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Stem Cell Treatment for Hearing Loss is Available at ASCI

Stem Cell Treatment for Hearing LossStem Cells for Hearing Loss

 

Related Articles New strategies for the restoration of hearing loss: challenges and opportunities. Br Med Bull. 2013;105:69-84 Authors: Rivolta MN Abstract INTRODUCTION: For most types of hearing impairments, a definitive therapy would rest on the ability to restore hair cells and the spiral ganglion neurons. The only established technique to treat deafness is based on the functional replacement of hair cells with a cochlear implant, but this still has important limitations. SOURCES OF DATA: A systematic revision of the relevant literature is presented. AREAS OF AGREEMENT: New curative strategies, ranging from stem cells to gene and molecular therapy, are under development. AREAS OF CONTROVERSY: Although still experimental, they have delivered some initial promissory results that allow us to look at them with cautious optimism. GROWING POINTS: The isolation of human auditory cells, the generation of protocols to control their differentiation into sensory lineages, their promising application in vivo and the identification of key genes to target molecularly offer an exciting landscape. AREAS TIMELY FOR DEVELOPING RESEARCH: In this chapter, I discuss the latest advances in the field and how they are being translated into a clinical application. PMID: 23175701 [PubMed - indexed for MEDLINE]
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Related Articles Intra-tympanic delivery of short interfering RNA into the adult mouse cochlea. Hear Res. 2013 Feb;296:36-41 Authors: Oishi N, Chen FQ, Zheng HW, Sha SH Abstract Trans-tympanic injection into the middle ear has long been the standard for local delivery of compounds in experimental studies. Here we demonstrate the advantages of the novel method of intra-tympanic injection through the otic bone for the delivery of compounds or siRNA into the adult mouse cochlea. First, a fluorescently-conjugated scrambled siRNA probe was applied via intra-tympanic injection into the middle ear cavity and was detected in sensory hair cells and nerve fibers as early as 6 h after the injection. The fluorescent probe was also detected in other cells of the organ of Corti, the lateral wall, and in spiral ganglion cells 48 h after the injection. Furthermore, intra-tympanic delivery of Nox3 siRNA successfully reduced immunofluorescence associated with Nox3 in outer hair cells 72 h after injection by 20%. Drug or siRNA delivery via intra-tympanic injection does not compromise the tympanic membrane or interfere with noise-induced hearing loss, while trans-tympanic injections significantly altered the cochlear response to noise exposure. In summary, intra-tympanic injection through the otic bone into the middle ear cavity provides a promising approach for delivery of compounds or siRNA to cochlear hair cells of adult mice, relevant for the study of mechanisms underlying inner ear insults and, specifically, noise-induced hearing loss. PMID: 23183031 [PubMed - indexed for MEDLINE]
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Related Articles Hydrogel limits stem cell dispersal in the deaf cochlea: implications for cochlear implants. J Neural Eng. 2012 Dec;9(6):065001 Authors: Nayagam BA, Backhouse SS, Cimenkaya C, Shepherd RK Abstract Auditory neurons provide the critical link between a cochlear implant and the brain in deaf individuals, therefore their preservation and/or regeneration is important for optimal performance of this neural prosthesis. In cases where auditory neurons are significantly depleted, stem cells (SCs) may be used to replace the lost population of neurons, thereby re-establishing the critical link between the periphery (implant) and the brain. For such a therapy to be therapeutically viable, SCs must be differentiated into neurons, retained at their delivery site and damage caused to the residual auditory neurons minimized. Here we describe the transplantation of SC-derived neurons into the deaf cochlea, using a peptide hydrogel to limit their dispersal. The described approach illustrates that SCs can be delivered to and are retained within the basal turn of the cochlea, without a significant loss of endogenous auditory neurons. In addition, the tissue response elicited from this surgical approach was restricted to the surgical site and did not extend beyond the cochlear basal turn. Overall, this approach illustrates the feasibility of targeted cell delivery into the mammalian cochlea using hydrogel, which may be useful for future cell-based transplantation strategies, for combined treatment with a cochlear implant to restore function. PMID: 23186887 [PubMed - indexed for MEDLINE]
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Related Articles Prosaposin-derived peptide alleviates ischaemia-induced hearing loss. Acta Otolaryngol. 2013 May;133(5):462-8 Authors: Terashita T, Saito S, Nabeka H, Hato N, Wakisaka H, Shimokawa T, Kobayashi N, Gyo K, Matsuda S Abstract CONCLUSION: An 18-mer peptide derived from the neurotrophic region of prosaposin (PS-pep) prevents hearing loss and cochlear damage due to transient cochlear ischaemia by activating an anti-apoptotic pathway. PS-pep is a potent candidate molecule for alleviating ischaemia-induced hearing loss. OBJECTIVE: PS-pep was investigated for its protective effects against ischaemia-induced hearing loss and cochlear damage. METHODS: Ischaemia was induced in both cochleae in Mongolian gerbils by pulling the ligatures around both vertebral arteries in an anterior direction using 5 g weights for 15 min. PS-pep was synthesized artificially and administered subcutaneously four times after the induction of transient cochlear ischaemia. RESULTS: An increase in the auditory brainstem response threshold was alleviated in animals treated with 2.0 mg/kg PS-pep. Histological examinations conducted on day 7 showed that the loss of inner hair cells (IHCs) was more prominent than that of outer hair cells. Higher doses of PS-pep significantly alleviated IHC loss. An increase in the anti-apoptotic factor bcl-2 was also noted in the IHCs treated with PS-pep. PMID: 23216090 [PubMed - indexed for MEDLINE]
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Related Articles Taurine attenuates bilirubin-induced neurotoxicity in the auditory system in neonatal guinea pigs. Int J Pediatr Otorhinolaryngol. 2013 May;77(5):647-54 Authors: Ye HB, Wang J, Zhang WT, Shi HB, Yin SK Abstract OBJECTIVES: Previous work showed that taurine protects neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by maintaining intracellular calcium homeostasis, membrane integrity, and mitochondrial function, thereby preventing apoptosis from occurring, in primary neuron cultures. In this study, we investigated whether taurine could protect the auditory system against the neurotoxicity associated with hyperbilirubinemia in an in vivo model. METHODS: Hyperbilirubinemia was established in neonatal guinea pigs by intraperitoneal injection of UCB. Hearing function was observed in electrocochleograms (ECochGs) and auditory brainstem responses (ABRs) recorded before and 1, 8, 24, and 72 h after UCB injection. For morphological evaluations, animals were sacrificed at 8h post-injection, and the afferent terminals beneath the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and their fibers were examined. RESULTS: It was found that UCB injection significantly increased latencies and inter-wave intervals, and thresholds of ABR and compound action potentials, and caused marked damage to type I SGNs, their axons, and terminals to cochlear IHCs. When baby guinea pigs were pretreated with taurine for 5 consecutive days and then injected with bilirubin, electrophysiological abnormalities and morphological damage were attenuated significantly in both the peripheral and central auditory system. CONCLUSIONS: From these observations, it was concluded that taurine limited bilirubin-induced neural damage in the auditory system. These findings may contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating hearing loss in neonatal jaundice. PMID: 23273639 [PubMed - indexed for MEDLINE]
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Related Articles The protective effect of conditioning on noise-induced hearing loss is frequency-dependent. Acta Med Iran. 2012;50(10):664-9 Authors: Pourbakht A, Imani A Abstract We compared the extent of temporary threshold shift (TTS) and hair cell loss following high level 4 kHz noise exposure with those preconditioned with moderate level 1 and 4 kHz octave band noise. Fifteen Male albino guinea pigs (300- 350 g in weight) were randomly allocated into three groups: those exposed to 4 kHz octave band noise at 102 dB SPL (group 1, n=5); those conditioned with 1 kHz octave band noise at 85 dB SPL, 6 hours per day for 5 days, then exposed to noise (group 2, n=5); those conditioned with 4 kHz octave band noise at 85 dB SPL, then exposed to noise (group 3, n=5). An hour and one week after noise exposure, threshold shifts were evaluated by auditory-evoked brainstem response (ABR) and then animals were euthanized for histological evaluation. We found that TTS and cochlear damage caused by noise exposure were significantly reduced by 1 kHz and 4 kHz conditioning (P<0.001). We also showed that 4 kHz protocol attenuates noise- induced TTS but no significant TTS reduction occurred by 1 kHz conditioning. Both protocol protected noise-induced cochlear damage. We concluded that lower tone conditioning could not protect against higher tone temporary noise-induced hearing loss, thus conditioning is a local acting and frequency-dependent phenomenon. PMID: 23275293 [PubMed - indexed for MEDLINE]
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Related Articles Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience. Pediatr Blood Cancer. 2013 Jul;60(7):1135-40 Authors: Moreno L, Vaidya SJ, Pinkerton CR, Lewis IJ, Imeson J, Machin D, Pearson AD, European Neuroblastoma Study Group, Children's Cancer and Leukaemia Group (CCLG) (formerly UKCCSG) Abstract BACKGROUND: Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. PROCEDURE: The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. RESULTS: Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. CONCLUSIONS: This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial. PMID: 23281263 [PubMed - indexed for MEDLINE]
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Related Articles Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron. 2013 Jan 9;77(1):58-69 Authors: Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano HJ, Okano H, Edge AS Abstract Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a γ-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness. PMID: 23312516 [PubMed - indexed for MEDLINE]
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Related Articles A brief history of hair cell regeneration research and speculations on the future. Hear Res. 2013 Mar;297:42-51 Authors: Rubel EW, Furrer SA, Stone JS Abstract Millions of people worldwide suffer from hearing and balance disorders caused by loss of the sensory hair cells that convert sound vibrations and head movements into electrical signals that are conveyed to the brain. In mammals, the great majority of hair cells are produced during embryogenesis. Hair cells that are lost after birth are virtually irreplaceable, leading to permanent disability. Other vertebrates, such as fish and amphibians, produce hair cells throughout life. However, hair cell replacement after damage to the mature inner ear was either not investigated or assumed to be impossible until studies in the late 1980s proved this to be false. Adult birds were shown to regenerate lost hair cells in the auditory sensory epithelium after noise- and ototoxic drug-induced damage. Since then, the field of hair cell regeneration has continued to investigate the capacity of the auditory and vestibular epithelia in vertebrates (fishes, birds, reptiles, and mammals) to regenerate hair cells and to recover function, the molecular mechanisms governing these regenerative capabilities, and the prospect of designing biologically-based treatments for hearing loss and balance disorders. Here, we review the major findings of the field during the past 25 years and speculate how future inner ear repair may one day be achieved. PMID: 23321648 [PubMed - indexed for MEDLINE]
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Related Articles Intracerebral neural stem cell transplantation improved the auditory of mice with presbycusis. Int J Clin Exp Pathol. 2013;6(2):230-41 Authors: Ren H, Chen J, Wang Y, Zhang S, Zhang B Abstract Stem cell-based regenerative therapy is a potential cellular therapeutic strategy for patients with incurable brain diseases. Embryonic neural stem cells (NSCs) represent an attractive cell source in regenerative medicine strategies in the treatment of diseased brains. Here, we assess the capability of intracerebral embryonic NSCs transplantation for C57BL/6J mice with presbycusis in vivo. Morphology analyses revealed that the neuronal rate of apoptosis was lower in the aged group (10 months of age) but not in the young group (2 months of age) after NSCs transplantation, while the electrophysiological data suggest that the Auditory Brain Stem Response (ABR) threshold was significantly decreased in the aged group at 2 weeks and 3 weeks after transplantation. By contrast, there was no difference in the aged group at 4 weeks post-transplantation or in the young group at any time post-transplantation. Furthermore, immunofluorescence experiments showed that NSCs differentiated into neurons that engrafted and migrated to the brain, even to sites of lesions. Together, our results demonstrate that NSCs transplantation improve the auditory of C57BL/6J mice with presbycusis. PMID: 23330008 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell transplantation in noise induced hearing loss. Int J Pediatr Otorhinolaryngol. 2013 Apr;77(4):469-72 Authors: Ajalloueyan M, Kouhi A, Asgari A, Salem M, Hasanalifard M Abstract OBJECTIVE: To investigate efficacy of bone marrow stem cell implantation in rehabilitation of noise induced hearing loss in rats. MATERIALS AND METHODS: Hearing loss was induced in male rats by a continuous wide-band noise (8-16 kHz/120 dB/120 min). Ten microliter of stem cell containing solution was injected by a Hamilton syringe with 30 G needle through the round window membrane. Hearing status was examined by, distortion product otoacoustic emissions using DP-OAE. Animals were studied in 4 different groups: (1) Normal hearing animals, undergoing sham surgery (no injection done, only round window membrane ruptured and sealed). (2) Deaf animals, undergoing sham surgery. (3) Deaf animals undergoing surgery and injection of solvent (artificial perilymph). (4) Deaf animals undergoing surgery and injection of artificial perilymph containing BMSCs. RESULTS: DP-Gram in rat with normal hearing undergoing sham surgery show that procedure has neither negative impact on normal cochlear nor on deaf cochleas. No significant difference (p=0.25) between ears excludes artificial perilymph as a confounding factor. There is no significant difference between ears in animals receiving BMSCs. CONCLUSIONS: Implanted cells with normal histologic structures have no physiologic function and hearing rehabilitation. Further studies by monitoring the survival of these cells with histologic and appropriate biomarkers will help to investigate differentiation process of these cells. PMID: 23333285 [PubMed - indexed for MEDLINE]
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Related Articles Prospects for replacement of auditory neurons by stem cells. Hear Res. 2013 Mar;297:106-12 Authors: Shi F, Edge AS Abstract Sensorineural hearing loss is caused by degeneration of hair cells or auditory neurons. Spiral ganglion cells, the primary afferent neurons of the auditory system, are patterned during development and send out projections to hair cells and to the brainstem under the control of largely unknown guidance molecules. The neurons do not regenerate after loss and even damage to their projections tends to be permanent. The genesis of spiral ganglion neurons and their synapses forms a basis for regenerative approaches. In this review we critically present the current experimental findings on auditory neuron replacement. We discuss the latest advances with a focus on (a) exogenous stem cell transplantation into the cochlea for neural replacement, (b) expression of local guidance signals in the cochlea after loss of auditory neurons, (c) the possibility of neural replacement from an endogenous cell source, and (d) functional changes from cell engraftment. PMID: 23370457 [PubMed - indexed for MEDLINE]
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Related Articles Adenovector-mediated gene delivery to human umbilical cord mesenchymal stromal cells induces inner ear cell phenotype. Cell Reprogram. 2013 Feb;15(1):43-54 Authors: Devarajan K, Forrest ML, Detamore MS, Staecker H Abstract Hearing is one of our main sensory systems and having a hearing disorder can have a significant impact in an individual's quality of life. Sensory neural hearing loss (SNHL) is the most common form of hearing loss; it results from the degeneration of inner ear sensory hair cells and auditory neurons in the cochlea, cells that are terminally differentiated. Stem cell-and gene delivery-based strategies provide an opportunity for the replacement of these cells. In recent years, there has been an increasing interest in gene delivery to mesenchymal stem cells. In this study, we evaluated the potential of human umbilical cord mesenchymal stromal cells (hUCMSCs) as a possible source for regenerating inner ear hair cells. The expression of Atoh1 induced the differentiation of hUCMSCs into cells that resembled inner ear hair cells morphologically and immunocytochemically, evidenced by the expression of hair cell-specific markers. The results demonstrated for the first time that hUCMSCs can differentiate into hair cell-like cells, thus introducing a new potential tissue engineering and cell transplantation approach for the treatment of hearing loss. PMID: 23379581 [PubMed - indexed for MEDLINE]
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Related Articles Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med. 2013 Mar;19(3):345-50 Authors: Lentz JJ, Jodelka FM, Hinrich AJ, McCaffrey KE, Farris HE, Spalitta MJ, Bazan NG, Duelli DM, Rigo F, Hastings ML Abstract Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns. Hereditary deafness is often mediated by the improper development or degeneration of cochlear hair cells. Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention. Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness. An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice. These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness. PMID: 23380860 [PubMed - indexed for MEDLINE]
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Related Articles Otoprotective effects of erythropoietin on Cdh23erl/erl mice. Neuroscience. 2013 May 1;237:1-6 Authors: Han F, Yu H, Zheng T, Ma X, Zhao X, Li P, Le L, Su Y, Zheng QY Abstract The Cdh23(erl/erl) mice are a novel mouse model for DFNB12 and are characterized by progressive hearing loss. In this study, erythropoietin (EPO) was given to the Cdh23(erl/erl) mice by intraperitoneal injection every other day from P7 for 7 weeks. Phosphate-buffered saline-treated or untreated Cdh23(erl/erl) mice were used as controls. Auditory-evoked brainstem response (ABR) thresholds and distortion product oto-acoustic emission (DPOAE) were measured in the mouse groups at the age of 4, 6 and 8 weeks. The results show that EPO can significantly decrease the ABR thresholds in the Cdh23(erl/erl) mice as compared with those of the untreated mice at stimulus frequencies of click, 8-, 16- and 32-kHz at three time points. Meanwhile, DPOAE amplitudes in the EPO-treated Cdh23(erl/erl) mouse group were significantly higher than those of the untreated groups at f2 frequency of 15383 Hz at the three time points. Furthermore, the mean percentage of outer hair cell loss at middle through basal turns of cochleae was significantly lower in EPO-treated Cdh23(erl/erl) mice than in the untreated mice (P<0.05). This is the first report that EPO acts as an otoprotectant in a DFNB12 mouse model with progressive hearing loss. PMID: 23384607 [PubMed - indexed for MEDLINE]
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Related Articles Relations between cochlear histopathology and hearing loss in experimental cochlear implantation. Hear Res. 2013 Apr;298:27-35 Authors: O'Leary SJ, Monksfield P, Kel G, Connolly T, Souter MA, Chang A, Marovic P, O'Leary JS, Richardson R, Eastwood H Abstract This study reviews the cochlear histology from four hearing preservation cochlear implantation experiments conducted on 73 guinea pigs from our institution, and relates histopathological findings to residual hearing. All guinea pigs had normal hearing prior to surgery and underwent cochlear implantation via a cochleostomy with a silastic-platinum dummy electrode. Pure tone auditory brainstem response (ABR) thresholds from 2 to 32 kHz were recorded prior to surgery, and at one and four weeks postoperatively. The cochleae were then fixed in paraformaldehyde, decalcified, paraffin embedded, and mid-modiolar sections were prepared. The treatment groups were as follows: 1) Systemic dexamethasone, 0.2 mg/kg administered 1 h before implantation, 2) Local dexamethasone, 2% applied topically to the round window for 30 min prior to cochlear implantation, 3) Local n-acetyl cysteine, 200 μg applied topically to the round window for 30 min prior to implantation, 4) inoculation to keyhole-limpet hemocyanin (KLH) prior to implantation, and 5) untreated controls. There was a significant correlation between the extent of the tissue reaction in the cochlea and the presence of foreign body giant cells (FBGCs), new bone formation and injury to the osseous spiral lamina (OSL). The extent of the tissue response, as a percentage of the area of the scala tympani, limited the best hearing that was observed four weeks after cochlear implantation. Poorer hearing at four weeks correlated with a more extensive tissue response, lower outer hair cell (OHC) counts and OSL injury in the basal turn. Progressive hearing loss was also correlated with the extent of tissue response. Hearing at 2 kHz, which corresponds to the region of the second cochlear turn, did not correspond with loco-regional inner hair cell (IHC), OHC or SGC counts. We conclude that cochlear injury is associated with poorer hearing early after implantation. The tissue response is related to indices of cochlear inflammation and injury. An extensive tissue response limits hearing at four weeks, and correlates with progressive hearing loss. These latter effects may be due to inflammation, but would also be consistent with interference of cochlear mechanics. PMID: 23396095 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell transplantation via the cochlear lateral wall for replacement of degenerated spiral ganglion neurons. Hear Res. 2013 Apr;298:1-9 Authors: Zhang PZ, He Y, Jiang XW, Chen FQ, Chen Y, Shi L, Chen J, Chen X, Li X, Xue T, Wang Y, Mi WJ, Qiu JH Abstract Spiral ganglion neurons (SGNs) are poorly regenerated in the mammalian inner ear. Because of this, stem cell transplantation has been used to replace injured SGNs, and several studies have addressed this approach. However, the difficulty of delivering stem cells into the cochlea and encouraging their migration to Rosenthal's canal (RC), where the SGNs are located, severely restricts this therapeutic strategy. In this study, we attempted to establish a new stem cell transplantation route into the cochlea via the cochlear lateral wall (CLW). First, we tested the precision of this route by injecting Fluorogold into the CLW and next assessed its safety by mock surgeries. Then, using a degenerated SGN animal model, we transplanted neural stem cells (NSCs), derived from the olfactory bulb of C57BL/6-green fluorescent protein (GFP) mice, via the CLW route and examined the cells' distribution in the cochlea. We found the CLW transplantation route is precise and safe. In addition, NSCs migrated into RC with a high efficiency and differentiated into neurons in a degenerated SGN rat model after the CLW transplantation. This result revealed that the basilar membrane (BM) may have crevices permitting the migration of NSCs. The result of this study demonstrates a novel route for cell transplantation to the inner ear, which is important for the replacement of degenerated SGNs and may contribute to the treatment of sensorineural hearing loss. PMID: 23403006 [PubMed - indexed for MEDLINE]
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Related Articles Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds. J Gene Med. 2013 Mar-Apr;15(3-4):123-33 Authors: Wang Y, Sun Y, Chang Q, Ahmad S, Zhou B, Kim Y, Li H, Lin X Abstract BACKGROUND: Gene transfer into the inner ear is a promising approach for treating sensorineural hearing loss. The special electrochemical environment of the scala media raises a formidable challenge for effective gene delivery at the same time as keeping normal cochlear function intact. The present study aimed to define a suitable strategy for preserving hearing after viral inoculation directly into the scala media performed at various postnatal developmental stages. METHODS: We assessed transgene expression of green fluorescent protein (GFP) mediated by various types of adeno-associated virus (AAV) and lentivirus (LV) in the mouse cochlea. Auditory brainstem responses were measured 30 days after inoculation to assess effects on hearing. RESULTS: Patterns of GFP expression confirmed extensive exogenous gene expression in various types of cells lining the endolymphatic space. The use of different viral vectors and promoters resulted in specific cellular GFP expression patterns. AAV2/1 with cytomegalovirus promoter apparently gave the best results for GFP expression in the supporting cells. Histological examination showed normal cochlear morphology and no hair cell loss after either AAV or LV injections. We found that hearing thresholds were not significantly changed when the injections were performed in mice younger than postnatal day 5, regardless of the type of virus tested. CONCLUSIONS: Viral inoculation and expression in the inner ear for the restoration of hearing must not damage cochlear function. Using normal hearing mice as a model, we have achieved this necessary step, which is required for the treatment of many types of congenital deafness that require early intervention. PMID: 23413036 [PubMed - indexed for MEDLINE]
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Related Articles Recurrent adult choroid plexus carcinoma treated with high-dose chemotherapy and syngeneic stem cell (bone marrow) transplant. J Neurol Surg A Cent Eur Neurosurg. 2013 Dec;74 Suppl 1:e149-54 Authors: Samuel TA, Parikh J, Sharma S, Giller CA, Sterling K, Kapoor S, Pirkle C, Jillella A Abstract Choroid plexus carcinomas (CPCs) are rare epithelial central nervous system tumors. CPC occurs mainly in infants and young children, comprising ≈ 1 to 4% of all pediatric brain neoplasms. There is very limited information available regarding tumor biology and CPC treatment due to its rarity. There have been various case reports and meta-analyses of reported cases with CPC. Surgical resection is often challenging but remains a well-established treatment option. Chemotherapy is often reserved for recurrent or refractory cases, but the goal of treatment is usually palliative. We present a case of recurrent, adult CPC with disseminated leptomeningeal involvement treated with salvage chemotherapy including high-dose ifosfamide, carboplatin, and etoposide; once a remission was achieved, this response was consolidated with a syngeneic stem cell (bone marrow) transplant after a preparative regimen of high-dose chemotherapy with carboplatin, etoposide, and thiotepa. Although the patient tolerated the transplant well and remained disease-free for 12 months, she subsequently succumbed to relapsed disease 18 months posttransplant. We believe that this is the first report of using syngeneic stem cell transplant in CPC to consolidate a remission achieved by salvage chemotherapy. PMID: 23427033 [PubMed - indexed for MEDLINE]
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Related Articles Otoprotective effect of recombinant erythropoietin in a model of newborn hypoxic-ischemic encephalopathy. Int J Pediatr Otorhinolaryngol. 2013 May;77(5):739-46 Authors: Olgun Y, Kırkım G, Kolatan E, Kıray M, Bağrıyanık A, Şerbetçioğlu B, Yılmaz O, Gökmen N, Ellidokuz H, Kumral A, Sütay S Abstract OBJECTIVE: The aim of this study is to test the hypotheses that central auditory pathology as well as inner ear pathology is contributing mechanisms to observed hypoxic-ischemic encephalopathy (HIE) induced hearing loss and that recombinant erythropoietin (rhEPO) will reduce this cellular pathology and attenuate hearing loss. METHODS: Twenty-eight 7-day Wistar albino rat pups were divided into four groups: Control group (n=8) was given only intraperitoneal saline solution. Sham group (n=5) had only a midline neck incisions without carotid ligation under general anesthesia and administration of intraperitoneal saline solution. HIE group (n=8) and rhEPO treated group (n=7) were subjected to left common carotid artery ligation followed by 2.5h hypoxia exposure to a mixture of 8% oxygen and 92% pure nitrogen. HIE group was injected with intraperitoneal saline solution, while the rhEPO treated group received rhEPO 100 U/kg within the same volume as the saline-alone solution. At the end of the seventh week of age hearing (ABRs) was evaluated in response to clicks, 6 kHz and 8 kHz tone burst stimuli. Animals were sacrificed and both temporal lobes, cochleas and brainstems of the animals were collected. Tissue samples were evaluated with light microscopy, immunohistochemical studies, including TUNEL and caspase-3 stainings, and electron microscopy. RESULTS: Hearing thresholds were elevated in HIE animals. In rhEPO treated animals, ABR values were similar to controls. HIE caused apoptotic changes in brainstem structures as shown by light microscopy and immunohistochemical methods. Apoptotic changes also were found within the organ of Corti, spiral ganglion cells and neurons of temporal lobe by electron microscopic investigation. In rhEPO animals many of these apoptotic changes were observed, but reduced compared to untreated animals. CONCLUSIONS: Mechanisms underlying HIE-induced hearing loss are based on apoptosis in inner ear; however central auditory pathway pathology occurs as well, likely contributing to changes in auditory processing and perception of complex signals not reflected by the ABR threshold shifts. For both clinical and basic significance 'rhRPO' is found to reduce those effects. PMID: 23433994 [PubMed - indexed for MEDLINE]
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Related Articles Chronic neurotrophin delivery promotes ectopic neurite growth from the spiral ganglion of deafened cochleae without compromising the spatial selectivity of cochlear implants. J Comp Neurol. 2013 Aug 15;521(12):2818-32 Authors: Landry TG, Fallon JB, Wise AK, Shepherd RK Abstract Cochlear implants restore hearing cues in the severe-profoundly deaf by electrically stimulating spiral ganglion neurons (SGNs). However, SGNs degenerate following loss of cochlear hair cells, due at least in part to a reduction in the endogenous neurotrophin (NT) supply, normally provided by hair cells and supporting cells of the organ of Corti. Delivering exogenous NTs to the cochlea can rescue SGNs from degeneration and can also promote the ectopic growth of SGN neurites. This resprouting may disrupt the cochleotopic organization upon which cochlear implants rely to impart pitch cues. Using retrograde labeling and confocal imaging of SGNs, we determined the extent of neurite growth following 28 days of exogenous NT treatment in deafened guinea pigs with and without chronic electrical stimulation (ES). On completion of this treatment, we measured the spread of neural activation to intracochlear ES by recording neural responses across the cochleotopically organized inferior colliculus using multichannel recording techniques. Although NT treatment significantly increased both the length and the lateral extent of growth of neurites along the cochlea compared with deafened controls, these anatomical changes did not affect the spread of neural activation when examined immediately after 28 days of NT treatment. NT treatment did, however, result in lower excitation thresholds compared with deafened controls. These data support the application of NTs for improved clinical outcomes for cochlear implant patients. PMID: 23436344 [PubMed - indexed for MEDLINE]
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Related Articles Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense. J Neurosci. 2013 Feb 27;33(9):4011-23 Authors: Fetoni AR, De Bartolo P, Eramo SL, Rolesi R, Paciello F, Bergamini C, Fato R, Paludetti G, Petrosini L, Troiani D Abstract This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway. PMID: 23447610 [PubMed - indexed for MEDLINE]
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Related Articles Downregulation of Cav1.3 calcium channel expression in the cochlea is associated with age-related hearing loss in C57BL/6J mice. Neuroreport. 2013 Apr 17;24(6):313-7 Authors: Chen J, Chu H, Xiong H, Yu Y, Huang X, Zhou L, Chen Q, Bing D, Liu Y, Wang S, Cui Y Abstract Age-related hearing loss (ARHL) is the most common human morbidity. However, the molecular mechanisms underlying ARHL are little known. In the present study, the expression of Ca(v)1.3 calcium channels in the C57BL/6J ARHL mouse cochlea was investigated. The hearing threshold was assessed by auditory brainstem response and the expressions of Ca(v)1.3.3 calcium channels at the protein and mRNA levels were detected by immunohistochemistry, western blot, and real-time RT-PCR. Associated with the auditory brainstem response threshold increased with age, the Ca(v)1.3.3 expression was gradually decreased. In comparison with 4-week-old mice, Ca(v)1.3.3 expressions in the cochlea at 14, 24, and 48 weeks of age were significantly and gradually decreased at both the protein and the mRNA levels. Immunohistochemistry showed that the expression of Ca(v)1.3.3 was apparently reduced at the inner hair cells, outer hair cells, and stria vascularis in the cochlear lateral wall in the aged mice. Our findings indicate that Ca(v)1.3.3 calcium channel expression in the cochlea is reduced in the ARHL mice and is associated with ARHL. The data also support a view that Ca(v)1.3.3 calcium channel is a good target for prevention and therapy of ARHL. PMID: 23470431 [PubMed - indexed for MEDLINE]
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Related Articles Sepsis otopathy: experimental sepsis leads to significant hearing impairment due to apoptosis and glutamate excitotoxicity in murine cochlea. Dis Model Mech. 2013 May;6(3):745-54 Authors: Schmutzhard J, Glueckert R, Pritz C, Blumer MJ, Bitsche M, Lackner P, Fille M, Riechelmann H, Harkamp M, Sitthisak T, Schrott-Fischer A Abstract Hearing loss is frequent in intensive care patients and can be due to several causes. However, sepsis has not been examined as a possible cause. The aim of this study is to assess the influence of experimental sepsis on hearing thresholds and to evaluate pathological changes in the cochlea. The cecal ligation puncture technique was used to induce sepsis in 18 mice. Results were compared with those from 13 sham-operated and 13 untreated control mice. The hearing thresholds of the animals were evaluated with auditory evoked brainstem responses prior to the induction of sepsis and again at the peak of the disease. Immediately after the second measurement, the mice were sacrificed and the inner ears harvested and prepared for further evaluation. The cochleae were examined with light microscopy, electron microscopy and immunohistochemistry for Bax, cleaved caspase-3 and Bcl-2. The mice with sepsis showed a significant hearing loss but not the control groups. Induction of apoptosis could be shown in the supporting cells of the organ of Corti. Furthermore, excitotoxicity could be shown at the basal pole of the inner hair cells. In this murine model, sepsis leads to significant hearing impairment. The physiological alteration could be linked to apoptosis in the supporting cells of the organ of Corti and to a disturbance of the synapses of the inner hair cells. PMID: 23471916 [PubMed - indexed for MEDLINE]
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Related Articles Engineered deafness reveals that mouse courtship vocalizations do not require auditory experience. J Neurosci. 2013 Mar 27;33(13):5573-83 Authors: Mahrt EJ, Perkel DJ, Tong L, Rubel EW, Portfors CV Abstract Auditory experience during development is necessary for normal language acquisition in humans. Although songbirds, some cetaceans, and maybe bats may also be vocal learners, vocal learning has yet to be well established for a laboratory mammal. Mice are potentially an excellent model organism for studying mechanisms underlying vocal communication. Mice vocalize in different social contexts, yet whether they learn their vocalizations remains unresolved. To address this question, we compared ultrasonic courtship vocalizations emitted by chronically deaf and normal hearing adult male mice. We deafened CBA/CaJ male mice, engineered to express diphtheria toxin (DT) receptors in hair cells, by systemic injection of DT at postnatal day 2 (P2). By P9, almost all inner hair cells were absent and by P16 all inner and outer hair cells were absent in DTR mice. These mice did not show any auditory brainstem responses as adults. Wild-type littermates, also treated with DT at P2, had normal hair cells and normal auditory brainstem responses. We compared the temporal structure of vocalization bouts, the types of vocalizations, the patterns of syllables, and the acoustic features of each syllable type emitted by hearing and deaf males in the presence of a female. We found that almost all of the vocalization features we examined were similar in hearing and deaf animals. These findings indicate that mice do not need auditory experience during development to produce normal ultrasonic vocalizations in adulthood. We conclude that mouse courtship vocalizations are not acquired through auditory feedback-dependent learning. PMID: 23536072 [PubMed - indexed for MEDLINE]
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Related Articles Bacterial cellulose nanofibrillar patch as a wound healing platform of tympanic membrane perforation. Adv Healthc Mater. 2013 Nov;2(11):1525-31 Authors: Kim J, Kim SW, Park S, Lim KT, Seonwoo H, Kim Y, Hong BH, Choung YH, Chung JH Abstract Bacterial cellulose (BC)-based biomaterials on medical device platforms have gained significant interest for tissue-engineered scaffolds or engraftment materials in regenerative medicine. In particular, BC has an ultrafine and highly pure nanofibril network structure and can be used as an efficient wound-healing platform since cell migration into a wound site is strongly meditated by the structural properties of the extracellular matrix. Here, the fabrication of a nanofibrillar patch by using BC and its application as a new wound-healing platform for traumatic tympanic membrane (TM) perforation is reported. TM perforation is a very common clinical problem worldwide and presents as conductive hearing loss and chronic perforations. The BC nanofibrillar patch can be synthesized from Gluconacetobacter xylinus; it is found that the patch contained a network of nanofibrils and is transparent. The thickness of the BC nanofibrillar patch is found to be approximately 10.33 ± 0.58 μm, and the tensile strength and Young's modulus of the BC nanofibrillar patch are 11.85 ± 2.43 and 11.90 ± 0.48 MPa, respectively, satisfying the requirements of an ideal wound-healing platform for TM regeneration. In vitro studies involving TM cells show that TM cell proliferation and migration are stimulated under the guidance of the BC nanofibrillar patch. In vivo animal studies demonstrate that the BC nanofibrillar patch promotes the rate of TM healing as well as aids in the recovery of TM function. These data demonstrate that the BC nanofibrillar patch is a useful wound-healing platform for TM perforation. PMID: 23554356 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell transplantation to the mouse cochlea as a treatment for childhood sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2013 Jun;77(6):936-42 Authors: Kasagi H, Kuhara T, Okada H, Sueyoshi N, Kurihara H Abstract OBJECTIVE: There is no treatment established for congenital sensorineural hearing loss because the majority of the cases are hereditary. Although congenital sensorineural hearing loss is thought to be hereditary, this hearing loss occur postnatally. We hypothesized that the transplantation of MSCs (mesenchymal stem cells) to the cochlea would be an effective therapy for stopping or delaying the progression of sensorineural hearing loss in childhood. METHODS: Cultured mouse MSCs were labeled with EGFP (enhanced green fluorescence protein) using retroviruses. EGFP-MSCs were transplanted into the posterior semicircular canal of mice at 2-3 weeks (young group) and 24-26 weeks (adult group) of age by a novel perilymphatic perfusion technique. Engraftment of MSCs was evaluated immunohistologically at 1 week and 2 weeks after transplantation. RESULTS: In young mice, migrated MSCs were detected in the cochlea tissue by immunofluorescence for EGFP and by immunohistochemistry for fibronectin. The differentiation of migrated MSCs into fibrocyte-like cells was demonstrated by immunofluorescence for connexin 26. There were no adverse effects on auditory function by MSC transplantation, and the auditory brain stem responses threshold did not significantly shift after surgery. In contrast, neither MSC migration nor differentiation was detected in the adult mice canal after MSC transplantation. CONCLUSION: The bone marrow derived MSCs were successfully transplanted into the cochlea of young mice by the perilymphatic perfusion technique and were further differentiated into fibrocyte-like cells without any adverse effects on auditory function. PMID: 23561635 [PubMed - indexed for MEDLINE]
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Related Articles Insensitivity of the audiogram to carboplatin induced inner hair cell loss in chinchillas. Hear Res. 2013 Aug;302:113-20 Authors: Lobarinas E, Salvi R, Ding D Abstract Noise trauma, aging, and ototoxicity preferentially damage the outer hair cells of the inner ear, leading to increased hearing thresholds and poorer frequency resolution. Whereas outer hair cells make synaptic connections with less than 10% of afferent auditory nerve fibers (type-II), inner hair cells make connections with over 90% of afferents (type-I). Despite these extensive connections, little is known about how selective inner hair cell loss impacts hearing. In chinchillas, moderate to high doses of the anticancer compound carboplatin produce selective inner hair cell and type-I afferent loss with little to no effect on outer hair cells. To determine the effects of carboplatin-induced inner hair cell loss on the most widely used clinical measure of hearing, the audiogram, pure-tone thresholds were determined behaviorally before and after 75 mg/kg carboplatin. Following carboplatin treatment, small effects on audiometric thresholds were observed even with extensive inner hair cell losses that exceed 80%. These results suggest that conventional audiometry is insensitive to inner hair cell loss and that only small populations of inner hair cells appear to be necessary for detecting tonal stimuli in a quiet background. PMID: 23566980 [PubMed - indexed for MEDLINE]
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Related Articles [Cell therapy for hereditary hearing loss with stem cell homing factors]. Nihon Yakurigaku Zasshi. 2013 Apr;141(4):191-4 Authors: Kamiya K PMID: 23575423 [PubMed - indexed for MEDLINE]
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Related Articles [Therapeutic approaches using in vitro induction system of hair cells from ES/iPS cells]. Nihon Yakurigaku Zasshi. 2013 Apr;141(4):195-8 Authors: Oshima K PMID: 23575424 [PubMed - indexed for MEDLINE]
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Related Articles Possible toxicity of tuberculostatic agents in a patient with a novel TYMP mutation leading to mitochondrial neurogastrointestinal encephalomyopathy. J Neurogenet. 2013 Jun;27(1-2):19-22 Authors: Mihaylova V, Guergueltcheva V, Cherninkova S, Penev L, Georgieva G, Stoyanova K, Todorova A, Tournev I Abstract Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystemic disorder caused by TYMP gene mutations. Here, we report on the first MNGIE patient diagnosed in Bulgaria who carries a novel homozygous TYMP mutation (p.Leu347Pro). The patient presented with gastrointestinal complaints, cachexia, hearing loss, ptosis, ophthalmoparesis, polyneuropathy, cognitive impairment, and leukoencephalopathy on magnetic resonance imaging (MRI) examination of the brain. The patient's motor capacity declined significantly, leading to wheelchair dependence several months following administration of tuberculostatic treatment, suggesting mitochondrial toxicity of these agents. The advanced stage of the disease and the poor medical condition prevented us from performing allogenic hematopoietic stem cell transplantation (HSCT). Early diagnosis is important not only for genetic counseling but also in view of the timely treatment with allogenic HSCT. PMID: 23590577 [PubMed - indexed for MEDLINE]
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Related Articles Synthesis of neamine-based pseudodisaccharides as potential vestibulotoxic agents to treat vertigo in Ménière's disease. Carbohydr Res. 2013 May 24;373:97-102 Authors: Pinsetta FR, Kawano DF, de Carvalho MR, de Oliveira JA, Corrado AP, Hyppolito MÂ, Carvalho I Abstract Ménière's disease (MD) is a progressive disease of the inner ear characterized by recurring attacks of disabling vertigo, hearing loss and tinnitus. Patients who do not respond to vestibular sedatives or steroids may require an intratympanic application of aminoglycoside antibiotics, which destroys the vestibular function of the affected ear in order to avoid the debilitating vertigo attacks. Although effective, this procedure causes hearing loss in almost one third of the patients due to the aminoglycosides cochlear toxicity. Here we describe the synthesis of two pseudodisaccharides structurally related to neamime aiming to mimic the aminoglycosides pharmacophore core by replacing their toxic amine by azide and hydroxyl groups. Products 1 and 2 selectively promoted 'in vivo' damage to vestibular tissues without causing hearing loss or cochlear toxicity. Therefore, these pseudodisaccharides stand as promising lead compounds for the development of a safer and more effective therapeutic procedure to manage the symptoms of MD severe dizziness. PMID: 23603190 [PubMed - indexed for MEDLINE]
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Related Articles Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss. Neurobiol Dis. 2013 Aug;56:25-33 Authors: Kao SY, Kempfle JS, Jensen JB, Perez-Fernandez D, Lysaght AC, Edge AS, Stankovic KM Abstract Osteoprotegerin (OPG) is a key regulator of bone remodeling. Mutations and variations in the OPG gene cause many human diseases that are characterized by not only skeletal abnormalities but also poorly understood hearing loss: Paget's disease, osteoporosis, and celiac disease. To gain insight into the mechanisms of hearing loss in OPG deficiency, we studied OPG knockout (Opg(-/-)) mice. We show that they develop sensorineural hearing loss, in addition to conductive hearing loss due to abnormal middle-ear bones. OPG deficiency caused demyelination and degeneration of the cochlear nerve in vivo. It also activated ERK, sensitized spiral ganglion cells (SGC) to apoptosis, and inhibited proliferation and survival of cochlear stem cells in vitro, which could be rescued by treatment with exogenous OPG, an ERK inhibitor, or bisphosphonate. Our results demonstrate a novel role for OPG in the regulation of SGC survival, and suggest a mechanism for sensorineural hearing loss in OPG deficiency. PMID: 23607938 [PubMed - indexed for MEDLINE]
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Related Articles Ototoxicity of olive oil in a chinchilla animal model. Laryngoscope. 2013 Aug;123(8):2009-12 Authors: Emami N, Daniel SJ Abstract OBJECTIVES/HYPOTHESIS: Olive oil is often used by patients to soften ear wax or to relieve ear canal obstruction. It is also sold in drugstores as a cerumenolytic. To date, no study has assessed the safety of ototopical olive oil on hearing in the presence of tympanic membrane perforation. The present study aimed to assess the safety of ototopic olive oil on hearing in the presence of tympanic membrane perforation. STUDY DESIGN: Prospective, randomized, controlled trial in a chinchilla animal model. MATERIALS AND METHODS: Eleven chinchillas underwent bilateral myringotomy. In each animal, one ear was randomly assigned to receive olive oil (experimental ear), while the contralateral control ear received normal saline. Auditory brain response (ABR) test was performed at baseline and then 7, 14, and 30 days following the application. RESULTS: At 30 days follow-up, there was no significant change in auditory brain response thresholds at 8, 16, 20, or 25 kHz. Scanning electron microscope imaging showed no damage to the hair cells. CONCLUSION: Olive oil does not seem to cause hearing loss in chinchillas with perforated tympanic membranes. Future clinical studies are required. PMID: 23616417 [PubMed - indexed for MEDLINE]
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Related Articles The potential of stem cells for the restoration of auditory function in humans. Regen Med. 2013 May;8(3):309-18 Authors: Hu Z, Ulfendahl M Abstract Hearing loss is one of the most common disabilities, affecting approximately 10% of the population. Hair cells and spiral ganglion neurons are usually damaged in most cases of hearing loss. Currently, there is virtually no biological approach to replace damaged hearing cells. Recent developments in stem cell technology provide new opportunities for the treatment of deafness. Two major strategies have been investigated: differentiation of endogenous stem cells into new hair cells; and introduction of exogenous cells into the inner ear to substitute injured hearing neurons. Although there is still a learning curve in stem cell-based replacement, the probability exists to utilize personalized stem cells to eventually provide a novel intervention for patients with deafness in future clinical research trials. PMID: 23627825 [PubMed - indexed for MEDLINE]
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Related Articles [Electrophysiological characteristics of EABR and its value assessment of cochlear implant]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2013 Jan;27(1):8-12 Authors: Wang Y, Pan T, Zhou N, Ma F Abstract OBJECTIVE: To evaluate the electrophysiological characteristics of electrically evoked auditory brainstem responses (EABR) and its application in cochlear implantation, especially in evaluating acoustic nerve survival. METHOD: An auditory evoked potential instrument was used to record responses and Cochlear Nucleus 24CA implants were used to generate electrical stimulation. We measured EABR in 23 patients with cochlear implants and compared EABR with behavioral measures and neural response telemetry (NRT). RESULT: EABR III-V waveforms were recognized in all of the 23 patients. The characteristics and origins of EABR waveforms were similar to those of ABR. The average EABR threshold was (172.61 +/- 14.61) CL. At 20 CL above threshold, the average latencies of Wave III, V were (2.93 +/- 0.18)ms, (4.80 +/- 0.28)ms which were 1-2 ms shorter than ABR latencies. But III-V intervals remained at (1.86 +/- 0.18)ms. EABR thresholds were strongly correlated with behavioral performance and NRT thresholds, while EABR input-output function is correlated with behavioral dynamic range (DR). CONCLUSION: EABR is such an effective method to objectively evaluate the function of auditory pathway which can estimate residual spiral ganglion cell count. This is consistent with the foreign study leading to the conclusion that DR reflects spiral ganglion cell survival. PMID: 23646423 [PubMed - indexed for MEDLINE]
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Related Articles β-Actin and fascin-2 cooperate to maintain stereocilia length. J Neurosci. 2013 May 8;33(19):8114-21 Authors: Perrin BJ, Strandjord DM, Narayanan P, Henderson DM, Johnson KR, Ervasti JM Abstract Stereocilia are actin-based protrusions on auditory sensory hair cells that are deflected by sound waves to initiate the conversion of mechanical energy to neuronal signals. Stereocilia maintenance is essential because auditory hair cells are not renewed in mammals. This process requires both β-actin and γ-actin as knock-out mice lacking either isoform develop distinct stereocilia pathology during aging. In addition, stereocilia integrity may hinge on immobilizing actin, which outside of a small region at stereocilia tips turns over with a very slow, months-long half-life. Here, we establish that β-actin and the actin crosslinking protein fascin-2 cooperate to maintain stereocilia length and auditory function. We observed that mice expressing mutant fascin-2 (p.R109H) or mice lacking β-actin share a common phenotype including progressive, high-frequency hearing loss together with shortening of a defined subset of stereocilia in the hair cell bundle. Fascin-2 binds β-actin and γ-actin filaments with similar affinity in vitro and fascin-2 does not depend on β-actin for localization in vivo. Nevertheless, double-mutant mice lacking β-actin and expressing fascin-2 p.R109H have a more severe phenotype suggesting that each protein has a different function in a common stereocilia maintenance pathway. Because the fascin-2 p.R109H mutant binds but fails to efficiently crosslink actin filaments, we propose that fascin-2 crosslinks function to slow actin depolymerization at stereocilia tips to maintain stereocilia length. PMID: 23658152 [PubMed - indexed for MEDLINE]
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Related Articles Hematopoietic stem cell transplantation for children with primary immunodeficiency diseases: single center experience in Jordan. Pediatr Transplant. 2013 Jun;17(4):394-402 Authors: Amayiri N, Al-Zaben A, Ghatasheh L, Frangoul H, Hussein AA Abstract HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty-eight patients were identified. The median age was 16 months (3 months-17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA-matched related HSCT, eight received maternal un-manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti-tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1-67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges. PMID: 23692601 [PubMed - indexed for MEDLINE]
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Related Articles Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system. J Neurosci. 2013 May 22;33(21):9113-21 Authors: Tong H, Kopp-Scheinpflug C, Pilati N, Robinson SW, Sinclair JL, Steinert JR, Barnes-Davies M, Allfree R, Grubb BD, Young SM, Forsythe ID Abstract The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K(+) currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure. PMID: 23699522 [PubMed - indexed for MEDLINE]
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Related Articles 'Ecstasy' enhances noise-induced hearing loss. Hear Res. 2013 Aug;302:96-106 Authors: Church MW, Zhang JS, Langford MM, Perrine SA Abstract 'Ecstasy' or 3,4-methylenedioxy-N-methamphetamine (MDMA) is an amphetamine abused for its euphoric, empathogenic, hallucinatory, and stimulant effects. It is also used to treat certain psychiatric disorders. Common settings for Ecstasy use are nightclubs and "rave" parties where participants consume MDMA and dance to loud music. One concern with the club setting is that exposure to loud sounds can cause permanent sensorineural hearing loss. Another concern is that consumption of MDMA may enhance such hearing loss. Whereas this latter possibility has not been investigated, this study tested the hypothesis that MDMA enhances noise-induced hearing loss (NIHL) by exposing rats to either MDMA, noise trauma, both MDMA and noise, or neither treatment. MDMA was given in a binge pattern of 5 mg/kg per intraperitoneal injections every 2 h for a total of four injections to animals in the two MDMA-treated groups (MDMA-only and Noise + MDMA). Saline injections were given to the animals in the two non-MDMA groups (Control and Noise-only). Following the final injection, noise trauma was induced by a 10 kHz tone at 120 dB SPL for 1 h to animals in the two noise trauma-treated groups (Noise-only and Noise + MDMA). Hearing loss was assessed by the auditory brainstem response (ABR) and cochlear histology. Results showed that MDMA enhanced NIHL compared to Noise-only and that MDMA alone caused no hearing loss. This implies that "clubbers" and "rave-goers" are exacerbating the amount of NIHL when they consume MDMA and listen to loud sounds. In contrast to earlier reports, the present study found that MDMA by itself caused no changes in the click-evoked ABR's wave latencies or amplitudes. PMID: 23711768 [PubMed - indexed for MEDLINE]
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Related Articles Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1. Auris Nasus Larynx. 2013 Dec;40(6):539-42 Authors: Hori R, Nakagawa T, Yamamoto N, Hamaguchi K, Ito J Abstract OBJECTIVE: The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. METHODS: Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. RESULTS: Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. CONCLUSION: The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1. PMID: 23735735 [PubMed - indexed for MEDLINE]
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Related Articles Using rheopheresis for stem cell transplantation-associated thrombotic microangiopathy (TA-TMA). Transfus Apher Sci. 2013 Oct;49(2):234-7 Authors: González-Vicent M, Herrero B, Guillén M, Sevilla J, Díaz MÁ Abstract Stem cell Transplantation-Associated Thrombotic Microangiopathy (TA-TMA) is an awful complication with high morbidity and mortality. The reported incidence varies from 0.5% to 75% due to the difficulty of diagnosis in these patients. They do not respond to plasma exchange and despite new treatments, such as defibrotide and rituximab, mortality rate ranges between 60% and 90%. Rheopheresis is a specific application of membrane differential filtration for extracorporeal hemorheotherapy that has been used in the diabetic foot syndrome, venous leg ulcer, pulmonary hypertension, sudden hearing loss, macula degeneration and peripheral arterial occlusive disease. The main therapeutic basis of Rheopheresis is the reduction of blood and plasma viscosity that results in improvements of microcirculation and blood flow. The physiopathologic mechanism associated with TA-TMA is the loss of endothelial cell integrity with hypercoagulability secondary to infections, immunosuppressive therapy and graft-versus-host disease. Because of this, we believe that treatment with Rheoapheresis may improve microcirculation and resolve TA-TMA. We report two patients diagnosed of severe TA-MA successfully treated with Rheopheresis using a selective fibrinogen adsorption system (Rheosorb) with a LIFE-18 apheresis unit (Miltenyi Biotec), an integrated plasma therapy instrument. PMID: 23768689 [PubMed - indexed for MEDLINE]
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Related Articles Connexin 43 and hearing: possible implications for retrocochlear auditory processing. Laryngoscope. 2013 Dec;123(12):3185-93 Authors: Kim AH, Nahm E, Sollas A, Mattiace L, Rozental R Abstract OBJECTIVES/HYPOTHESIS: To examine the relationship between hearing and connexin 43, a dominant gap junctional protein in the central nervous system. STUDY DESIGN: Original research. METHODS: Connexin 43 heterozygous mice are used to assess its mutational effect on hearing. Results are compared to controls consisting of connexin 43, wild type and CBA/J mice. Hearing is assessed using auditory brainstem response and distortion product otoacoustic emissions tests. Distribution of connexin 43 in the organ of Corti and the retrocochlear auditory centers (eight nerve, cochlear nucleus, olivary complex, lateral lemniscus, inferior colliculus, respectively) is examined. Fluorescent markers are used to elucidate cell types. RESULTS: Mean click auditory brainstem response threshold for the young connexin 43 heterozygous mice (3-4 months) was 36.7 ± 12.6 dB compared to 25 ± 0 dB for control mice (P < 0.05). Mean threshold difference became more pronounced (68 ± 7.5 dB vs. 31 ± 2.2 dB) at 10 months (P < 0.05). Tonal auditory brainstem response testing showed elevated thresholds (>60 dB) at all frequencies (4-32 kHz) compared to the controls. Distortion product otoacoustic emissions (DPOAE) were present in all the mice, although the older connexin 43 heterozygous mice responded at higher thresholds. The pattern of connexin 43 immunoreactivity was distinctive from connexin 26 and 30, showing minimal presence in the organ of Corti but robustly present in the retrocochlear centers. CONCLUSION: Connexin 43 heterozygous mice demonstrated greater degree of hearing loss compared to age-matched controls. It is abundantly found in the retrocochlear auditory centers. The mechanism of hearing loss in these mice does not appear to be related to hair cell loss. PMID: 23817980 [PubMed - indexed for MEDLINE]
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Related Articles Osteopontin does not mitigate cisplatin ototoxicity or nephrotoxicity in adult mice. Otolaryngol Head Neck Surg. 2013 Oct;149(4):614-20 Authors: Schmitt NC, Rubel EW Abstract OBJECTIVE: The goal of this study was to determine whether osteopontin, a molecule with a variety of biologic effects including cell death inhibition, plays an important role in protection of the inner ear and kidney from the toxic effects of the chemotherapeutic drug cisplatin. STUDY DESIGN: In vivo study using a model system of cisplatin toxicity in adult mice. SETTING: Virginia Merrill Bloedel Hearing Research Center, University of Washington. SUBJECTS AND METHODS: Osteopontin+/+ and Osteopontin-/- adult mice were treated with intraperitoneal cisplatin (20 mg/kg) or saline (control). Osteopontin levels were investigated by immunohistochemistry. Auditory brainstem response thresholds and cochlear histology were used to assess ototoxicity, while serum creatinine and renal histology were used to assess nephrotoxicity. For quantitative experiments, 8 to 18 animals were included in each treatment group. RESULTS: At 72 hours after cisplatin treatment, there was a slight increase in osteopontin levels within the kidney but not in the inner ear. There was no difference in auditory brainstem response threshold shifts, outer hair cell death, or serum creatinine between Osteopontin+/+ and Osteopontin-/- mice. Cochlear and renal histologic damage following cisplatin appeared to be similar in Osteopontin+/+ and Osteopontin-/- mice. CONCLUSION: Osteopontin is not required for development of normal auditory or renal function. Osteopontin is unlikely to play a role in protection of the inner ear or kidney from acute cisplatin toxicity. Slight increases in renal osteopontin 72 hours after cisplatin injury may be important for regeneration of proximal tubule cells. PMID: 23884286 [PubMed - indexed for MEDLINE]
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Related Articles Deafness induction in mice. Otol Neurotol. 2013 Oct;34(8):1496-502 Authors: Jansen TT, Bremer HG, Topsakal V, Hendriksen FG, Klis SF, Grolman W Abstract HYPOTHESIS: How to induce most efficiently severe sensorineural hearing loss in mice using a single coadministration of an aminoglycoside antibiotic and a loop diuretic? BACKGROUND: The coadministration of aminoglycosides and a loop diuretic has been widely used to induce hair cell and spiral ganglion cell loss in guinea pigs. However, the development of new treatment strategies against sensorineural hearing loss, such as tissue engineering techniques, requires the use of mouse models. Previous attempts to induce hearing loss in mice have rendered inconsistent results because of resistance to aminoglycoside-induced ototoxicity. Especially inner hair cells seem to be resistant to aminoglycoside-induced ototoxicity. METHODS: In the present study, we aim to optimize hearing loss in mice, using a single high-dose kanamycin (700 and 1,000 mg/kg) injection followed by a furosemide (100 mg/kg) administration. Although previous studies used intraperitoneal furosemide injections 30 minutes after kanamycin administration, we used intravenous furosemide injections administered within 5 minutes after kanamycin treatment. RESULTS: Auditory brain stem responses illustrated severe threshold shifts, and histologic analysis showed marked outer hair cell destruction as well as spiral ganglion cell loss. The present protocol results in more severe inner hair cell loss when compared with the results of previous researches. CONCLUSION: We conclude that severe sensorineural hearing loss can be induced in mice. Moreover, we found that this mouse model can be augmented via the use of rapid intravenous furosemide administrations to maximize inner hair cell loss. PMID: 23884329 [PubMed - indexed for MEDLINE]
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Related Articles Noise-induced changes in expression levels of NADPH oxidases in the cochlea. Hear Res. 2013 Oct;304:145-52 Authors: Vlajkovic SM, Lin SC, Wong AC, Wackrow B, Thorne PR Abstract UNLABELLED: NADPH oxidases are enzymes that transport electrons across the plasma membrane and generate superoxide radical from molecular oxygen. The current study investigated the expression and distribution of NOX/DUOX members of the NADPH oxidase family (NOX1-5 and DUOX1-2) in the rat cochlea and their regulation in response to noise. Wistar rats (8-10 weeks) were exposed for 24 h to band noise (8-12 kHz) at moderate (100 dB) or traumatic (110 dB) sound pressure levels (SPL). Animals exposed to ambient noise (45-55 dB SPL) served as controls. Immunohistochemistry demonstrated predominant expression of all NOX/DUOX isoforms in the sensory and supporting cells of the organ of Corti, with very limited immunoexpression in the lateral wall tissues and spiral ganglion neurons. Noise exposure induced up-regulation of NOX1 and DUOX2 in the cochlea, whereas NOX3 was down-regulated. A significant reduction in the intensity of NOX3 immunolabeling was observed in the inner sulcus region of the cochlea after exposure to noise. Post-exposure inhibition of NADPH oxidases by Diphenyleneiodonium (DPI), a broadly selective NADPH oxidase inhibitor, mitigated noise-induced hearing loss. CONCLUSION: Noise-induced up-regulation of NOX1 and DUOX2 could be linked to cochlear injury. In contrast, down-regulation of NOX3 may represent an endogenous protective mechanism to reduce oxidative stress in the noise-exposed cochlea. Inhibition of NADPH oxidases is potentially a novel pathway for therapeutic management of noise-induced hearing loss. PMID: 23899412 [PubMed - indexed for MEDLINE]
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Related Articles Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs. Hear Res. 2013 Oct;304:159-66 Authors: King EB, Salt AN, Kel GE, Eastwood HT, O'Leary SJ Abstract Clinically, gentamicin has been used extensively to treat the debilitating symptoms of Mèniére's disease and is well known for its vestibulotoxic properties. Until recently, it was widely accepted that the round window membrane (RWM) was the primary entry route into the inner ear following intratympanic drug administration. In the current study, gentamicin was delivered to either the RWM or the stapes footplate of guinea pigs (GPs) to assess the associated hearing loss and histopathology associated with each procedure. Vestibulotoxicity of the utricular macula, saccular macula, and crista ampullaris in the posterior semicircular canal were assessed quantitatively with density counts of hair cells, supporting cells, and stereocilia in histological sections. Cochleotoxicity was assessed quantitatively by changes in threshold of auditory brainstem responses (ABR), along with hair cell and spiral ganglion cell counts in the basal and second turns of the cochlea. Animals receiving gentamicin applied to the stapes footplate exhibited markedly higher levels of hearing loss between 8 and 32 kHz, a greater reduction of outer hair cells in the basal turn of the cochlea and fewer normal type I cells in the utricle in the vestibule than those receiving gentamicin on the RWM or saline controls. This suggests that gentamicin more readily enters the ear when applied to the stapes footplate compared with RWM application. These data provide a potential explanation for why gentamicin preferentially ablates vestibular function while preserving hearing following transtympanic administration in humans. PMID: 23899413 [PubMed - indexed for MEDLINE]
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Related Articles Friend or foe? Effect of oral resveratrol on cisplatin ototoxicity. Laryngoscope. 2014 Mar;124(3):760-6 Authors: Olgun Y, Kırkım G, Kolatan E, Kıray M, Bagrıyanık A, Olgun A, Kızmazoglu DC, Ellıdokuz H, Serbetcıoglu B, Altun Z, Aktas S, Yılmaz O, Günerı EA Abstract OBJECTIVES/HYPOTHESIS: Our objectives were to study effects of orally administered resveratrol (RV) against cisplatin (CDDP) ototoxicity in different doses and to investigate ultrastructural changes in the cochlea and brainstem. STUDY DESIGN: In vivo study using an animal model. METHODS: Thirty-two male Wistar albino rats were divided into six groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were made. In groups I, II, and III, only saline, RV, and CDDP were given, respectively. Group IV, V, and VI animals were administered 10 mg/kg/day, 1 mg/kg/day, and 0.1 mg/kg/day of RV for 10 days, respectively, before 16 mg/kg CDDP injections were administered on day 11. All animals were sacrificed after repeated DPOAEs and ABR measurements were made on day 14. Cochleas of animals were investigated with transmission electron microscopy. Apoptosis were investigated with caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in the brainstem. RESULTS: In groups IV and V, DPOAEs and ABR findings revealed that oral administration of RV 10 mg/kg/day and 1 mg/kg/day doses before CDDP injection enhanced ototoxicity. In group VI, electomicroscopy revealed better ultrastructural findings than in the cisplatin group; however, these changes were not reflected in the audiological findings accordingly. CONCLUSIONS: Our results implied that there were noticeable differences between different oral RV doses used for cisplatin ototoxicity. Especially in higher doses, RV was observed to enhance cisplatin ototoxicity. PMID: 23900991 [PubMed - indexed for MEDLINE]
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Related Articles G-CSF attenuates noise-induced hearing loss. Neurosci Lett. 2014 Mar 6;562:102-6 Authors: Shi ZT, Lin Y, Wang J, Wu J, Wang RF, Chen FQ, Mi WJ, Qiu JH Abstract In this study, we investigated the effects of granulocyte colony-stimulating factor (G-CSF) for the treatment of noise-induced hearing loss (NIHL) in a guinea pig model. Forty guinea pigs were randomly divided into four groups: control, noise (white noise, 3 h/d for 2 days at 115 dB), noise+G-CSF (350 μg/kg/d for 5 days), and noise+saline. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) were used to determine the hearing threshold and outer hair cell function, respectively, in each group. Cochlear morphology was examined to evaluate hair cell injury induced by intense noise exposure. Fourteen days after noise exposure, the noise+G-CSF group had a lower ABR value than the noise group (P<0.05) or the noise+saline group (P<0.01). At most frequencies, the DPOAE value of the noise+G-CSF group showed a significant rise (P<0.05) compared to the noise group or the noise+saline group. Neither the ABR value nor the DPOAE value differed between the noise group and the noise+saline group. The morphology of the phalloidin-stained organ of Corti was consistent with the functional measurements. In conclusion, G-CSF can preserve hearing in an experimental model of NIHL in guinea pigs, by preserving hair cells after intense noise exposure. PMID: 23916659 [PubMed - indexed for MEDLINE]
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Related Articles Ototoxicity of aluminum acetate/benzethonium chloride otic solution in the chinchilla animal model. Laryngoscope. 2013 Oct;123(10):2521-5 Authors: Pitaro J, Mood ZA, Daniel SJ Abstract OBJECTIVES/HYPOTHESIS: To determine the ototoxic potential of aluminum acetate (0.5%)/benzethonium chloride (0.03%) otic solution in the chinchilla animal model. STUDY DESIGN: A randomized, prospective, controlled study was conducted in the chinchilla animal model. METHODS: Fourteen female chinchillas were used. After an incision was made in each tympanic membrane, baseline auditory brainstem response measurements were performed at 16, 20, and 25 kHz. One ear was randomized to receive aluminum acetate (0.5%)/benzethonium chloride (0.03%), whereas the other ear served as the control and received 0.9% NaCl. Solutions were applied transtympanically once a day for 3 consecutive days. Postapplication auditory brainstem response measurements were done at day 7 and day 30. In half of the animals, scanning electron microscopy was done following the last auditory brainstem response measurement. RESULTS: A statistically significant difference was found between the mean threshold shifts in the experimental and control ears at all frequencies on both 7 and 30 days postapplication (P < .02). Increased ossification of the cochleae was seen in experimental ears (n = 12). Scanning electron microscopy study demonstrated outer hair cell damage and/or loss in the experimental ears. No significant morphological changes were detected on scanning electron microscopy obtained from the control ears. CONCLUSIONS: Application of aluminum acetate (0.5%)/benzethonium chloride (0.03%) otic solution causes hearing loss in chinchillas when a tympanic membrane perforation exists. Further studies are needed to test the effect of this otic solution on hearing. LEVEL OF EVIDENCE: 4. PMID: 23918745 [PubMed - indexed for MEDLINE]
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Related Articles Liposome-encapsulated hemoglobin alleviates hearing loss after transient cochlear ischemia: an experimental study in the gerbil. Neurosci Lett. 2013 Oct 11;553:176-80 Authors: Okada M, Kawaguchi AT, Hakuba N, Hyodo J, Hato N, Gyo K Abstract The effects of liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier, were experimentally investigated in gerbils in the context of alleviation of hearing loss after transient cochlear ischemia. Animals were randomly assigned to receive 2 mL/kg of either LEH (P₅₀O₂=15 mmHg) or saline 1h after the experimental induction of 15 min of ischemia. Sequential recordings of auditory brainstem response (ABR) showed that administration of LEH prevented hearing loss due to cochlear ischemia. The mean ABR threshold at 32 kHz on day 1 was 21 ± 7 dB in the LEH group (n=6) and 45 ± 6 dB in the saline group (n=6). Thereafter, hearing impairment gradually improved up to day 7 in both groups. The animals were then subjected to histological study, which revealed that there was more substantial loss of the inner hair cells, but not the outer hair cells, in the saline group as compared to the LEH group. These results suggest that LEH is an efficient agent with regard to protection against hearing loss and underlying hair cell damager due to ischemic insult. PMID: 23994393 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic effect of adeno-associated virus (AAV)-mediated ADNF-9 expression on cochlea of kanamycin-deafened guinea pigs. Acta Otolaryngol. 2013 Oct;133(10):1022-9 Authors: Zheng G, Zhu Z, Zhu K, Wei J, Jing Y, Duan M Abstract CONCLUSION: rAAV-NT4-ADNF-9 could ameliorate the damage to auditory function and repair previous impairment of cochlear hair cell loss induced by kanamycin. OBJECTIVE: To investigate the therapeutic effect of ADNF-9 on cochlear hair cells using the recombinant adeno-associated virus (AAV) carrying fusion gene NT4-ADNF-9 and the kanamycin-deafened guinea pig model. METHODS: Forty white guinea pigs with normal auricle reflex and normal auditory brainstem responses (ABRs) were randomly divided into four groups. Kanamycin was administered to the animals in groups A, B, and C to establish the deafened guinea pig model. rAAV-NT4-ADNF-9, vector only, and artificial perilymph were then delivered to the cochlear tissue of animals in groups A, B, and C, respectively, through the round window membrane. Animals in group D did not receive any treatment and acted as normal controls. The hearing thresholds on the surgery side were recorded before and after the transfection treatment. Fourteen days after treatment, cochleae were removed for paraffin slide preparation and cochlear surface preparation. A phase contrast microscope was used to observe the protective effect of ADNF-9 on hair cells. RESULTS: Significant reduction of the ABR threshold was observed after rAAV-NT4-ADNF-9 treatment (p < 0.05). After 14 days of treatment, the ABR threshold was also significantly different between the rAAV-NT4-ADNF-9-infected group and the non-infected group. Moreover, phase contrast microscopy showed significantly less hair cell damage or hair cell loss in the group treated with rAAV-NT4-ADNF-9 than in the groups treated with vector only or artificial perilymph (p < 0.05). PMID: 24032567 [PubMed - indexed for MEDLINE]
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Related Articles Sound localization ability and glycinergic innervation of the superior olivary complex persist after genetic deletion of the medial nucleus of the trapezoid body. J Neurosci. 2013 Sep 18;33(38):15044-9 Authors: Jalabi W, Kopp-Scheinpflug C, Allen PD, Schiavon E, DiGiacomo RR, Forsythe ID, Maricich SM Abstract The medial nucleus of the trapezoid body (MNTB) in the superior olivary complex (SOC) is an inhibitory hub considered critical for binaural sound localization. We show that genetic ablation of MNTB neurons in mice only subtly affects this ability by prolonging the minimum time required to detect shifts in sound location. Furthermore, glycinergic innervation of the SOC is maintained without an MNTB, consistent with the existence of parallel inhibitory inputs. These findings redefine the role of MNTB in sound localization and suggest that the inhibitory network is more complex than previously thought. PMID: 24048834 [PubMed - indexed for MEDLINE]
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Related Articles Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss. J Neurosci. 2013 Sep 18;33(38):15086-94 Authors: Huang M, Kantardzhieva A, Scheffer D, Liberman MC, Chen ZY Abstract Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure. PMID: 24048839 [PubMed - indexed for MEDLINE]
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Related Articles Hunter syndrome (Mucopolysaccharidosis type II), severe phenotype: long term follow-up on patients undergone to hematopoietic stem cell transplantation. Minerva Pediatr. 2013 Oct;65(5):487-96 Authors: Annibali R, Caponi L, Morganti A, Manna M, Gabrielli O, Ficcadenti A Abstract AIM: Our study aim is the evaluation of long-term effects of hematopoietic stem cell transplantation on Italian patients with severe Hunter syndrome. METHODS: Four boys, suffering from Hunter syndrome, severe phenotype, received hematopoietic stem cell transplantation between 2 years 6 months and 2 years 11 months of age, from 1992 to 2001. A complete multidisciplinary evaluation of hematopoietic stem cell transplantation long-term effects was performed periodically. RESULTS: All patients achieved successful engraftment. Urine glycosaminoglycans excretion was reduced or normalized, and the activity of leukocyte iduronate-2-sulphatase enzyme, absent before hematopoietic stem cell transplantation, remained constant, in all patients. Dysostosis multiplex progressed over time, according to the natural evolution of the disease. Joint stiffness improved in all affected districts. Hepatosplenomegaly decreased until it disappeared. The cardiovascular involvement stayed unchanged, as well as hearing loss. Skin became hyperelastical; face features seemed less coarse if compared to the natural evolution of the disease. Cerebral white matter alterations were constant in time. On the contrary, the hematopoietic stem cell transplantation did not prove to have long-term effectiveness on neurological symptoms of Hunter syndrome. CONCLUSION: The hematopoietic stem cell transplantation was successful in slowing the progression of Hunter syndrome, and even the evolution of neurological feature of the disease was slower in the first years after this treatment. PMID: 24056375 [PubMed - indexed for MEDLINE]
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Related Articles The protective effect of Salvia miltiorrhiza on gentamicin-induced ototoxicity. Am J Otolaryngol. 2014 Mar-Apr;35(2):171-9 Authors: Shi L, An Y, Wang A, Gao Q, Yang Y Abstract OBJECTIVE: The clinical use of aminoglycoside antibiotics is limited in most countries because of auditory toxicity side effects. However, their use is common in developing countries because they are inexpensive and convenient. Salvia miltiorrhiza extracts are used clinically in China for their antioxidant properties. We investigated the effect of a clinically approved injectable S. miltiorrhiza solution on inducible nitric oxide synthase (iNOS) generation induced by the aminoglycoside antibiotic gentamicin and an ototoxicity protective mechanism. METHODS: Sixty adult guinea pigs were used in this study and divided into four groups. Auditory brainstem response (ABR) testing was performed before and after treatments and animals were sacrificed for morphological and immunostaining assays after determining threshold shifts in ABR. The cochleae were examined by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to observe ultrastructural changes. In addition, hair cell loss, iNOS and caspase-3 expression, and apoptosis were measured. RESULTS: The result showed that hearing loss, iNOS overexpression accompanied with disorganization in the cochlea, and terminal deoxynucleotidyl transferase- mediated dUTP- biotin nick end labeling (TUNEL)-stained positive cells in animals treated with gentamicin. However, pretreatment with S. miltiorrhiza (3g/kg/day for 10 days) decreased gentamicin-induced hearing loss, attenuated iNOS and caspase-3 expression, and decreased the number of apoptotic cells. Furthermore, it also reduced the ultrastructural damage due to ototoxicity as observed by SEM and TEM. CONCLUSIONS: These findings indicate that S. miltiorrhiza protects against gentamicin-induced ototoxicity and could apply to the protection of ototoxicity. PMID: 24119490 [PubMed - indexed for MEDLINE]
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Related Articles The role of transmembrane channel-like proteins in the operation of hair cell mechanotransducer channels. J Gen Physiol. 2013 Nov;142(5):493-505 Authors: Kim KX, Beurg M, Hackney CM, Furness DN, Mahendrasingam S, Fettiplace R Abstract Sound stimuli elicit movement of the stereocilia that make up the hair bundle of cochlear hair cells, putting tension on the tip links connecting the stereocilia and thereby opening mechanotransducer (MT) channels. Tmc1 and Tmc2, two members of the transmembrane channel-like family, are necessary for mechanotransduction. To assess their precise role, we recorded MT currents elicited by hair bundle deflections in mice with null mutations of Tmc1, Tmc2, or both. During the first postnatal week, we observed a normal MT current in hair cells lacking Tmc1 or Tmc2; however, in the absence of both isoforms, we recorded a large MT current that was phase-shifted 180°, being evoked by displacements of the hair bundle away from its tallest edge rather than toward it as in wild-type hair cells. The anomalous MT current in hair cells lacking Tmc1 and Tmc2 was blocked by FM1-43, dihydrostreptomycin, and extracellular Ca(2+) at concentrations similar to those that blocked wild type. MT channels in the double knockouts carried Ca(2+) with a lower permeability than wild-type or single mutants. The MT current in double knockouts persisted during exposure to submicromolar Ca(2+), even though this treatment destroyed the tip links. We conclude that the Tmc isoforms do not themselves constitute the MT channel but are essential for targeting and interaction with the tip link. Changes in the MT conductance and Ca(2+) permeability observed in the absence of Tmc1 mutants may stem from loss of interaction with protein partners in the transduction complex. PMID: 24127526 [PubMed - indexed for MEDLINE]
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Related Articles A novel otoferlin splice-site mutation in siblings with auditory neuropathy spectrum disorder. Audiol Neurootol. 2013;18(6):374-82 Authors: Runge CL, Erbe CB, McNally MT, Van Dusen C, Friedland DR, Kwitek AE, Kerschner JE Abstract We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered. PMID: 24135434 [PubMed - indexed for MEDLINE]
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Related Articles D-methionine pre-loading reduces both noise-induced permanent threshold shift and outer hair cell loss in the chinchilla. Int J Audiol. 2013 Dec;52(12):801-7 Authors: Claussen AD, Fox DJ, Yu XC, Meech RP, Verhulst SJ, Hargrove TL, Campbell KC Abstract OBJECTIVE: This study tested multiple dosing epochs of pre-loaded D-methionine (D-met) for otoprotection from noise-induced hearing loss (NIHL). DESIGN: 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. STUDY SAMPLE: 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. RESULTS: ABR threshold shifts from baseline to day-21 post-noise exposure were reduced in all D-met groups versus controls, reaching significance (p < 0.05) in the 3-day group. D-met groups showed reduced OHC loss relative to controls at day-21 post-noise exposure, reaching significance (p < 0.05) 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. CONCLUSIONS: D-met administration in advance of noise-exposure, without further administration, significantly protects from noise-induced ABR threshold shift and OHC loss. PMID: 24175619 [PubMed - indexed for MEDLINE]
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Related Articles Effect of both local and systemically administered dexamethasone on long-term hearing and tissue response in a Guinea pig model of cochlear implantation. Audiol Neurootol. 2013;18(6):392-405 Authors: Lee J, Ismail H, Lee JH, Kel G, O'Leary J, Hampson A, Eastwood H, O'Leary SJ Abstract Dexamethasone administered prior to cochlear implantation has been shown to reduce the loss of residual hearing in experimental settings. However, its effect on the tissue response around the implant has not been extensively studied. In this study dexamethasone sodium phosphate was administered to guinea pigs via local delivery to the round window (2% dexamethasone for 120 min prior to surgery, 'local 2/120', or 20% dexamethasone for 30 min prior to surgery) or intravenously (2 mg/kg dexamethasone for 60 min) prior to implantation. Auditory brainstem responses (ABR) were monitored for 3 months, after which the cochleae were embedded in Spurr's resin and sectioned. The extent of the tissue response and the survival of the neurosensory structures were analysed. Both local 2/120 and systemically delivered dexamethasone improved ABR thresholds when compared with control animals. Systemic dexamethasone also reduced the tissue response around the electrode. This suggests that whilst both locally and systemically administered dexamethasone can protect residual hearing after cochlear implantation, their effects upon the tissue response to implantation may differ. PMID: 24192718 [PubMed - indexed for MEDLINE]
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Related Articles Postnatal development of auditory central evoked responses and thalamic cellular properties. Dev Neurobiol. 2014 May;74(5):541-55 Authors: Venkataraman Y, Bartlett EL Abstract During development, the sense of hearing changes rapidly with age, especially around hearing onset. During this period, auditory structures are highly sensitive to alterations of the acoustic environment, such as hearing loss or background noise. This sensitivity includes auditory temporal processing, which is important for processing complex sounds, and for acquiring reading and language skills. Developmental changes can be observed at multiple levels of brain organization-from behavioral responses to cellular responses, and at every auditory nucleus. Neuronal properties and sound processing change dramatically in auditory cortex neurons after hearing onset. However, development of its primary source, the auditory thalamus, or medial geniculate body (MGB), has not been well studied over this critical time window. Furthermore, to understand how temporal processing develops, it is important to determine the relative maturation of temporal processing not only in the MGB, but also in its inputs. Cellular properties of rat MGB neurons were studied using in vitro whole-cell patch-clamp recordings, at ages postnatal day (P) 7-9; P15-17, and P22-32. Auditory evoked potentials were measured in P14-17 and P22-32 rats. MGB action potentials became about five times faster, and the ability to generate spike trains increased with age, particularly at frequencies of 50 Hz and higher. Evoked potential responses, including auditory brainstem responses (ABR), middle latency responses (MLR), and amplitude modulation following responses, showed increased amplitudes with age, and ABRs and MLRs additionally showed decreased latencies with age. Overall, temporal processing at subthalamic nuclei is concurrently maturing with MGB cellular properties. PMID: 24214269 [PubMed - indexed for MEDLINE]
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Related Articles The astroglial reaction along the mouse cochlear nerve following inner ear damage. Otolaryngol Head Neck Surg. 2014 Jan;150(1):121-5 Authors: Hu Z, Zhang B, Luo X, Zhang L, Wang J, Bojrab D, Jiang H Abstract OBJECTIVE: Determine how the astroglial cells of the peripheral and central nervous system transitional zone (PCTZ) react to sensorineural hearing loss using a mouse cochlear nerve model. STUDY DESIGN: Prospective, basic science. SETTING: Research laboratory. SUBJECTS AND METHODS: Neomycin was injected into the mouse inner ear to cause chemically induced hearing loss. Auditory brainstem responses (ABRs) were used to determine hearing threshold shifts after neomycin treatment. Immunofluorescence was used to detect the expression of proteins specific for hair cells, spiral ganglion neurons, astrocytes, and the myelin components of both oligodendrocytes and Schwann cells. RESULTS: ABR threshold shifts and immunofluorescence results supported that hair cells and spiral ganglion neurons were damaged in neomycin-treated mice. Immunofluorescence showed the peripheral and central nervous system (PNS and CNS) transitional zone of the cochlear nerve at the interface of the myelin components of the PNS and CNS. In the control mice, the expression of glial fibrillary acidic protein (GFAP) was observed proximally to the PCTZ closer to the CNS, which is their normal location. However, in neomycin-treated animals the expression of GFAP was detected distally to the PCTZ and was found close to the spiral lamina level in the basal cochlear turn, suggesting that GFAP-expressing astrocytes migrated across the PCTZ and reached the PNS. CONCLUSION: The GFAP positive astrocyte processes extended across the PCTZ along the mouse cochlear nerve following chemically induced sensorineural hearing loss. PMID: 24225176 [PubMed - indexed for MEDLINE]
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Related Articles Mitochondrial 12S ribosomal RNA A1555G mutation associated with cardiomyopathy and hearing loss following high-dose chemotherapy and repeated aminoglycoside exposure. J Pediatr. 2014 Feb;164(2):413-5 Authors: Skou AS, Tranebjærg L, Jensen T, Hasle H Abstract A 19-month-old girl with the A1555G mitochondrial mutation in the 12S ribosomal RNA gene and acute myelogenous leukemia developed dilated cardiomyopathy and bilateral sensorineural hearing loss before undergoing allogeneic stem cell transplantation. She had received gentamicin during episodes of febrile neutropenia. Testing for the A1555G mutation is recommended in patients frequently treated with aminoglycosides. PMID: 24252789 [PubMed - indexed for MEDLINE]
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Related Articles Mutation of Foxo3 causes adult onset auditory neuropathy and alters cochlear synapse architecture in mice. J Neurosci. 2013 Nov 20;33(47):18409-24 Authors: Gilels F, Paquette ST, Zhang J, Rahman I, White PM Abstract Auditory neuropathy is a form of hearing loss in which cochlear inner hair cells fail to correctly encode or transmit acoustic information to the brain. Few genes have been implicated in the adult-onset form of this disease. Here we show that mice lacking the transcription factor Foxo3 have adult onset hearing loss with the hallmark characteristics of auditory neuropathy, namely, elevated auditory thresholds combined with normal outer hair cell function. Using histological techniques, we demonstrate that Foxo3-dependent hearing loss is not due to a loss of cochlear hair cells or spiral ganglion neurons, both of which normally express Foxo3. Moreover, Foxo3-knock-out (KO) inner hair cells do not display reductions in numbers of synapses. Instead, we find that there are subtle structural changes in and surrounding inner hair cells. Confocal microscopy in conjunction with 3D modeling and quantitative analysis show that synaptic localization is altered in Foxo3-KO mice and Myo7a immunoreactivity is reduced. TEM demonstrates apparent afferent degeneration. Strikingly, acoustic stimulation promotes Foxo3 nuclear localization in vivo, implying a connection between cochlear activity and synaptic function maintenance. Together, these findings support a new role for the canonical damage response factor Foxo3 in contributing to the maintenance of auditory synaptic transmission. PMID: 24259566 [PubMed - indexed for MEDLINE]
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Related Articles Electrophysiological properties of neurosensory progenitors derived from human embryonic stem cells. Stem Cell Res. 2014 Jan;12(1):241-9 Authors: Needham K, Hyakumura T, Gunewardene N, Dottori M, Nayagam BA Abstract In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, stem cell-derived neurons may provide a potential source of replacement cells. The success of such a therapy relies upon producing a population of functional neurons from stem cells, to enable precise encoding of sound information to the brainstem. Using our established differentiation assay to produce sensory neurons from human stem cells, patch-clamp recordings indicated that all neurons examined generated action potentials and displayed both transient sodium and sustained potassium currents. Stem cell-derived neurons reliably entrained to stimuli up to 20 pulses per second (pps), with 50% entrainment at 50 pps. A comparison with cultured primary auditory neurons indicated similar firing precision during low-frequency stimuli, but significant differences after 50 pps due to differences in action potential latency and width. The firing properties of stem cell-derived neurons were also considered relative to time in culture (31-56 days) and revealed no change in resting membrane potential, threshold or firing latency over time. Thus, while stem cell-derived neurons did not entrain to high frequency stimulation as effectively as mammalian auditory neurons, their electrical phenotype was stable in culture and consistent with that reported for embryonic auditory neurons. PMID: 24280418 [PubMed - indexed for MEDLINE]
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Related Articles Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab. Pediatr Blood Cancer. 2014 May;61(5):928-30 Authors: Unal S, Sag E, Kuskonmaz B, Kesici S, Bayrakci B, Ayvaz DC, Tezcan I, Yalnızoglu D, Uckan D Abstract Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. PMID: 24307660 [PubMed - indexed for MEDLINE]
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Related Articles Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse. Neuroscience. 2014 Feb 14;259:184-93 Authors: Tang X, Zhu X, Ding B, Walton JP, Frisina RD, Su J Abstract Age-related hearing loss - presbycusis - is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate GABAA receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit β2, and N-methyl-d-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons (SGN) of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40dB from 3 to 48kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40dB from 6 to 49kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1amplitude. mRNA and protein expression of GABAAR α1 and AChR β2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss. PMID: 24316061 [PubMed - indexed for MEDLINE]
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Related Articles Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res. 2014 Mar;309:124-35 Authors: Takada Y, Beyer LA, Swiderski DL, O'Neal AL, Prieskorn DM, Shivatzki S, Avraham KB, Raphael Y Abstract Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (Cx26) mutation, in which cre-Sox10 drives excision of the Cx26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of Cx26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal's canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus with the BDNF gene insert (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal's canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and especially in a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve, thereby improving the outcome of cochlear implant therapy in these ears. PMID: 24333301 [PubMed - indexed for MEDLINE]
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Related Articles Inner ear symptoms and disease: pathophysiological understanding and therapeutic options. Med Sci Monit. 2013;19:1195-210 Authors: Ciuman RR Abstract In recent years, huge advances have taken place in understanding of inner ear pathophysiology causing sensorineural hearing loss, tinnitus, and vertigo. Advances in understanding comprise biochemical and physiological research of stimulus perception and conduction, inner ear homeostasis, and hereditary diseases with underlying genetics. This review describes and tabulates the various causes of inner ear disease and defines inner ear and non-inner ear causes of hearing loss, tinnitus, and vertigo. The aim of this review was to comprehensively breakdown this field of otorhinolaryngology for specialists and non-specialists and to discuss current therapeutic options in distinct diseases and promising research for future therapies, especially pharmaceutic, genetic, or stem cell therapy. PMID: 24362017 [PubMed - indexed for MEDLINE]
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Related Articles Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study. J Vet Dent. 2013;30(3):140-5 Authors: Lewis JR, O'Brien TG, Skorupski KA, Krick EL, Reiter AM, Jennings MW, Jurney CH, Shofer FS Abstract This study assessed proof-of-concept for use of polyamine inhibitor 2-diluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (SCC) in client-owned cats. Polyamine levels in tumor tissue and normal oral mucosa were quantified before and after treatment. DFMO was administered orally to 14 client-owned cats with histologically confirmed oral SCC. Patients were monitored for gastrointestinal, dermatologic, auditory, hematological, and biochemical abnormalities. Total polyamine levels in tumor tissue decreased after treatment, as did the specific polyamine putrescine in both tumor tissue and normal mucosa. Ototoxicity was observed in 5 of 6 cats receiving pre- and post-treatment brainstem auditory evoked potential tests. Subclinical thrombocytopenia was observed in 6 of 14 cats. One cat showed mild post-anesthetic tremors that resolved without treatment. Oral administration of DFMO at doses used in this study resulted in significantly decreased tumor polyamine levels without life-threatening clinical or hematological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC. PMID: 24371920 [PubMed - indexed for MEDLINE]
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Related Articles Diabetes: Targeting endoplasmic reticulum to combat juvenile diabetes. Nat Rev Endocrinol. 2014 Mar;10(3):129-30 Authors: Urano F Abstract Limited options for clinical management of patients with juvenile-onset diabetes mellitus call for a novel therapeutic paradigm. Two innovative studies support endoplasmic reticulum as an emerging target for combating both autoimmune and heritable forms of this disease. PMID: 24393784 [PubMed - indexed for MEDLINE]
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Related Articles Acoustical stimulus changes the expression of stromal cell-derived factor-1 in the spiral ganglion neurons of the rat cochlea. Neurosci Lett. 2014 Feb 21;561:140-5 Authors: Zhang PZ, Cao XS, Jiang XW, Wang J, Liang PF, Wang SJ, Mi WJ, Chen FQ, Chen Y, Xue T, Chen J, Qiu JH Abstract Neural stem cell (NSC) transplantation into the cochlea has been tested as a treatment for spiral ganglion neuron (SGN) degenerative disease and injury in various animal models. A recent study has shown evidence of functional recovery after transplantation of the stem cells into a degenerated-SGN model. Chemokine stromal cell-derived factor-1 (SDF-1, or known as CXC chemokine ligand-12, CXCL-12) signaling through CXCR4 has previously been identified as a key step in the homing of the stem cells within the injury areas; meanwhile, studies have revealed that the SDF-1/CXCR4 axis is also involved in axon guidance and pathfinding. A study found that transplanted neural precursor cells can migrate to the root of the auditory nerve when animals are subjected to an augmented acoustic environment (AAE). In accordance with these studies, we hypothesize that AAE will up-regulate the expression of SDF-1 in acoustic nerves. We tested our hypothesis by examining the expression of SDF-1 in different acoustic environments, and the results were confirmed by the auditory brainstem response (ABR), immunohistochemical and RT-PCR analyses. The results showed that SDF-1 was expressed at a relatively low level in the SGNs under normal animal unit acoustic conditions (40-50 dB). Moreover, it was significantly up-regulated in the SGNs under the 75 dB (augmented physiological process without hearing loss) and 90 dB AAE (pathological process with light hearing loss) conditions; however, under the 115 dB AAE (pathological process with severe hearing loss) condition, the expression of SDF-1 was not up-regulated. The results confirmed that appropriately augmented acoustical stimuli lead to the up-regulation of SDF-1, which may assist in the migration of the transplanted cells and the subsequent establishment of essential synaptic contacts between the exogenous cells and the host auditory pathway. PMID: 24394908 [PubMed - indexed for MEDLINE]
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Related Articles The effect of caffeine on hearing in a guinea pig model of acoustic trauma. Am J Otolaryngol. 2014 Mar-Apr;35(2):99-105 Authors: Mujica-Mota MA, Gasbarrino K, Rappaport JM, Shapiro RS, Daniel SJ Abstract OBJECTIVE: Caffeine is a widely consumed substance affecting the metabolism of adenosine and cellular metabolism of calcium. Noise also affects these metabolic pathways while inducing hearing loss. The aim of this study was to determine the effect of daily intake of caffeine on hearing loss after an episode of acoustic trauma in guinea pigs. MATERIALS AND METHODS: In this pilot study, forty guinea pigs were randomly divided into four groups: group I (control, n=10) received intraperitoneal saline, group II (n=10) received intraperitoneal caffeine (120 mg/kg/day) for 14 days, group III (n=10) was exposed to noise (tone of 6 kHz at 120 dB for one hour) and group IV (n=10) was exposed to noise as group III and received caffeine as group II. Auditory brainstem responses were measured at four different frequencies (8, 16, 20, and 25 kHz) prior to and at intervals of 1h, 3 days, 10 days, and 14 days after the initial treatment. On day 14, morphological analysis was performed to assess the effects of caffeine on acoustic trauma. RESULTS: Aggravated hearing loss was observed in group IV after 10 days of follow-up. After 14 days, one of the four frequencies (8 kHz) tested showed statistically significant greater impairment in hearing (8.2 ± 3.6 dB, p=0.026). Auditory hair cells showed no difference while spiral ganglion cell counts were diminished in group IV (p<0.05). CONCLUSION: These findings indicate that caffeine may have a detrimental effect on hearing recovery after a single event of acoustic trauma. PMID: 24406118 [PubMed - indexed for MEDLINE]
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Related Articles Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss. J Physiol. 2014 Apr 1;592(Pt 7):1581-600 Authors: Grande G, Negandhi J, Harrison RV, Wang LY Abstract Structure and function of central synapses are profoundly influenced by experience during developmental sensitive periods. Sensory synapses, which are the indispensable interface for the developing brain to interact with its environment, are particularly plastic. In the auditory system, moderate forms of unilateral hearing loss during development are prevalent but the pre- and postsynaptic modifications that occur when hearing symmetry is perturbed are not well understood. We investigated this issue by performing experiments at the large calyx of Held synapse. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are innervated by calyx of Held terminals that originate from the axons of globular bushy cells located in the contralateral ventral cochlear nucleus. We compared populations of synapses in the same animal that were either sound deprived (SD) or sound experienced (SE) after unilateral conductive hearing loss (CHL). Middle ear ossicles were removed 1 week prior to hearing onset (approx. postnatal day (P) 12) and morphological and electrophysiological approaches were applied to auditory brainstem slices taken from these mice at P17-19. Calyces in the SD and SE MNTB acquired their mature digitated morphology but these were structurally more complex than those in normal hearing mice. This was accompanied by bilateral decreases in initial EPSC amplitude and synaptic conductance despite the CHL being unilateral. During high-frequency stimulation, some SD synapses displayed short-term depression whereas others displayed short-term facilitation followed by slow depression similar to the heterogeneities observed in normal hearing mice. However SE synapses predominantly displayed short-term facilitation followed by slow depression which could be explained in part by the decrease in release probability. Furthermore, the excitability of principal cells in the SD MNTB had increased significantly. Despite these unilateral changes in short-term plasticity and excitability, heterogeneities in the spiking fidelity among the population of both SD and SE synapses showed similar continuums to those in normal hearing mice. Our study suggests that preservations in the heterogeneity in spiking fidelity via synaptic remodelling ensures symmetric functional stability which is probably important for retaining the capability to maximally code sound localization cues despite moderate asymmetries in hearing experience. PMID: 24469075 [PubMed - indexed for MEDLINE]
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Related Articles Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol. 2014 Aug;16(8):1129-36 Authors: Schreiber JE, Gurney JG, Palmer SL, Bass JK, Wang M, Chen S, Zhang H, Swain M, Chapieski ML, Bonner MJ, Mabbott DJ, Knight SJ, Armstrong CL, Boyle R, Gajjar A Abstract BACKGROUND: The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. METHODS: Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis. RESULTS: Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes. CONCLUSIONS: Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions. PMID: 24497405 [PubMed - in process]
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Related Articles Safety and otoprotection of metformin in radiation-induced sensorineural hearing loss in the guinea pig. Otolaryngol Head Neck Surg. 2014 May;150(5):859-65 Authors: Mujica-Mota MA, Salehi P, Devic S, Daniel SJ Abstract OBJECTIVE: There is currently no treatment available to prevent radiation-induced sensorineural hearing loss. Metformin has antineoplastic effects and is able to regulate the mitochondrial production of reactive oxygen species after cellular stress, which is one of the mechanisms involved in apoptosis after radiation damage. The objective of this study was to determine the safety and radioprotective properties of metformin against radiation-induced cochlear damage both in vitro and in vivo. STUDY DESIGN: In vitro and prospective animal study. SETTING: Animal Care Facilities of the Montreal Children's Hospital Research Institute. METHODS: Cultured auditory hair cells (HEI-OC1) were exposed to different concentrations of metformin to determine its safety. Cells were incubated with different metformin concentrations and subjected to radiation. Cell viability after experiments was determined with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Sixteen guinea pigs were divided in 2 groups: drinking tap water (n = 8) and drinking water containing metformin (n = 8). The animals were unilaterally irradiated for 20 days (total dose 70 Gy), and the ears were divided in 4 groups: control (n = 8), irradiated (n = 8), metformin (n = 8), and experimental (n = 8). Auditory brainstem responses were assessed before and 1, 6, and 16 weeks after completion of radiotherapy. RESULTS: Metformin was not cytotoxic or radioprotective in cultured auditory hair cells. Experimental ears had less hearing loss than radiated ones; however, differences were not statistically significant (P > .05). CONCLUSION: Metformin is not ototoxic or radioprotective in vitro or in vivo. Ears solely subjected to metformin had better hearing thresholds than the rest of the groups. PMID: 24500877 [PubMed - indexed for MEDLINE]
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Related Articles Dynamic distribution of ototoxic gentamicin entry into inner hair cells of mice. Acta Otolaryngol. 2014 Apr;134(4):345-51 Authors: Liu K, Shi C, Sun Y, Xu Y, Shi L, Shi L, Wang X, Ji F, Hou Z, Yang S Abstract CONCLUSION: Dynamic distribution of ototoxic gentamicin entry into inner hair cells (IHCs) may cause an interruption of cochlear ribbon synapse. OBJECTIVE: To explore the pattern of uptake of gentamicin into IHCs, as well as its possible contribution to hearing loss. METHODS: Adult C57 mice were injected intraperitoneally with gentamicin (100 mg/kg, conjugated with Texas Red ester) continuously for 14 days. The hearing thresholds were detected by auditory brainstem response (ABR) examinations. Immunostaining and confocal microscopy were utilized to trace gentamicin distribution, as well as the expression of RIBEYE/CtBP2 in mouse IHCs. Scanning electron microscopy (SEM) observation was used to find possible alterations of stereocilia. RESULTS: The distribution of gentamicin in IHCs was first found on the 4th day and the accumulation of gentamicin was increased significantly on the 7th day after treatment, corresponding to the maximal elevation of the hearing threshold. However, the accumulation of gentamicin on the 14th day did not show significant differences compared with the level found on the 7th day. In addition, the uptake of gentamicin was excessively identified at or near the synaptic ribbons of IHCs throughout the 4th, 7th, and 14th days after the treatment, suggesting that cochlear ribbon synapses could be affected by ototoxic gentamicin exposure. PMID: 24521345 [PubMed - indexed for MEDLINE]
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Related Articles Sonic hedgehog and retinoic Acid induce bone marrow-derived stem cells to differentiate into glutamatergic neural cells. J Immunoassay Immunochem. 2015;36(1):1-15 Authors: Yu Z, Wu S, Liu Z, Lin H, Chen L, Yuan X, Zhang Z, Liu F, Zhang C Abstract Studies have showed that transplanted stem cells in the inner ear won't regenerate to replace the damaged sensory hair cells. They can spontaneously differentiate into mesenchymal cells and fibrocytes in the damaged inner ear. Only mature sensory cells of MSCs-derived possess the great potency for cell transplantation in the treatment of sensorineural hearing loss. So, we try to establish an efficient generation of the glutamatergic sensory neural phenotype for the cell transplantation of the hearing loss. We isolated MSCs from femoral and tibial bones according to their adherence to culture dishes. After purification, proliferation, and passaged, cells became homogeneous in appearance, showing more uniformity and grew in a monolayer with a typical spindle-shape morphology. The cell surface markers were assessed using FACS to characterize the isolated cells. For neural induction to harvest the glutamatergic sensory neurons, passage 3 MSCs were incubated with preinduced medium for 24 hr, and neural-induced medium for an additional 14 days. The cells exhibit a typical neural shape. RT-PCR analysis indicated that the mRNA levels of the neural cell marker nestin, Tau, MAP-2, β-tubulin III, GluR-3, and GluR-4 were higher compared with primary MSCs. Immunohistochemistry and western-blotting proofed that nestin, MAP-2, β-tubulin III, and GluR-4 proteins indeed exhibit their expression difference in the induced cells compared to the MSCs. We show an efficient protocol by the combined applications of Sonic Hedgehog (Shh) and Retinoic Acid (RA) to induce MSCs to differentiate into the glutamatergic sensory neuron which were identified from the morphological, biochemical, and molecular characteristics. PMID: 24547891 [PubMed - in process]
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Related Articles [Hearing research news: from the periphery to the center]. HNO. 2014 Feb;62(2):88-92 Authors: Euteneuer S, Praetorius M Abstract In the clinical setting, a patient's hearing level is usually quantified by determining the hearing threshold in pure tone and speech audiometry. The measurement and analysis of auditory brainstem responses (ABRs) for quantification of hearing impairment go beyond the scope of routine ENT diagnostic practice. In basic scientific studies, ABRs are commonly used to determine hearing thresholds in animal models. In the last few years, analysis of suprathreshold ABRs, particularly ABR wave I suprathreshold amplitudes, have led to the discovery and understanding of previously undetected hearing impairments in noise-induced and age-related hearing loss models. Deafferentation of inner hair cells and auditory nerve fiber degeneration were identified as pathophysiological correlates to the observed reduction in ABR wave I amplitudes. Such reductions in ABR wave 1 amplitudes could also be identified in chronic tinnitus patients with apparently normal hearing. Recent functional magnetic resonance tomography studies in humans have shown that the limbic system can influence the perception of tinnitus by interacting with an endogenous noise-cancelling system. This highlights the importance of psychotherapeutic treatment approaches for chronic tinnitus. PMID: 24549507 [PubMed - indexed for MEDLINE]
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Related Articles [Gene therapy and stem cells for the inner ear: a review]. HNO. 2014 Feb;62(2):93-9 Authors: Breinbauer HA, Praetorius M Abstract Within the field of otolaryngology, the inner ear is perhaps the most important target for which stem cell and gene therapy may comprise elements of primary intervention strategies in the future. As it has done in the past, sensorineural hearing loss still represents a major therapeutic challenge-and it will continue to do so in the future. Current management strategies are not cause-orientated. Since the first experiments aimed at developing a middle ear-specific gene-based therapy by Fujiyoshi in 1994, several new discoveries have been made. In the laboratory, advances in the fields of genetics, molecular signalling, stem cell biology and hair cell development and regeneration have been made. Through these advances, the potential roll of cellular and intracellular tools for the future treatment of hearing loss has been recognized. This paper comprises a review of the current status of important areas of research. PMID: 24549508 [PubMed - indexed for MEDLINE]
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Related Articles Efferent feedback slows cochlear aging. J Neurosci. 2014 Mar 26;34(13):4599-607 Authors: Liberman MC, Liberman LD, Maison SF Abstract The inner ear receives two types of efferent feedback from the brainstem: one pathway provides gain control on outer hair cells' contribution to cochlear amplification, and the other modulates the excitability of the cochlear nerve. Although efferent feedback can protect hair cells from acoustic injury and thereby minimize noise-induced permanent threshold shifts, most prior studies focused on high-intensity exposures (>100 dB SPL). Here, we show that efferents are essential for long-term maintenance of cochlear function in mice aged 1 year post-de-efferentation without purposeful acoustic overexposure. Cochlear de-efferentation was achieved by surgical lesion of efferent pathways in the brainstem and was assessed by quantitative analysis of immunostained efferent terminals in outer and inner hair cell areas. The resultant loss of efferent feedback accelerated the age-related amplitude reduction in cochlear neural responses, as seen in auditory brainstem responses, and increased the loss of synapses between hair cells and the terminals of cochlear nerve fibers, as seen in confocal analysis of the organ of Corti immunostained for presynaptic and postsynaptic markers. This type of neuropathy, also seen after moderate noise exposure, has been termed "hidden hearing loss", because it does not affect thresholds, but can be seen in the suprathreshold amplitudes of cochlear neural responses, and likely causes problems with hearing in a noisy environment, a classic symptom of age-related hearing loss in humans. Since efferent reflex strength varies among individuals and can be measured noninvasively, a weak reflex may be an important risk factor, and prognostic indicator, for age-related hearing impairment. PMID: 24672005 [PubMed - indexed for MEDLINE]
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Related Articles Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. Am J Health Syst Pharm. 2014 May 1;71(9):711-6 Authors: Dee B, Lombardi Thomas L, Gulbis A Abstract PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. PMID: 24733133 [PubMed - indexed for MEDLINE]
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Related Articles Rapamycin alleviates cisplatin-induced ototoxicity in vivo. Biochem Biophys Res Commun. 2014 Jun 13;448(4):443-7 Authors: Fang B, Xiao H Abstract BACKGROUND: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity. METHODS: Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intraperitoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialdehyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule-associated protein light chain 3 (LC3) and Beclin-1. RESULTS: The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression. CONCLUSION: Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy. PMID: 24796670 [PubMed - indexed for MEDLINE]
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Related Articles Sound strategies for hearing restoration. Science. 2014 May 9;344(6184):1241062 Authors: Géléoc GS, Holt JR Abstract Hearing loss is the most common sensory deficit in humans, with some estimates suggesting up to 300 million affected individuals worldwide. Both environmental and genetic factors contribute to hearing loss and can cause death of sensory cells and neurons. Because these cells do not regenerate, the damage tends to accumulate, leading to profound deafness. Several biological strategies to restore auditory function are currently under investigation. Owing to the success of cochlear implants, which offer partial recovery of auditory function for some profoundly deaf patients, potential biological therapies must extend hearing restoration to include greater auditory acuity and larger patient populations. Here, we review the latest gene, stem-cell, and molecular strategies for restoring auditory function in animal models and the prospects for translating these approaches into viable clinical therapies. PMID: 24812404 [PubMed - indexed for MEDLINE]
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Related Articles Exogenous IL-4-expressing bone marrow mesenchymal stem cells for the treatment of autoimmune sensorineural hearing loss in a guinea pig model. Biomed Res Int. 2014;2014:856019 Authors: Tan CQ, Gao X, Guo L, Huang H Abstract Bone marrow mesenchymal stem cells (BMSCs) expressing recombinant IL-4 have the potential to remediate inflammatory diseases. We thus investigated whether BMSCs expressing exogenous IL-4 could alleviate autoimmune sensorineural hearing loss. BMSCs isolated from guinea pigs were transfected with recombinant lentivirus expressing IL-4. A total of 33 animals were divided into three groups. Group A received scala tympani injection of IL-4-expressing BMSCs, and Group B received control vector-expressing BMSCs, and Group C received phosphate-buffered saline. The distribution of implanted BMSCs in the inner ears was assessed by immunohistochemistry and fluorescence microscopy. Auditory brain-stem response (ABR) was monitored to evaluate the auditory changes. Following BMSCs transplantation, the threshold levels of ABR wave III decreased in Groups A and B and significant differences were observed between these two groups (P < 0.05). Transplanted BMSCs distributed in the scala tympani and scala vestibuli. In some ears with hearing loss, there was a decrease in the number of spiral ganglion cells and varying degrees of endolymphatic hydrops or floccule. Following transplantation, the lentivirus-infected BMSCs migrated to the inner ear and produced IL-4. Our results demonstrate that, upon transplantation, BMSCs and BMSCs expressing recombinant IL-4 have the ability to remediate the inflammatory injury in autoimmune inner ear diseases. PMID: 24864261 [PubMed - in process]
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Related Articles Cisplatin exposure damages resident stem cells of the mammalian inner ear. Dev Dyn. 2014 Oct;243(10):1328-37 Authors: Slattery EL, Oshima K, Heller S, Warchol ME Abstract BACKGROUND: Cisplatin is a widely used chemotherapeutic agent that can also cause ototoxic injury. One potential treatment for cisplatin-induced hearing loss involves the activation of endogenous inner ear stem cells, which may then produce replacement hair cells. In this series of experiments, we examined the effects of cisplatin exposure on both hair cells and resident stem cells of the mouse inner ear. RESULTS: Treatment for 24 hr with 10 µM cisplatin caused significant loss of hair cells in the mouse utricle, but such damage was not evident until 4 days after the cisplatin exposure. In addition to killing hair cells, cisplatin treatment also disrupted the actin cytoskeleton in remaining supporting cells, and led to increased histone H2AX phosphorylation within the sensory epithelia. Finally, treatment with 10 µM cisplatin appeared to have direct toxic effects on resident stem cells in the mouse utricle. Exposure to cisplatin blocked the proliferation of isolated stem cells and prevented sphere formation when those cells were maintained in suspension culture. CONCLUSION: The results suggest that inner ear stem cells may be injured during cisplatin ototoxicity, thus limiting their ability to mediate sensory repair. PMID: 24888499 [PubMed - in process]
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Related Articles Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus-frequency, and transiently evoked otoacoustic emissions. J Neurosci. 2014 Jul 30;34(31):10325-38 Authors: Cheatham MA, Goodyear RJ, Homma K, Legan PK, Korchagina J, Naskar S, Siegel JH, Dallos P, Zheng J, Richardson GP Abstract α-Tectorin (TECTA), β-tectorin (TECTB), and carcinoembryonic antigen-related cell adhesion molecule 16 (CEACAM) are secreted glycoproteins that are present in the tectorial membrane (TM), an extracellular structure overlying the hearing organ of the inner ear, the organ of Corti. Previous studies have shown that TECTA and TECTB are both required for formation of the striated-sheet matrix within which collagen fibrils of the TM are imbedded and that CEACAM16 interacts with TECTA. To learn more about the structural and functional significance of CEACAM16, we created a Ceacam16-null mutant mouse. In the absence of CEACAM16, TECTB levels are reduced, a clearly defined striated-sheet matrix does not develop, and Hensen's stripe, a prominent feature in the basal two-thirds of the TM in WT mice, is absent. CEACAM16 is also shown to interact with TECTB, indicating that it may stabilize interactions between TECTA and TECTB. Although brain-stem evoked responses and distortion product otoacoustic emissions are, for most frequencies, normal in young mice lacking CEACAM16, stimulus-frequency and transiently evoked emissions are larger. We also observed spontaneous otoacoustic emissions (SOAEs) in 70% of the homozygous mice. This incidence is remarkable considering that <3% of WT controls have SOAEs. The predominance of SOAEs >15 kHz correlates with the loss of Hensen's stripe. Results from mice lacking CEACAM16 are consistent with the idea that the organ of Corti evolved to maximize the gain of the cochlear amplifier while preventing large oscillations. Changes in TM structure appear to influence the balance between energy generation and dissipation such that the system becomes unstable. PMID: 25080593 [PubMed - indexed for MEDLINE]
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Related Articles Inner ear stem cells derived feeder layer promote directional differentiation of amniotic fluid stem cells into functional neurons. Hear Res. 2014 Oct;316:57-64 Authors: Zong L, Chen K, Zhou W, Jiang D, Sun L, Zhang X, Jiang H Abstract Intact spiral ganglion neurons are required for cochlear implantation or conventional hearing amplification as an intervention for sensorineural hearing loss. Treatment strategies to replace the loss of spiral ganglion neurons are needed. Recent reports have suggested that amniotic fluid-derived stem cells are capable of differentiating into neuron-like cells in response to cytokines and are not tumorigenic. Amniotic fluid stem cells represent a potential resource for cellular therapy of neural deafness due to spiral ganglion pathology. However, the directional differentiation of amniotic fluid stem cells is undetermined in the absence of cytokines and the consequence of inner ear supporting cells from the mouse cochlea organ of Corti on the differentiation of amniotic fluid stem cells remains to be defined. In an effort to circumvent these limitations, we investigated the effect of inner ear stem cells derived feeder layer on amniotic fluid stem cells differentiation in vitro. An inner ear stem cells derived feeder layer direct contact system was established to induce differentiation of amniotic fluid stem cells. Our results showed that inner ear stem cells derived feeder layer successfully promoted directional differentiation of amniotic fluid stem cells into neurons with characteristics of functionality. Furthermore, we showed that Wnt signaling may play an essential role in triggering neurogenesis. These findings indicate the potential use of inner ear stem cells derived feeder layer as a nerve-regenerative scaffold. A reliable and effective amniotic fluid stem cell differentiation support structure provided by inner ear stem cells derived feeder layer should contribute to efforts to translate cell-based strategies to the clinic. PMID: 25124154 [PubMed - in process]
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Related Articles Inner ear hair cell regeneration: A look from the past to the future. Neural Regen Res. 2013 Aug 25;8(24):2284-9 Authors: Santaolalla F, Salvador C, Martínez A, Sánchez JM, Del Rey AS Abstract Most recent studies on regeneration of inner ear hair cells focus on use of stem cells, gene therapy and neurotrophic factors. Cochlear gene therapy has been successfully used in the treatment of neurosensory hearing loss. This suggests that cochlear hair cell regeneration is possible. The objective of this paper is to review research and clinical application of inner near hair cell regeneration. PMID: 25206538 [PubMed]
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Related Articles Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett. 2014 Nov 7;583:65-9 Authors: Oishi N, Kendall A, Schacht J Abstract Metformin (N,N-dimethylbiguanidine) is a widely employed oral hypoglycemic agent for the management of type 2 diabetes mellitus. Its antioxidant properties and safe clinical use raise the possibility of preventing gentamicin-induced hearing loss in patients. Therefore, we screened the usefulness of metformin against gentamicin toxicity in murine cochlear explants and in the guinea pig in vivo. We confirmed in organ culture that metformin blocks the gentamicin-induced translocation of endonuclease G into the nucleus of outer hair cells and attenuates hair cell loss. In vivo, gentamicin treatment with 80, 100, or 130mg/kg body weight for 14 days induced significant threshold shifts as determined by auditory brain stem responses. Metformin (30, 75, or 100mg/kg for 14 days) was well tolerated without any indication of auditory side effects. However, co-administration of metformin with gentamicin in various permutations did not prevent loss of auditory function. On the contrary, combined treatment at higher dosages aggravated the gentamicin-induced threshold shifts and caused additional adverse reactions including body weight loss and premature deaths in some animals. These results caution against the use of metformin co-treatment with aminoglycosides and confirm the need for in vivo studies in order to evaluate potentially protective agents selected by in vitro screens. PMID: 25240593 [PubMed - in process]
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Related Articles JAK2/STAT3 inhibition attenuates noise-induced hearing loss. PLoS One. 2014;9(9):e108276 Authors: Wilson T, Omelchenko I, Foster S, Zhang Y, Shi X, Nuttall AL Abstract Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress-mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity. PMID: 25275304 [PubMed - in process]
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Related Articles Strategies for developing novel therapeutics for sensorineural hearing loss. Front Pharmacol. 2014;5:206 Authors: Nakagawa T Abstract Sensorineural hearing loss (SNHL) is a common disability in the world; however, at present, options for the pharmacological treatment of SNHL are very limited. Previous studies involving human temporal bone analyses have revealed that the degeneration of the cochlea is a common mechanism of SNHL. A major problem for the development of novel pharmacotherapy for SNHL has been the limited regeneration capacity in mammalian cochlear cells. However, recent progress in basic studies has led to several effective strategies for the induction of regeneration in the mammalian cochlea, in accordance with the stage of degeneration. In addition, recent advances in the identification of human deafness genes and their characterization in mouse models have elucidated cellular and/or molecular mechanisms of SNHL, which will contribute to clarify molecular targets of pharmacotherapy for treatment of SNHL. PMID: 25278894 [PubMed]
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Related Articles Effect of erythropoietin on acoustically traumatized rat cochlea: an immunohistochemical study. Anal Quant Cytopathol Histpathol. 2014 Aug;36(4):213-21 Authors: Gürgen O, Gürgen SG, Kirkim G, Kolatan E, Gürkan S, Güvenç Y, Eskiizmir G Abstract OBJECTIVE: To investigate the audiological and histopathological effects of erythropoietin on acoustic overstimulation in rats. STUDY DESIGN: Twenty-two male Wistar albino rats were divided into 3 groups: sham group (n = 7), erythropoietin injection group (n = 8), and saline injection group (n = 7). Both erythropoietin and saline injection groups were exposed to white noise (100 decibel [dB] sound pressure level [SPL]) for 3 hours. Auditory brainstem responses were measured before, immediately after, and on the 7th day of noise exposure. All animals were sacrificed on the 7th day and temporal bones were collected. The serial sections of the cochleae were stained by caspase-3 and caspase-9 immunostaining and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method in order to detect apoptotic cells. RESULTS: In the saline group statistically significant differences were detected between the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli. However, when the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli were compared in the erythropoietin injection group, no statistically significant difference was determined. Histopathologic evaluations demonstrated that erythropoietin decreased the amount of apoptotic cells in the cochlea. CONCLUSION: Erythropoietin is likely to prevent the acute threshold changes and decrease the amount of apoptosis in cochlea after acoustic overstimulation in rats. PMID: 25291859 [PubMed - indexed for MEDLINE]
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Related Articles Application of insulin-like growth factor-1 in the treatment of inner ear disorders. Front Pharmacol. 2014;5:208 Authors: Yamamoto N, Nakagawa T, Ito J Abstract Sensorineural hearing loss (SNHL) is considered an intractable disease, given that hair and supporting cells (HCs and SCs) of the postnatal mammalian cochlea are unable to regenerate. However, with progress in regenerative medicine in the 21st century, several innovative approaches for achieving regeneration of inner ear HCs and SCs have become available. These methods include stem cell transplantation, overexpression of specific genes, and treatment with growth factors. Insulin-like growth factor-1 (IGF-1) is one of the growth factors that are involved in the development of the inner ear. Treatment with IGF-1 maintains HC numbers in the postnatal mammalian cochlea after various types of HC injuries, with activation of two major pathways downstream of IGF-1 signaling. In the aminoglycoside-treated neonatal mouse cochlear explant culture, promotion of the cell-cycle in SCs as well as inhibition of HC apoptosis was observed in the IGF-1-treated group. Activation of downstream molecules was observed in SCs and, in turn, SCs contribute to the maintenance of HC numbers. Using comprehensive analysis of the gene expression, the candidate effector molecules of the IGF-1 signaling pathway in the protection of HCs were identified as Netrin1 and Gap43. Based on these studies, a clinical trial has sought to investigate the effects of IGF-1 on SNHL. Sudden SNHL (SSHL) that was refractory to systemic steroids was treated with IGF-1 in a gelatin hydrogel and the outcome was compared with a historical control of hyperbaric oxygen therapy. The proportion of patients showing hearing improvement was significantly higher in the IGF-1-treatment group at 24 weeks after treatment than in the control group. A randomized clinical trial is ongoing to compare the effect of IGF-1 treatment with that of intra-tympanic steroids for SSHL that is refractory to systemic steroids. PMID: 25309440 [PubMed]
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Related Articles Mucopolysaccharidosis type II, Hunter's syndrome. Pediatr Endocrinol Rev. 2014 Sep;12 Suppl 1:107-13 Authors: Tylki-Szymańska A Abstract Hunter syndrome is caused by deficiency of the lysososmal enzyme iduronate-2-sulphatase that cleaves O-linked sulphate moieties from dermatan sulphate and heparan sulphate and leads to accumulation of GAGs. The disease is a X-linked condition affecting males and rarely females, clinically divided into severe (2/3) and attenuated types. Children with severe form, diagnosed at 12-36 months, have coarse facial feature, short stature, joint stiffness, short neck, broad chest, large head circumference, watery diarrhea, skeletal changes, progressive and profound mental retardation, retinal degeneration' hearing loss, cardiomyopathy, valvular involvement, with progressive thickening and stiffening of the valve leaflets leading to mitral and aortic regurgitation and stenosis . Recurrent and prolonged rhinitis with persistent nasal discharge are the first symptoms of airway disease that manifests itself as noisy breathing and later sleep apnea. Some patients develop ivory-colored skin lesions on the upper back and sides of the upper arms, pathogenomic of Hunter syndrome. The scalp hair becomes coarse, straight and bristly. Inguinal and umbilical hernias occur caused by the disturbed structure of connective tissue and increased liver and spleen volume. Patients with attenuated form have normal intelligence and a milder phenotype. Physical features diagnosed later are similar but less pronounced but progress to severe disease. Sceening is by quantitative assessment of urinary GAGs excretion. Qualitative assessment of GAG by electrophoresis can distinguish the type of mucopolysaccharidosis. Definitive diagnosis is based on enzyme activity assay in leukocytes, fibroblasts or plasma. Molecular testing is recommended mainly for genetic counseling and carrier detection. Limited experience of Haematopoietic stem cell therapy in MPS II showed progressive neurodegeneration. Recombinant 125 Idursulfase, is indicated for long-term treatment. The response appears to depend on the severity of the disease and the age treatment is started, Improvements in a composite endpoint comprising: change in walking distance percentage of predicted forced vital capacity (%FVC) ,decrease in liver and spleen volume and urinary GAG levels were encouraging. Current research is focused on pharmacological chaperones, gene therapy and substrate reduction therapy and therapies that, unlike Idursulfase, do cross the blood-brain barrier. PMID: 25345092 [PubMed - indexed for MEDLINE]
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Related Articles Alpha-mannosidosis - a review of genetic, clinical findings and options of treatment. Pediatr Endocrinol Rev. 2014 Sep;12 Suppl 1:185-91 Authors: Borgwardt L, Lund AM, Dali CI Abstract Alpha-mannosidosis (OMIM 248500) is a rare, autosomal recessive, multisystemic, progressive lysosomal storage disorder caused by a deficiency of alpha-mannosidase. It has been described in humans, cattle, domestic cats, mice and guinea pigs. In humans, alpha-mannosidosis results in progressive facial- and skeletal abnormalities, motor impairment, hearing impairment, intellectual disability, recurrent infections and immune deficiency. This review provides detailed information regarding the variability of manifestations and a description of current treatment and treatment under investigation for alpha-mannosidosis. The pathology, genetics and clinical pictures, including impairments in the activity of daily living are discussed. PMID: 25345101 [PubMed - indexed for MEDLINE]
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Related Articles Grafting and early expression of growth factors from adipose-derived stem cells transplanted into the cochlea, in a Guinea pig model of acoustic trauma. Front Cell Neurosci. 2014;8:334 Authors: Fetoni AR, Lattanzi W, Eramo SL, Barba M, Paciello F, Moriconi C, Rolesi R, Michetti F, Troiani D, Paludetti G Abstract Noise exposure causes damage of multiple cochlear cell types producing permanent hearing loss with important social consequences. In mammals, no regeneration of either damaged hair cells or auditory neurons has been observed and no successful treatment is available to achieve a functional recovery. Loads of evidence indicate adipose-derived stem cells (ASCs) as promising tools in diversified regenerative medicine applications, due to the high degree of plasticity and trophic features. This study was aimed at identifying the path of in vivo cell migration and expression of trophic growth factors, upon ASCs transplantation into the cochlea, following noise-induced injury. ASCs were isolated in primary culture from the adipose tissue of a guinea pig, transduced using a viral vector to express the green fluorescent protein, and implanted into the scala tympani of deafened animals. Auditory function was assessed 3 and 7 days after surgery. The expression of trophic growth factors was comparatively analyzed using real-time PCR in control and noise-injured cochlear tissues. Immunofluorescence was used to assess the in vivo localization and expression of trophic growth factors in ASCs and cochleae, 3 and 7 days following homologous implantation. ASC implantation did not modify auditory function. ASCs migrated from the perilymphatic to the endolymphatic compartment, during the analyzed time course. Upon noise exposure, the expression of chemokine ligands and receptors related to the PDGF, VEGF, and TGFbeta pathways, increased in the cochlear tissues, possibly guiding in vivo cell migration. Immunofluorescence confirmed the increased expression, which appeared to be further strengthened by ASCs' implantation. These results indicated that ASCs are able to migrate at the site of tissue damage and express trophic factors, upon intracochlear implantation, providing an original proof of principle, which could pave the way for further developments of ASC-based treatments of deafness. PMID: 25368551 [PubMed]
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Related Articles Treating hearing disorders with cell and gene therapy. J Neural Eng. 2014 Nov 24;11(6):065001 Authors: Gillespie LN, Richardson RT, Nayagam BA, Wise AK Abstract Hearing loss is an increasing problem for a substantial number of people and, with an aging population, the incidence and severity of hearing loss will become more significant over time. There are very few therapies currently available to treat hearing loss, and so the development of new therapeutic strategies for hearing impaired individuals is of paramount importance to address this unmet clinical need. Most forms of hearing loss are progressive in nature and therefore an opportunity exists to develop novel therapeutic approaches to slow or halt hearing loss progression, or even repair or replace lost hearing function. Numerous emerging technologies have potential as therapeutic options. This paper details the potential of cell- and gene-based therapies to provide therapeutic agents to protect sensory and neural cells from various insults known to cause hearing loss; explores the potential of replacing lost sensory and nerve cells using gene and stem cell therapy; and describes the considerations for clinical translation and the challenges that need to be overcome. PMID: 25420002 [PubMed - as supplied by publisher]
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Related Articles Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts. Front Cell Neurosci. 2014;8:382 Authors: He Y, Cai C, Tang D, Sun S, Li H Abstract In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21(Cip1) and p27(Kip1) expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID: 25431550 [PubMed]
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Related Articles Perspectives for the treatment of sensorineural hearing loss by cellular regeneration of the inner ear. Acta Otorrinolaringol Esp. 2014 Nov 20; Authors: Almeida-Branco MS, Cabrera S, Lopez-Escamez JA Abstract Sensorineural hearing loss is a caused by the loss of the cochlear hair cells with the consequent deafferentation of spiral ganglion neurons. Humans do not show endogenous cellular regeneration in the inner ear and there is no exogenous therapy that allows the replacement of the damaged hair cells. Currently, treatment is based on the use of hearing aids and cochlear implants that present different outcomes, some difficulties in auditory discrimination and a limited useful life. More advanced technology is hindered by the functional capacity of the remaining spiral ganglion neurons. The latest advances with stem cell therapy and cellular reprogramming have developed several possibilities to induce endogenous regeneration or stem cell transplantation to replace damaged inner ear hair cells and restore hearing function. With further knowledge of the cellular and molecular biology of the inner ear and its embryonic development, it will be possible to use induced stem cells as in vitro models of disease and as replacement cellular therapy. Investigation in this area is focused on generating cellular therapy with clinical use for the treatment of profound sensorineural hearing loss. PMID: 25459416 [PubMed - as supplied by publisher]
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