页

作者： Li‑Zhong Du Neonatal Intensive Care Unit Children’s Hospital Zhejiang University School of MedicineNational Clinical Research Center for Child Health3333 Binsheng RoadHangzhou 310052China

Neonatal sepsis is an illness caused by bloodstream bacteria or fungal infections that affect newborn infants under 28 days of *** stands as a significant contributor to morbidity and mortality in neonatal intensive care units(NICUs).With the improved survival rates of very low-birth-weight or extremely premature infants,a growing number of these vulnerable infants are receiving intensive care and undergoing invasive procedures,making nosocomial infections a persistent challenge in *** mortality rate associated with neonatal sepsis varies depending on factors such as birth weight,gestational age,and other *** can also lead to a range of long-term health consequences,including neurodevelopmental disabilities like cerebral palsy,visual or hearing impairments,and cognitive ***,neonatal sepsis is linked to various adverse outcomes,including respiratory complications,bronchopulmonary dysplasia,nutritional and growth issues,and immunological dysfunction[1].Due to its atypical clinical presentation and the low rate of specific diagnostic indicators,such as a positive blood culture,accurately diagnosing neonatal sepsis is ***,the appropriateness of antibiotic treatment is often a matter of controversy.

关键词： neonatal mortality diagnosis

HIGH-THROUGHPUT TECHNOLOGIES FOR GENE EXPRESSION ANALYSES:WHAT WE HAVE LEARNED FOR NOISE-INDUCED COCHLEAR DEGENERATION

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Journal of Otology 2013年第1期8卷 25-31页

作者： Hu Bo Hua center for hearing and Deafness University at Buffalothe State University of New York 137 Cary Hall

Noise-induced hearing loss is a common cause of acquired hearing loss in the adult population. Acoustic overstimulation causes cochlear damage through mechanical stress to the tissue. Consequently, complex molec-ular changes are initiated, and these changes lead to morphological and biological alterations in the cochlea, which in turn compromise the cochlear function and cause hearing loss. In the past 10 years, there have been significant advances in our understanding of the molecular mechanisms of noise-induced hearing loss. These advances are attributed, in part, to the development of high-throughput technologies for the global analyses of molecular changes. In this review, we briefly describe the newly developed methods for investigating the mo-lecular responses of the cochlea to acoustic trauma and the knowledge generated from these studies. We also discuss the strengths and limitations of each technique and the major challenges to investigate cochlear degen-eration following acoustic injury.

关键词： Noise cochlea RNA high-throughput protein

Interaction between auditory and motor systems in speech perception

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Neuroscience Bulletin 2014年第3期30卷 490-496页

作者： Zhe-Meng Wu Ming-Li Chen Xi-Hong Wu Liang Li Department of Psychology Speech and Hearing Research Center Key Laboratory of Machine Perception (Ministry of Education) PKU-IDG/McGovern Institute for Brain Research Peking University

Based on the Motor Theory of speech perception, the interaction between the auditory and motor systems plays an essential role in speech perception. Since the Motor Theory was proposed, it has received remarkable attention in the field. However, each of the three hypotheses of the theory still needs further verification. In this review, we focus on how the auditory-motor anatomical and functional associations play a role in speech perception and discuss why previous studies could not reach an agreement and particularly whether the motor system involvement in speech perception is task-load dependent. Finally, we suggest that the function of the auditory-motor link is particularly useful for speech perception under adverse listening conditions and the further revised Motor Theory is a potential solution to the ＂cocktail-party＂ problem.

关键词： auditory-motor interaction Motor Theory of speech perception motor cortex "cocktail-party" problem.