Stem Cell Treatment for Hearing Loss is Available at ASCI

Related Articles Anti-epileptic drugs delay age-related loss of spiral ganglion neurons via T-type calcium channel. Hear Res. 2011 Aug;278(1-2):106-12 Authors: Lei D, Gao X, Perez P, Ohlemiller KK, Chen CC, Campbell KP, Hood AY, Bao J Abstract Loss of spiral ganglion neurons is a major cause of age-related hearing loss (presbycusis). Despite being the third most prevalent condition afflicting elderly persons, there are no known medications to prevent presbycusis. Because calcium signaling has long been implicated in age-related neuronal death, we investigated T-type calcium channels. This family is comprised of three members (Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3), based on their respective main pore-forming alpha subunits: α1G, α1H, and α1I. In the present study, we report a significant delay of age-related loss of cochlear function and preservation of spiral ganglion neurons in α1H null and heterozygous mice, clearly demonstrating an important role for Ca(v)3.2 in age-related neuronal loss. Furthermore, we show that anticonvulsant drugs from a family of T-type calcium channel blockers can significantly preserve spiral ganglion neurons during aging. To our knowledge, this is the first report of drugs capable of diminishing age-related loss of spiral ganglion neurons. PMID: 21640179 [PubMed - indexed for MEDLINE]

Related Articles Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. J Neurosci. 2011 Jun 15;31(24):8883-93 Authors: Rocha-Sanchez SM, Scheetz LR, Contreras M, Weston MD, Korte M, McGee J, Walsh EJ Abstract Adult mammalian auditory hair cells (HCs) and their associated supporting cells (SCs) do not proliferate, and HC death leads to irreversible neurosensory hearing loss and balance impairment. In nonmammalian vertebrates, loss of HCs induces mitotic proliferation of adjacent nonsensory SCs and/or direct SC transdifferentiation to generate replacement cells. This results in the structural and functional recovery of the nonmammalian sensory systems. Potential replacement of mammalian auditory HCs, either by transplanting cells or by transforming existing cells through molecular therapy, has long been proposed. However, HC replacement strategies with clear therapeutic potential remain elusive. The retinoblastoma (pRB) family of cell cycle regulators, Rb1, Rbl1 (p107), and Rbl2 (p130), regulate the G(1)- to S-phase transition in proliferating cells. In the inner ear, the biochemical and molecular pathways involving pRBs, particularly p107 and p130, are relatively unexplored and their therapeutic suitability is yet to be determined. In this study, we analyzed the cochleae of adult p130 knock-out (p130(-/-)) mice and showed that lack of the p130 gene results in extra rows of HCs and SCs in the more apical regions of the cochlea. No evidence of transdifferentiation of these supernumerary SCs into HCs was observed in the p130(-/-) mouse. Nevertheless, unscheduled proliferation of SCs in the adult p130(-/-) cochlea coupled to downregulation of bona fide cell cycle inhibitors provides a mechanistic basis for the role of p130 as a regulator of SC and HC mitotic quiescence in the more apical regions of the cochlea. Interestingly, p130(-/-) mice exhibited nearly normal peripheral auditory sensitivity. PMID: 21677172 [PubMed - indexed for MEDLINE]

Related Articles Therapeutic efficacy of topical application of dexamethasone to the round window niche after acoustic trauma caused by intensive impulse noise in guinea pigs. J Laryngol Otol. 2011 Jul;125(7):673-85 Authors: Chi FL, Yang MQ, Zhou YD, Wang B Abstract OBJECTIVE: To assess the therapeutic efficacy of dexamethasone administered topically to the round window niche, following acoustic trauma induced by intensive impulse noise, in guinea pigs. METHODS: Adult, male, albino guinea pigs with a normal Preyer's reflex were exposed to 80 impulse noises (peak value 167 dB, duration 0.5 ms, interval 2 s). Dexamethasone (40 mg/ml) or saline was then topically applied to the round window niche. Each animal's auditory brainstem response was measured before and one day after exposure, and three weeks after topical treatment. Cochlear morphology was examined to assess hair cell loss and spiral ganglion cell damage. To assess oxidative activity, cochlear malondialdehyde and superoxide dismutase concentrations were determined three weeks post-treatment. Following topical application, the pharmacokinetic characteristics of dexamethasone in cochlear perilymph were analysed using high-performance liquid chromatography. RESULTS: Animals receiving dexamethasone showed reduced noise-induced outer hair cell loss (three weeks post-treatment), and significant attenuation of noise-induced auditory brainstem response threshold shifts (one day post-exposure and three weeks post-treatment), compared with controls. There was no difference in spiral ganglion morphology. Animals receiving dexamethasone also showed a significantly lower malondialdehyde concentration and a higher superoxide dismutase concentration, post-exposure. Following topical application, the perilymph dexamethasone level peaked at 5330.522 µg/ml (15 minutes post-treatment), and was 299.797 µg/ml 360 minutes later. CONCLUSION: Topical application of dexamethasone to the round window niche has protective effects against intensive impulse noise induced trauma in the guinea pig cochlea. This drug can diffuse into the inner ear through the round window membrane and persist in the perilymph for a relatively long period. The mechanism of protection may involve an anti-oxidant effect. PMID: 21693072 [PubMed - indexed for MEDLINE]

Related Articles Up-regulation of cochlear Hes1 expression in response to noise exposure. Acta Neurobiol Exp (Wars). 2011;71(2):256-62 Authors: Wang B, Liu Y, Zhu X, Chi F, Zhang Y, Yang M Abstract Hes1, a hairy and enhancer of split homolog, negatively regulates inner ear hair cell differentiation. The main objective of this study was to investigate the status of the Hes1 gene in the noise-damaged cochlea in relation to the degree of noise-induced hearing loss (NIHL). Adult albino guinea pigs were exposed to white-band noise (115 dB sound pressure level). Noise exposure for either 1 or 3 hours induced significant elevations of threshold in auditory brainstem response (ABR) compared with unexposed controls. Succinate dehydrogenase staining showed that white-band noise exposure caused significant outer hair cell losses. In addition, we found significant up-regulations of cochlear Hes1 mRNA and protein expressions following acoustic trauma, and Hes1 mRNA expression was positively correlated with NIHL. These findings suggest that up-regulation of Hes1 expression in response to noise exposure may be one of the underlying mechanisms of NIHL. PMID: 21734729 [PubMed - indexed for MEDLINE]

Related Articles Effects of delayed and extended antioxidant treatment on acute acoustic trauma. Free Radic Res. 2011 Oct;45(10):1162-72 Authors: Choi CH, Chen K, Du X, Floyd RA, Kopke RD Abstract OBJECTIVE: Hair cell death caused by acute acoustic trauma (AAT) reaches a secondary maximum at 7-10 days after noise exposure due to a second oxidative stress. Therefore, this study tested the effects of a combination of hydroxylated alpha-phenyl-tert-butylnitrone (4-OHPBN), N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine (ALCAR) on AAT when the duration of treatment was extended over the period of 7-10 days after noise exposure as well as when the initial treatment was delayed 24 to 48 h after noise exposure. METHODS: Thirty chinchilla were exposed to a 105 dB octave-band noise centred at 4 kHz for 6 h and received the following treatments: (1) noise + saline (2-5) 4-OHPBN (20 mg/kg) + NAC (50 mg/kg) + ALCAR (20 mg/kg) intraperitoneally injected beginning 24 or 48 h after noise exposure twice daily for the next 2, 8 or 9 days. Auditory brainstem response (ABR) threshold shifts, outer hair cell (OHC) counts and organ of Corti immunohistochemistry were analyzed. RESULTS: The combination administration decreased ABR threshold shifts, inhibited OHC loss and reduced 4-hydroxynonenal (4-HNE) immunostaining. Significant decreases in the threshold shifts and reduction in OHC loss were observed with a shorter delay before starting treatment (24 h) and longer duration (9 days) treatment. CONCLUSIONS: These results demonstrate that the administration of antioxidant drugs extended up to 10 days after noise exposure can effectively treat AAT in a chinchilla model. This may provide significant and potentially clinically important information about the effective therapeutic window for AAT treatment. PMID: 21756051 [PubMed - indexed for MEDLINE]

Related Articles Spiral ganglion neuron survival and function in the deafened cochlea following chronic neurotrophic treatment. Hear Res. 2011 Dec;282(1-2):303-13 Authors: Landry TG, Wise AK, Fallon JB, Shepherd RK Abstract Cochlear implants electrically stimulate residual spiral ganglion neurons (SGNs) to provide auditory cues for the severe-profoundly deaf. However, SGNs gradually degenerate following cochlear hair cell loss, leaving fewer neurons available for stimulation. Providing an exogenous supply of neurotrophins (NTs) has been shown to prevent SGN degeneration, and when combined with chronic intracochlear electrical stimulation (ES) following a short period of deafness (5 days), may also promote the formation of new neurons. The present study assessed the histopathological response of guinea pig cochleae treated with NTs (brain-derived neurotrophic factor and neurotrophin-3) with and without ES over a four week period, initiated two weeks after deafening. Results were compared to both NT alone and artificial perilymph (AP) treated animals. AP/ES treated animals exhibited no evidence of SGN rescue compared with untreated deafened controls. In contrast, NT administration showed a significant SGN rescue effect in the lower and middle cochlear turns (two-way ANOVA, p 

Related Articles Spontaneous reversibility of damage to outer hair cells after sodium salicylate induced ototoxicity. J Laryngol Otol. 2011 Aug;125(8):786-94 Authors: de Almeida-Silva I, de Oliveira JA, Rossato M, Salata FF, Hyppolito MA Abstract BACKGROUND: High sodium salicylate doses can cause reversible hearing loss and tinnitus, possibly due to reduced outer hair cell electromotility. Sodium salicylate is known to alter outer hair cell structure and function. This study determined the reversibility and cochlear recovery time after administration of an ototoxic sodium salicylate dose to guinea pigs with normal cochlear function. STUDY DESIGN: Prospective experimental investigation. METHODS: All animals received a single 500 mg sodium salicylate dose, but with different durations of action. Function was evaluated before drug administration and immediately before sacrifice. Cochleae were processed and viewed using scanning electron microscopy. RESULTS: Changes in outer hair cell function were observed to be present 2 hours after drug administration, with recovery of normal anatomy beginning after 24 hours. Subsequently, derangement and distortion of cilia reduced, with effects predominantly in row three. At 168 hours, cilia were near-normal but with mild distortions which interfered with normal cochlear physiology. CONCLUSIONS: Ciliary changes persisted for up to 168 hours after ototoxic sodium salicylate administration. PMID: 21781353 [PubMed - indexed for MEDLINE]

Related Articles Neuroendocrine adenoma of the middle ear (NAME) mimicking as chronic otitis media with an episode of facial nerve palsy. B-ENT. 2011;7(2):121-5 Authors: Tomazic PV, Beham A, Lackner A, Ropposch T, Stockreiter U, Walch C Abstract OBJECTIVES: To increase awareness of neuroendocrine adenomas of the middle ear (NAME), rare lesions often mistaken for other entities or chronic otitis media. Histogenesis remains controversial, although the consensus tends toward a pluripotent stem cell of the middle ear mucosa as the origin of the lesion. The tumour is characterised by dual differentiation with exocrine and endocrine components. The most common symptoms are conductive hearing loss, tinnitus and vertigo. The treatment of choice is complete surgical removal of the tumour with no adjuvant radiotherapy being required. CASE REPORT: We report the case of a 23-year-old man presenting with chronic otitis media, conductive hearing loss, vertigo and tinnitus who, some years previously, had suffered from an episode of facial nerve palsy. Conservative therapy failed and so surgery was performed. Tumour-like masses were encountered and histological and immunohistochemical examination revealed a neuroendocrine adenoma of the middle ear. CONCLUSION: This rare entity should be considered as differential diagnosis when treating chronic inflammatory disease not responding to conservative therapy or dealing with unclear expansive processes of the middle ear. MRI scans should be performed since CT scans are inconclusive. PMID: 21838097 [PubMed - indexed for MEDLINE]

Related Articles Adenosine kinase inhibition in the cochlea delays the onset of age-related hearing loss. Exp Gerontol. 2011 Nov;46(11):905-14 Authors: Vlajkovic SM, Guo CX, Telang R, Wong AC, Paramananthasivam V, Boison D, Housley GD, Thorne PR Abstract This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A(1) receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea. PMID: 21846498 [PubMed - indexed for MEDLINE]

Related Articles Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome. Hear Res. 2011 Dec;282(1-2):184-95 Authors: Hurd EA, Adams ME, Layman WS, Swiderski DL, Beyer LA, Halsey KE, Benson JM, Gong TW, Dolan DF, Raphael Y, Martin DM Abstract Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7(Gt)(/+) mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7(Gt)(/+) mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7(Gt)(/+) mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7(Gt)(/+) mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears. PMID: 21875659 [PubMed - indexed for MEDLINE]

Related Articles Combining cell-based therapies and neural prostheses to promote neural survival. Neurotherapeutics. 2011 Oct;8(4):774-87 Authors: Wise AK, Fallon JB, Neil AJ, Pettingill LN, Geaney MS, Skinner SJ, Shepherd RK Abstract Cochlear implants provide partial restoration of hearing for profoundly deaf patients by electrically stimulating spiral ganglion neurons (SGNs); however, these neurons gradually degenerate following the onset of deafness. Although the exogenous application of neurotrophins (NTs) can prevent SGN loss, current techniques to administer NTs for long periods of time have limited clinical applicability. We have used encapsulated choroid plexus cells (NTCells; Living Cell Technologies, Auckland, New Zealand) to provide NTs in a clinically viable manner that can be combined with a cochlear implant. Neonatal cats were deafened and unilaterally implanted with NTCells and a cochlear implant. Animals received chronic electrical stimulation (ES) alone, NTs alone, or combined NTs and ES (ES + NT) for a period of as much as 8 months. The opposite ear served as a deafened unimplanted control. Chronic ES alone did not result in increased survival of SGNs or their peripheral processes. NT treatment alone resulted in greater SGN survival restricted to the upper basal cochlear region and an increased density of SGN peripheral processes. Importantly, chronic ES in combination with NTs provided significant SGN survival throughout a wider extent of the cochlea, in addition to an increased peripheral process density. Re-sprouting peripheral processes were observed in the scala media and scala tympani, raising the possibility of direct contact between peripheral processes and a cochlear implant electrode array. We conclude that cell-based therapy is clinically viable and effective in promoting SGN survival for extended durations of cochlear implant use. These findings have important implications for the safe delivery of therapeutic drugs to the cochlea. PMID: 21904788 [PubMed - indexed for MEDLINE]

Related Articles Detection of intracochlear damage with cochlear implantation in a gerbil model of hearing loss. Otol Neurotol. 2011 Oct;32(8):1370-8 Authors: Choudhury B, Adunka OF, Demason CE, Ahmad FI, Buchman CA, Fitzpatrick DC Abstract HYPOTHESIS: Cochlear trauma due to electrode insertion can be detected in acoustic responses to low frequencies in an animal model with a hearing condition similar to patients using electroacoustic stimulation. BACKGROUND: Clinical evidence suggests that intracochlear damage during cochlear implantation negatively affects residual hearing. Recently, we demonstrated the usefulness of acoustically evoked potentials to detect cochlear trauma in normal-hearing gerbils. Here, gerbils with noise-induced hearing loss were used to investigate the effects of remote trauma on residual hearing. METHODS: Gerbils underwent high-pass (4-kHz cutoff) noise exposure to produce sloping hearing loss. After 1 month of recovery, each animal's hearing loss was determined from auditory brainstem responses and baseline intracochlear recording of the cochlear microphonic and compound action potential (CAP) obtained at the round window. Subsequently, electrode insertions were performed to produce basal trauma, whereas the acoustically generated potentials to a 1-kHz tone-burst were recorded after each step of electrode advancement. Hair cell counts were made to characterize the noise damage, and cochlear whole mounts were used to identify cochlear trauma due to the electrode. RESULTS: The noise exposure paradigm produced a pattern of hair cell, auditory brainstem response, and intracochlear potential losses that closely mimicked that of electrical and acoustic stimulation patients. Trauma in the basal turn, in the 15- to 30-kHz portion of the deafened region, remote from preserved hair cells, induced a decline in intracochlear acoustic responses to the hearing preserved frequency of 1 kHz. CONCLUSION: The results indicate that a recording algorithm based on physiological markers to low-frequency acoustic stimuli can identify cochlear trauma during implantation. Future work will focus on translating these results for use with current cochlear implant technology in humans. PMID: 21921858 [PubMed - indexed for MEDLINE]

Related Articles D-methionine (D-met) significantly rescues noise-induced hearing loss: timing studies. Hear Res. 2011 Dec;282(1-2):138-44 Authors: Campbell K, Claussen A, Meech R, Verhulst S, Fox D, Hughes L Abstract We have previously reported rescue from noise-induced auditory brainstem response (ABR) threshold shifts with d-methionine (d-met) administration 1 h after noise exposure. The present study investigated further d-met rescue intervals at 3, 5 and 7 h post-noise exposure. Chinchillas laniger were exposed to a 6 h 105 dB sound pressure level (dB SPL) octave band noise (OBN) and then administered d-met i.p. starting 3, 5, or 7 h after noise exposure; controls received saline i.p. immediately after noise exposure. ABR assessments were performed at baseline and on post-exposure days 1 and 21. Outer hair cell (OHC) loss was measured in cochleae obtained at sacrifice 21 days post-exposure. Administration of d-met starting at any of the delay times of 3-7 h post-noise exposure significantly reduced day 21 ABR threshold shift at 2 and 4 kHz and OHC loss at all hair cell regions measured (2, 4, 6 and 8 kHz). ABR threshold shifts in the control group at 6 and 8 kHz were only 8 and 11 dB respectively allowing little opportunity to observe protection at those 2 frequencies. PMID: 21924333 [PubMed - indexed for MEDLINE]

Related Articles Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene. J Med Genet. 2011 Oct;48(10):682-90 Authors: Yan X, Wang X, Wang Z, Sun S, Chen G, He Y, Mo JQ, Li R, Jiang P, Lin Q, Sun M, Li W, Bai Y, Zhang J, Zhu Y, Lu J, Yan Q, Li H, Guan MX Abstract The authors report here the clinical, genetic, molecular and biochemical characterisation of a large five-generation Han Chinese pedigree with maternally transmitted non-syndromic hearing loss. 17 of 35 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average age at onset of hearing loss in matrilineal relatives of this family is 29 years, while matrilineal relatives among families carrying other mitochondrial DNA mutations developed hearing loss with congenital conditions or early age at onset. Molecular analysis of their mitochondrial genome identified the novel heteroplasmic T12201C mutation in the transfer RNA (tRNA)(His) gene. The levels of T12201C mutation in matrilineal relatives of this family correlated with the severity and age at onset of non-syndromic hearing loss. By contrast, other heteroplasmic mitochondrial DNA mutations often cause syndromic hearing loss. The T12201C mutation destabilises a highly conservative base-pairing (5A-68U) on the acceptor stem of tRNA(His). tRNA northern analysis revealed that the T12201C mutation caused an ∼75% reduction in the steady-state level of tRNA(His). An in vivo protein labeling analysis showed an ∼47% reduction in the rate of mitochondrial translation in cells carrying the T12201C mutation. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration or N,N,Ń,Ń-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration. These data provide the first direct evidence that mitochondrial dysfunctions caused by the heteroplasmic tRNA(His) mutation lead to late-onset non-syndromic deafness. Thus, the authors' findings provide new insights into the understanding of pathophysiology and valuable information on the management and treatment of maternally inherited hearing loss. PMID: 21931169 [PubMed - indexed for MEDLINE]

Related Articles The convergence of cochlear implantation with induced pluripotent stem cell therapy. Stem Cell Rev. 2012 Sep;8(3):741-54 Authors: Gunewardene N, Dottori M, Nayagam BA Abstract According to 2010 estimates from The National Institute on Deafness and other Communication Disorders, approximately 17% (36 million) American adults have reported some degree of hearing loss. Currently, the only clinical treatment available for those with severe-to-profound hearing loss is a cochlear implant, which is designed to electrically stimulate the auditory nerve in the absence of hair cells. Whilst the cochlear implant has been revolutionary in terms of providing hearing to the severe-to-profoundly deaf, there are variations in cochlear implant performance which may be related to the degree of degeneration of auditory neurons following hearing loss. Hence, numerous experimental studies have focused on enhancing the efficacy of cochlear implants by using neurotrophins to preserve the auditory neurons, and more recently, attempting to replace these dying cells with new neurons derived from stem cells. As a result, several groups are now investigating the potential for both embryonic and adult stem cells to replace the degenerating sensory elements in the deaf cochlea. Recent advances in our knowledge of stem cells and the development of induced pluripotency by Takahashi and Yamanaka in 2006, have opened a new realm of science focused on the use of induced pluripotent stem (iPS) cells for therapeutic purposes. This review will provide a broad overview of the potential benefits and challenges of using iPS cells in combination with a cochlear implant for the treatment of hearing loss, including differentiation of iPS cells into an auditory neural lineage and clinically relevant transplantation approaches. PMID: 21956409 [PubMed - indexed for MEDLINE]

Related Articles Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol. 2012 Jan;233(1):172-81 Authors: Jørgensen JR, Fransson A, Fjord-Larsen L, Thompson LH, Houchins JP, Andrade N, Torp M, Kalkkinen N, Andersson E, Lindvall O, Ulfendahl M, Brunak S, Johansen TE, Wahlberg LU Abstract Neurotrophic factors are secreted proteins responsible for migration, growth and survival of neurons during development, and for maintenance and plasticity of adult neurons. Here we present a novel secreted protein named Cometin which together with Meteorin defines a new evolutionary conserved protein family. During early mouse development, Cometin is found exclusively in the floor plate and from E13.5 also in dorsal root ganglions and inner ear but apparently not in the adult nervous system. In vitro, Cometin promotes neurite outgrowth from dorsal root ganglion cells which can be blocked by inhibition of the Janus or MEK kinases. In this assay, additive effects of Cometin and Meteorin are observed indicating separate receptors. Furthermore, Cometin supports migration of neuroblasts from subventricular zone explants to the same extend as stromal cell derived factor 1a. Given the neurotrophic properties in vitro, combined with the restricted inner ear expression during development, we further investigated Cometin in relation to deafness. In neomycin deafened guinea pigs, two weeks intracochlear infusion of recombinant Cometin supports spiral ganglion neuron survival and function. In contrast to the control group receiving artificial perilymph, Cometin treated animals retain normal electrically-evoked brainstem response which is maintained several weeks after treatment cessation. Neuroprotection is also evident from stereological analysis of the spiral ganglion. Altogether, these studies show that Cometin is a potent new neurotrophic factor with therapeutic potential. PMID: 21985865 [PubMed - indexed for MEDLINE]

Related Articles Is intratympanic injection of erdosteine protective against cisplatin-induced ototoxicity? Neurotox Res. 2012 Apr;21(3):302-8 Authors: Saliba I, El Fata F Abstract Cisplatin induces ototoxicity in adult and pediatric population. Our aim was (1) to assess the protective effect of intratympanic injections of erdosteine in the prevention of cisplatin-induced ototoxicity and (2) to investigate inner ear protection using a scanning electron microscope. Ears of 20 Hartley guinea pigs were assigned to four subgroups and received an intratympanic injection of: E1-erdosteine 1.125 mg/cc, NS-normal saline, E2-erdosteine 2.25 mg/cc and E4-erdosteine 4.5 mg/cc. After 45 min, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated 8 times, once a week to achieve 24 mg/kg. Auditory brainstem responses were recorded before any injection and after 24 mg/kg of cisplatin for the frequencies 1, 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Average hearing loss in the NS subgroup was 29.8 dB which was lower than E1, E2 and E4 subgroups (40, 43.9, and 51.7 dB, respectively). Difference in the mean threshold increase was statistically significant between NS and the three erdosteine subgroups (P  0.05). However, difference was significant between E1 and E4 (P 

Related Articles Sensory epithelial cells acquire features of prosensory cells via epithelial to mesenchymal transition. Stem Cells Dev. 2012 Jul 1;21(10):1812-21 Authors: Zhang L, Hu Z Abstract Epithelial to mesenchymal transition (EMT) plays a critical role during normal development and in adult tissue repair. It is known that immortalized epithelial cells can undergo an EMT and become cancer stem cells, and that epithelial cells from mouse pancreatic islet and avian inner ear can acquire mesenchymal traits in vitro via EMT. However, it is unclear whether epithelial cells from mammalian sensory system can undergo an EMT and obtain features of stem/progenitor cells. In this study, we used mouse utricle sensory epithelial cells (MUCs) as a mammalian cell model to address this issue. When cultured on 2-dimensional substrates, dissociated MUCs gradually lost their columnar shape and started to expand on the substrate with downregulation of expression of epithelial junction markers and upregulation of genes and proteins that are widely shown in mesenchymal cells. Moreover, MUCs expressed genes and proteins that are usually presented in prosensory epithelial cells and stem cells. These MUCs showed potential to differentiate into epithelial cells via a reverse EMT when they were forced to suspend in culture medium. Our findings reveal that sensory epithelial cells from mammalian tissue can undergo an EMT to become cells expressing features of stem cells that can be induced to become epithelial cells via a reverse EMT. The outcomes of this study may provide a novel approach to generate epithelial progenitors for use in cell replacement therapy to treat a number of human diseases, such as hearing loss and vision loss. PMID: 22014028 [PubMed - indexed for MEDLINE]

Related Articles Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. J Transl Med. 2011;9:181 Authors: Ra JC, Kang SK, Shin IS, Park HG, Joo SA, Kim JG, Kang BC, Lee YS, Nakama K, Piao M, Sohl B, Kurtz A Abstract Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that ex-vivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here. PMID: 22017805 [PubMed - indexed for MEDLINE]

Related Articles Piezoelectric materials mimic the function of the cochlear sensory epithelium. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18390-5 Authors: Inaoka T, Shintaku H, Nakagawa T, Kawano S, Ogita H, Sakamoto T, Hamanishi S, Wada H, Ito J Abstract Cochlear hair cells convert sound vibration into electrical potential, and loss of these cells diminishes auditory function. In response to mechanical stimuli, piezoelectric materials generate electricity, suggesting that they could be used in place of hair cells to create an artificial cochlear epithelium. Here, we report that a piezoelectric membrane generated electrical potentials in response to sound stimuli that were able to induce auditory brainstem responses in deafened guinea pigs, indicating its capacity to mimic basilar membrane function. In addition, sound stimuli were transmitted through the external auditory canal to a piezoelectric membrane implanted in the cochlea, inducing it to vibrate. The application of sound to the middle ear ossicle induced voltage output from the implanted piezoelectric membrane. These findings establish the fundamental principles for the development of hearing devices using piezoelectric materials, although there are many problems to be overcome before practical application. PMID: 22025702 [PubMed - indexed for MEDLINE]

Related Articles Protective role of hydrogen sulfide against noise-induced cochlear damage: a chronic intracochlear infusion model. PLoS One. 2011;6(10):e26728 Authors: Li X, Mao XB, Hei RY, Zhang ZB, Wen LT, Zhang PZ, Qiu JH, Qiao L Abstract BACKGROUND: A reduction in cochlear blood flow plays an essential role in noise-induced hearing loss (NIHL). The timely regulation of cochlear perfusion determines the progression and prognosis of NIHL. Hydrogen sulfide (H(2)S) has attracted increasing interest as a vasodilator in cardiovascular systems. This study identified the role of H(2)S in cochlear blood flow regulation and noise protection. METHODOLOGY/PRINCIPAL FINDINGS: The gene and protein expression of the H(2)S synthetase cystathionine-γ-lyase (CSE) in the rat cochlea was examined using immunofluorescence and real-time PCR. Cochlear CSE mRNA levels varied according to the duration of noise exposure. A chronic intracochlear infusion model was built and artificial perilymph (AP), NaHS or DL-propargylglycine (PPG) were locally administered. Local sodium hydrosulfide (NaHS) significantly increased cochlear perfusion post-noise exposure. Cochlear morphological damage and hearing loss were alleviated in the NaHS group as measured by conventional auditory brainstem response (ABR), cochlear scanning electron microscope (SEM) and outer hair cell (OHC) count. The highest percentage of OHC loss occurred in the PPG group. CONCLUSIONS/SIGNIFICANCE: Our results suggest that H(2)S plays an important role in the regulation of cochlear blood flow and the protection against noise. Further studies may identify a new preventive and therapeutic perspective on NIHL and other blood supply-related inner ear diseases. PMID: 22046339 [PubMed - indexed for MEDLINE]

Related Articles Inhalation of hydrogen gas attenuates cisplatin-induced ototoxicity via reducing oxidative stress. Int J Pediatr Otorhinolaryngol. 2012 Jan;76(1):111-5 Authors: Qu J, Li X, Wang J, Mi W, Xie K, Qiu J Abstract OBJECTIVE: Cisplatin, an anticancer drug used extensively to treat a broad range of tumors, has strong ototoxic side effects induced by reactive oxygen species (ROS). Recently, it has been reported that hydrogen gas (H(2)) is a new antioxidant by selectively reducing hydroxyl radical, the most cytotoxic ROS. The present study was designed to investigate whether H(2) treatment is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress. METHODS: The animals were intraperitoneally given a 30 min infusion of 16 mg/kg cisplatin or the same volume of saline. H(2) treatment was given twice with 2% H(2) inhalation for 60 min starting at 1h and 6h after cisplatin or saline injection, respectively. The hearing status of all animals was evaluated by auditory brainstem responses (ABR). The hair cell damage was observed by phalloidin staining. In addition, the levels of oxidative products in serum and cochlear tissue were measured. RESULTS: We found that H(2) treatment significantly attenuated cisplatin-induced hearing loss evaluated by click-evoked and tone burst ABR threshold. Furthermore, histological analysis revealed that 2% H(2) treatment significantly alleviated cisplatin-induced hair cell damage in the organ of corti. In addition, cisplatin significantly increased the levels of malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α) in serum and cochlear tissue, which was attenuated by H(2) treatment. CONCLUSION: These results demonstrate that H(2) is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress. Therefore, H(2) has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the cisplatin ototoxicity. PMID: 22055279 [PubMed - indexed for MEDLINE]

Related Articles Acoustic over-exposure triggers burst firing in dorsal cochlear nucleus fusiform cells. Hear Res. 2012 Jan;283(1-2):98-106 Authors: Pilati N, Large C, Forsythe ID, Hamann M Abstract Acoustic over-exposure (AOE) triggers deafness in animals and humans and provokes auditory nerve degeneration. Weeks after exposure there is an increase in the cellular excitability within the dorsal cochlear nucleus (DCN) and this is considered as a possible neural correlate of tinnitus. The origin of this DCN hyperactivity phenomenon is still unknown but it is associated with neurons lying within the fusiform cell layer. Here we investigated changes of excitability within identified fusiform cells following AOE. Wistar rats were exposed to a loud (110 dB SPL) single tone (14.8 kHz) for 4 h. Auditory brainstem response recordings performed 3-4 days after AOE showed that the hearing thresholds were significantly elevated by about 20-30 dB SPL for frequencies above 15 kHz. Control fusiform cells fired with a regular firing pattern as assessed by the coefficient of variation of the inter-spike interval distribution of 0.19 ± 0.11 (n = 5). Three to four days after AOE, 40% of fusiform cells exhibited irregular bursting discharge patterns (coefficient of variation of the inter-spike interval distribution of 1.8 ± 0.6, n = 5; p 

Related Articles Brain-derived neurotrophic factor modulates auditory function in the hearing cochlea. J Assoc Res Otolaryngol. 2012 Feb;13(1):1-16 Authors: Sly DJ, Hampson AJ, Minter RL, Heffer LF, Li J, Millard RE, Winata L, Niasari A, O'Leary SJ Abstract Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and click-evoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation. PMID: 22086147 [PubMed - indexed for MEDLINE]

Related Articles Protection against ischemic cochlear damage by intratympanic administration of AM-111. Otol Neurotol. 2011 Dec;32(9):1422-7 Authors: Omotehara Y, Hakuba N, Hato N, Okada M, Gyo K Abstract OBJECTIVE: AM-111, a cell-permeable peptide inhibitor of c-Jun N-terminal kinase, was investigated for its protective effects against ischemic damage of the cochlea in gerbils. METHODS: Transient cochlear ischemia was introduced in animals by occluding the bilateral vertebral arteries for l5 minutes. Then, 10 μl of AM-111 at a concentration of l, 10, or 100 μM in hyaluronic acid gel formulation was applied onto the round window 30 minutes after the insult. Gel without active substance was used in a control group. Treatment effects were evaluated by auditory brainstem response (ABR) and histology of the inner ear. RESULTS: In controls, transient cochlear ischemia caused a 25.0 ± 5.0 dB increase in the ABR threshold at 8 kHz and a decrease of 13.3 ± 2.3% in inner hair cells at the basal turn on Day 7. Ischemic damage was mild at 2 and 4 kHz. When the animals were treated with AM-111 at 100 μM, cochlear damage was significantly reduced: the increase in ABR threshold was 3.3 ± 2.4 dB at 8 kHz, and the inner hair cell loss was 3.1 ± 0.6% at the basal turn on Day 7. The effects of AM-111 were concentration dependent: 100 μM was more effective than 1 or 10 μM. CONCLUSION: Direct application of AM-111 in gel formulation on the round window was effective in preventing acute hearing loss because of transient cochlear ischemia. PMID: 22089955 [PubMed - indexed for MEDLINE]

Related Articles Concise review: Inner ear stem cells--an oxymoron, but why? Stem Cells. 2012 Jan;30(1):69-74 Authors: Ronaghi M, Nasr M, Heller S Abstract Hearing loss, caused by irreversible loss of cochlear sensory hair cells, affects millions of patients worldwide. In this concise review, we examine the conundrum of inner ear stem cells, which obviously are present in the inner ear sensory epithelia of nonmammalian vertebrates, giving these ears the ability to functionally recover even from repetitive ototoxic insults. Despite the inability of the mammalian inner ear to regenerate lost hair cells, there is evidence for cells with regenerative capacity because stem cells can be isolated from vestibular sensory epithelia and from the neonatal cochlea. Challenges and recent progress toward identification of the intrinsic and extrinsic signaling pathways that could be used to re-establish stemness in the mammalian organ of Corti are discussed. PMID: 22102534 [PubMed - indexed for MEDLINE]

Related Articles Assessment of the ototoxicity of almond oil in a chinchilla animal model. Laryngoscope. 2011 Dec;121(12):2661-4 Authors: Peleva E, Mourad S, Citra D, Daniel SJ Abstract OBJECTIVES/HYPOTHESIS: Almond oil is frequently prescribed as a ceruminolytic, to soften ear wax or relieve ventilation tube occlusion. Ceruminolytics could lead to ototoxicity in the presence of a tympanic perforation. Reports on the safety of almond oil as a ceruminolytic is limited. The present study aimed to assess the effect of ototopic almond oil on hearing. STUDY DESIGN: Prospective, randomized, controlled trial in a chinchilla animal model. METHODS: Bilateral myringotomies were performed in 19 female chinchilla. One randomly selected ear received almond oil, whereas the other ear received saline applied transtympanically. Auditory Brainstem Response (ABR) testing was performed prior to application and at 14 and 30 days following application. Postmortem Scanning Electron Microscopy (SEM) images were obtained to assess cochlear hair cell status. RESULTS: At 30 days following application, there was no significant change in ABR thresholds at 16, 20, or 25 kHz. No cochlear hair cell loss was observed with SEM. CONCLUSIONS: In the chinchilla, when a tympanic perforation is present, almond oil does not seem to cause ototoxicity. Further studies are needed to better assess the effect of almond oil on hearing in humans. PMID: 22109768 [PubMed - indexed for MEDLINE]

Related Articles Nestin-expressing cells in the developing, mature and noise-exposed cochlear epithelium. Mol Cell Neurosci. 2012 Feb;49(2):104-9 Authors: Watanabe R, Morell MH, Miller JM, Kanicki AC, O'Shea KS, Altschuler RA, Raphael Y Abstract The auditory sensory epithelium in non-mammalian vertebrates can replace lost hair cells by transdifferentiation of supporting cells, but this regenerative ability is lost in the mammalian cochlea. Future cell-based treatment of hearing loss may depend on stem cell transplantation or on transdifferentiation of endogenous cells in the cochlea. For both approaches, identification of cells with stem cell features within the mature cochlea may be useful. Here we use a Nestin-β-gal mouse to examine the presence of Nestin positive cells in the mature auditory epithelium, and determine how overstimulation of the ear impacts these cells. Nestin positive cells were found in the apical turn of the cochlea lateral to the outer hair cell area. This pattern of expression persisted into mature age. The area of Nestin positive cells was increased after the noise lesion. This increase in area coincided with an increase in expression of the Nestin mRNA. The data suggest that cells with potential stem cell features remain in the mature mammalian cochlea, restricted to the apical turn, and that an additional set of signals is necessary to trigger their contribution to cell replacement therapy in the ear. As such, this population of cells could serve to generate cochlear stem cells for research and potential therapy, and may be a target for treatments based on induced transdifferentiation of endogenous cochlear cells. PMID: 22122823 [PubMed - indexed for MEDLINE]

Related Articles Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice. Hear Res. 2012 Jan;283(1-2):80-8 Authors: Kane KL, Longo-Guess CM, Gagnon LH, Ding D, Salvi RJ, Johnson KR Abstract Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23(Ahl)(+) and CBACa.B6-Cdh23(ahl) and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23(Ahl)(+), and the CBACa.B6-Cdh23(ahl) strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23(Ahl)(+) allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23(ahl) allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23(ahl) homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice. PMID: 22138310 [PubMed - indexed for MEDLINE]

Related Articles The effect of resveratrol on the prevention of cisplatin ototoxicity. Eur Arch Otorhinolaryngol. 2012 Oct;269(10):2185-8 Authors: Erdem T, Bayindir T, Filiz A, Iraz M, Selimoglu E Abstract One of the most important adverse effects of cisplatin, a chemotherapeutic agent which is widely used in the treatment of cancer patients, is hearing loss. This has primarily been associated with the loss of inner ear hairy and spiral ganglion cells due to oxidative stress. Resveratrol is known to be an antioxidant agent, which has the theoretical potential of preventing cisplatin-related ototoxicity. This experimental study was approved by Animal Ethics Committee of Inonu University (2008-20) and supported by Inonu University Scientific Research Projects Support Fund (2009-17). Thirty-four 3-month-old Wistar albino female rats weighing 210-270 g were used in the study. The animals were allocated into four groups: in cisplatin group (Group A), a single dose of 12 mg/kg cisplatin was administered intraperitoneally to 10 rats; in cisplatin + resveratrol group (Group B), a single dose of 12 mg/kg cisplatin and 10 mg/kg resveratrol were administered intraperitoneally for 5 days to 10 rats; in resveratrol group (Group C), 10 mg/kg resveratrol was administered intraperitoneally for 5 days to seven rats and in control group (Group D), resveratrol solvent (5% alcohol-95% physiological saline) was administered intraperitoneally for 5 days to seven rats. Resveratrol administration has begun 1 day before cisplatin administration in the group treated with cisplatin and resveratrol combination. Distortion product otoacoustic emission (DPOAE) (Grason Stadler, Madison, USA) measurements were performed in the same ear of all rats (right ear) under general anesthesia at baseline, 1st and 5th days after drug administration. Statistically significant distortion product amplitude reductions were found in the cisplatin group at 1,418, 2,003, 3,363, 5,660, 8,003 and 9,515 Hz frequencies. Whereas in the cisplatin + resveratrol group, statistically significant difference was found between 1st and 5th day measurements only at 3,996 Hz frequency. No significant differences were noted between the measurements either in the resveratrol or in the control groups. According to these results, cisplatin-related ototoxicity has been greatly prevented by resveratrol use. PMID: 22186767 [PubMed - indexed for MEDLINE]

Related Articles Role of PGE-type receptor 4 in auditory function and noise-induced hearing loss in mice. Neuropharmacology. 2012 Mar;62(4):1841-7 Authors: Hamaguchi K, Yamamoto N, Nakagawa T, Furuyashiki T, Narumiya S, Ito J Abstract This study explored the physiological roles of PGE-type receptor 4 (EP4) in auditory function. EP4-deficient mice exhibited slight hearing loss and a reduction of distortion-product otoacoustic emissions (DPOAEs) with loss of outer hair cells (OHCs) in cochleae. After exposure to intense noise, these mice showed significantly larger threshold shifts of auditory brain-stem responses (ABRs) and greater reductions of DPOAEs than wild-type mice. A significant increase of OHC loss was confirmed morphologically in the cochleae of EP4-deficient mice. Pharmacological inhibition of EP4 had a similar effect to genetic deletion, causing loss of both hearing and OHCs in C57BL/6 mice, indicating a critical role for EP4 signaling in the maintenance of auditory function. Pharmacological activation of EP4 significantly protected OHCs against noise trauma, and attenuated noise-induced hearing loss in C57BL/6 mice. These findings suggest that EP4 signaling is necessary for the maintenance of cochlear physiological function and for cochlear protection against noise-induced damage, in particular OHCs. EP4 might therefore be an effective target for cochlear disease therapeutics. PMID: 22198478 [PubMed - indexed for MEDLINE]

Related Articles Neural crest stem cells and their potential application in a therapy for deafness. Front Biosci (Schol Ed). 2012;4:121-32 Authors: Huisman MA, Rivolta MN Abstract Neurosensory hearing loss is a common condition that has major social and economic implications. Recent advances in stem cell research and in cochlear implantation are offering renewed hopes to people suffering from damage to the auditory hair cells and their associated neurons. Several putative donor cell types are currently being explored, including embryonic stem cells, different types of adult stem cell and the recently described induced-pluripotent stem cells. In this review, we draw attention to the potential application of neural crest stem cells for the treatment of deafness. This population shares a similar developmental origin with the cells of the otic placode, the molecular machinery controlling their maturation and differentiation is comparable and they can produce related sensory neurons. More importantly, pockets of neural crest stem cells remain in the adult body in regions of relatively easy access, facilitating their use for autologous transplantation and therefore avoiding the need for immunosuppression and the problems of tissue rejection. Their exploration and application to hearing conditions could facilitate the development of a clinically-viable, cell-based. PMID: 22202047 [PubMed - in process]

Related Articles A new oral otoprotective agent. Part 1: Electrophysiology data from protection against noise-induced hearing loss. Med Sci Monit. 2012 Jan;18(1):BR1-8 Authors: Cascella V, Giordano P, Hatzopoulos S, Petruccelli J, Prosser S, Simoni E, Astolfi L, Fetoni AR, Skarżyński H, Martini A Abstract BACKGROUND: Data from animal studies show that antioxidants can compensate against noise-induced stress and sensory hair cell death. The aim of this study was to evaluate the otoprotection efficacy of various versions of orally administered Acuval 400 against noise damage in a rat animal model. MATERIAL/METHODS: Fifty-five Sprague Dawley rats were divided into 4 groups: A) noise-exposed animals; B) animals exposed to noise and treated with the Acuval; C) animals exposed to noise and treated with a combination of Coenzyme Q10 and Acuval; D) animals treated only with Acuval and Coenzyme Q10 and with no exposure to noise. All solutions were administered orally 5 times: 24 and 2 hrs prior to noise exposure, and then daily for 3 days. The auditory function was assessed by measuring auditory brainstem responses (ABR) in the range from 2 to 32 kHz at times =1, 7, 14 and 21 days after noise exposure. RESULTS: At low frequencies (click and 4 kHz) animals from both A and B groups showed significant threshold shifts in the majority of the tested frequencies and tested times. For the same frequencies, animals from group C presented threshold levels similar to those from group D. At frequencies ≥ 8 kHz the protective performance of the 2 Acuval groups is more clearly distinguished from the noise group A. At 32 kHz the 2 Acuval groups perform equally well in terms of otoprotection. Animals in Group D did not show any significant differences in the hearing threshold during the experiment. CONCLUSIONS: The data of this study suggest that a solution containing Coenzyme Q10 and Acuval 400, administered orally, protects from noise-induced hearing loss. PMID: 22207104 [PubMed - indexed for MEDLINE]

Related Articles Astragaloside IV inhibits apoptotic cell death in the guinea pig cochlea exposed to impulse noise. Acta Otolaryngol. 2012 May;132(5):467-74 Authors: Xiong M, He Q, Lai H, Wang J Abstract CONCLUSION: The results suggest that the beneficial effect of astragaloside IV on impulse noise-induced hearing loss may be due to its ability to inhibit reactive oxygen species (ROS) and prevent apoptosis. OBJECTIVE: Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of diseases in China for its antioxidant properties. ROS and apoptosis are involved in damage induced by impulse noise trauma. We aimed to investigate if the beneficial effects of astragaloside IV on cochlea exposed to impulse noise are associated with the inhibition of ROS and the decrease in apoptosis. METHODS: 4-Hydroxynonenal (HNE) was used as the marker of ROS. Active-caspase-3 (cas-3) served as a marker for apoptosis. 4HNE and cas-3 were determined immunohistochemically. Guinea pigs in the experimental group were administered astragaloside IV intragastrically. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) 72 h before and after exposure to impulse noise. RESULTS: The results showed that astragaloside IV significantly reduced ABR deficits, and decreased the expression of ROS and cas-3. PMID: 22217340 [PubMed - indexed for MEDLINE]

Related Articles Isolating LacZ-expressing cells from mouse inner ear tissues using flow cytometry. J Vis Exp. 2011;(58):e3432 Authors: Jan TA, Chai R, Sayyid ZN, Cheng AG Abstract Isolation of specific cell types allows one to analyze rare cell populations such as stem/progenitor cells. Such an approach to studying inner ear tissues presents a unique challenge because of the paucity of cells of interest and few transgenic reporter mouse models. Here, we describe a protocol using fluorescence-conjugated probes to selectively label LacZ-positive cells from the neonatal cochleae. The most common underlying pathology of sensorineural hearing loss is the irreversible damage and loss of cochlear sensory hair cells, which are required to transduce sound waves to neural impulses. Recent evidence suggests that the murine auditory and vestibular organs harbor stem/progenitor cells that may have regenerative potential. These findings warrant further investigation, including identifying specific cell types with stem/progenitor cell characteristics. The Wnt signaling pathway has been demonstrated to play a critical role in maintaining stem/progenitor cell populations in several organ systems. We have recently identified Wnt-responsive Axin2-expressing cells in the neonatal cochlea, but their function is largely unknown. To better understand the behavior of these Wnt-responsive cells in vitro, we have developed a method of isolating Axin2-expressing cells from cochleae of Axin2-LacZ reporter mice. Using flow cytometry to isolate Axin2-LacZ positive cells from the neonatal cochleae, we could in turn execute a variety of experiments on live cells to interrogate their behavior as stem/progenitor cells. Here, we describe in detail the steps for the microdissection of neonatal cochlea, dissociation of these tissues, labeling of the LacZ-positive cells using a fluorogenic substrate, and cell sorting. Techniques for dissociating cochleae into single cells and isolating cochlear cells via flow cytometry have been described. We have made modifications to these techniques to establish a novel protocol to isolate LacZ-expressing cells from the neonatal cochlea. PMID: 22217925 [PubMed - indexed for MEDLINE]

Related Articles [Inner ear cell therapy for hereditary deafness with multipotent stem cells]. Nihon Rinsho. 2011 Dec;69(12):2215-9 Authors: Kamiya K, Ikeda K Abstract Congenital deafness affects about 1 in 1000 children and the half of them have genetic background such as connexin26 gene mutation. The strategy to rescue such hereditary deafness has not been developed yet. Inner ear cell therapy for hereditary deafness has been studied using some laboratory animals and multipotent stem cells, although the successful reports for the hearing recovery accompanied with supplementation of the normal functional cells followed by tissue repair and recovery of the cellular/molecular functions have been still few. To succeed in hearing recovery by inner ear cell therapy, appropriate cell type, surgical approach and the stem cell homing system to the niche are thought to be required. PMID: 22242322 [PubMed - indexed for MEDLINE]

Related Articles Contralateral suppression of transient-evoked otoacoustic emissions in children with sickle cell disease. Ear Hear. 2012 May-Jun;33(3):421-9 Authors: Stuart A, Preast JL Abstract OBJECTIVES: In previous studies, otoacoustic emissions (OAEs) have been found to be larger in normal-hearing children with sickle cell disease (SCD). It was hypothesized that some dysfunction or reduction in the medial olivocochlear efferent suppression of outer hair cell activity was responsible for this phenomenon. To test this hypothesis, contralateral suppression of transient-evoked otoacoustic emissions (TEOAEs) was examined in children with and without SCD. DESIGN: Thirteen African American school-aged normal-hearing children with homozygous SCD and 13 age- and gender-matched control children participated. TEOAEs were obtained bilaterally with 80 dB peSPL nonlinear click stimuli. To examine contralateral suppression, TEOAEs were obtained with 60 dB peSPL linear click stimuli with and without a contralateral 65 dB SPL white noise suppressor. RESULTS: Overall and half-octave band TEOAE levels were found to be larger in children with SCD relative to the normal control children (p < 0.05), consistent with previous reports of increased OAE levels. There was no significant difference (p > 0.05) in the absolute or proportional amount of TEOAE suppression as a function of group and ear. There were also no significant correlations or linear predictive relationships between TEOAE suppression and TEOAE level for either ear or group (p > 0.05). CONCLUSIONS: These findings do not support the notion that increased OAE levels in children with SCD are a consequence of abnormal medial olivocochlear system function as assessed with contralateral suppression of TEOAEs. PMID: 22246207 [PubMed - indexed for MEDLINE]

Related Articles Protective role of resveratrol against cisplatin induced ototoxicity in guinea pigs. Int J Pediatr Otorhinolaryngol. 2012 Mar;76(3):404-8 Authors: Yumusakhuylu AC, Yazici M, Sari M, Binnetoglu A, Kosemihal E, Akdas F, Sirvanci S, Yuksel M, Uneri C, Tutkun A Abstract OBJECTIVE: The aim of this study was to evaluate the effectiveness of systemic administration of resveratrol against cisplatin-induced ototoxicity in guinea pigs. MATERIALS AND METHODS: Healthy guinea pigs (n=24) were randomly divided into four groups. Group 1 (n=6) received resveratrol+cisplatin, group 2 (n=6) received 4% ethanol+cisplatin, group 3 (n=6) received cisplatin, and group 4 (n=6) received saline. Cisplatin was administered at a dose of 10mg/kg/day on days 14 and 15 of the study. Resveratrol (10mg/kg/day), 4% ethanol, and saline were administered throughout the study. Baseline auditory brainstem responses (ABR) (4 kHz, 8 kHz, and click stimulus) were determined for all groups. ABR was repeated 72 h after the last dose of cisplatin in order to record the threshold shifts. The ABR threshold shifts for the click stimulus, 4-kHz- and 8-kHz-frequency stimuli were compared after drug administration. After follow-up ABRs the animals sacrificed under deep sedation and their cochleae were removed. Left cochleae were immediately harvested for measurement of level of reactive oxygen species (ROS). Right cochleae were prepared for histological changes which were observed by scanning electron microscopy (SEM). RESULTS: For the all stimulus, there was a significant threshold difference among the groups (p

Related Articles [Study on discrepant protein expression in rat auditory cortex under impulse noise exposure]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2011 Oct;46(10):839-43 Authors: Liao H, Yang K, Hua QQ, Yang SM, Gao YK Abstract OBJECTIVE: Impulse noise was adopted in adult rats to built acute deafferent animal model. Differential proteomics techniques were applied to detect the changes of protein expression in the auditory cortex before and after the noise exposure. METHODS: Thirty adult SD rats were divided into three groups: normal group, rats with acute noise exposure and rats 28 days recovery after noise exposure (n=10/group). All animals were exposed to impulse noise at 156 dB for 50 pulses with a rise-time of 100 µs and duration of around 0.25 ms. ABR was used to evaluate the auditory function. The two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS) were used to identified the differential protein expression. RESULTS: Compared with the normal group, ABR thresholds were found significantly increased at 2, 4, 8, 16, 32 kHz (P

Related Articles Matrix metalloproteinase inhibitor attenuates cochlear lateral wall damage induced by intratympanic instillation of endotoxin. Int J Pediatr Otorhinolaryngol. 2012 Apr;76(4):544-8 Authors: Choi CH, Jang CH, Cho YB, Jo SY, Kim MY, Park BY Abstract OBJECTIVE: Oxytetracycline and ilomastat are inhibitors of matrix metalloproteinases (MMPs). Their efficacy in protecting against cochlear damage induced by the intratympanic instillation of lipopolysaccharide (LPS), as a means of inducing labyrinthitis, was investigated. MATERIALS AND METHODS: Experiments were performed in 21 young male guinea pigs. Intratympanic instillation of LPS was done in the control group (n=7). Intratympanic instillation of oxytetracycline or ilomastat was done after LPS instillation in the experimental group. Measurements of auditory brainstem response (ABR) and cochlear blood flow (CBF) were performed. The organ of Corti was evaluated by field emission scanning electron microscopy (FE-SEM). The blood-labyrinth barrier (BLB) integrity was evaluated with Evans blue uptake. Gelatin zymography was used to assess the expression of active MMP-2 and MMP-9. RESULTS: Ears treated with MMP inhibitors were significantly protected from hearing loss compared to the LPS group. In LPS group, there was a significant decrease of CBF. However, experimental group displayed a statistically significant recovery of CBF. FE-SEM revealed hair cell damage in the LPS-treated group, but hair cells presented a normal appearance in MMP inhibitors. The LPS group showed a marked increase of Evans blue extravasation in the cochlea. However, MMP inhibitors significantly reduced the BLB opening. Active MMP-9 was expressed in the LPS group. Treatment with MMP inhibitors attenuated active MMP-9 expression. CONCLUSION: The MMP inhibitors oxytetracycline and ilomastat protect from cochlear lateral wall damage caused by LPS-induced labyrinthitis. PMID: 22326209 [PubMed - indexed for MEDLINE]

Related Articles Antioxidant treatment reduces blast-induced cochlear damage and hearing loss. Hear Res. 2012 Mar;285(1-2):29-39 Authors: Ewert DL, Lu J, Li W, Du X, Floyd R, Kopke R Abstract Exposure to blast overpressure has become one of the hazards of both military and civilian life in many parts of the world due to war and terrorist activity. Auditory damage is one of the primary sequela of blast trauma, affecting immediate situational awareness and causing permanent hearing loss. Protecting against blast exposure is limited by the inability to anticipate the timing of these exposures, particularly those caused by terrorists. Therefore a therapeutic regimen is desirable that is able to ameliorate auditory damage when administered after a blast exposure has occurred. The purpose of this study was to determine if administration of a combination of antioxidants 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) beginning 1 h after blast exposure could reduce both temporary and permanent hearing loss. To this end, a blast simulator was developed and the operational conditions established for exposing rats to blast overpressures comparable to those encountered in an open-field blast of 14 pounds per square inch (psi). This blast model produced reproducible blast overpressures that resulted in physiological and physical damage to the auditory system that was proportional to the number and amplitude of the blasts. After exposure to 3 consecutive 14 psi blasts 100% of anesthetized rats had permanent hearing loss as determined at 21 days post exposure by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Animals treated with HPN-07 and NAC after blast exposure showed a significant reduction in ABR threshold shifts and DPOAE level shifts at 2-16 kHz with significant reduction in inner hair cell (IHC) and outer hair cell (OHC) loss across the 5-36 kHz region of the cochlea compared with control animals. The time course of changes in the auditory system was documented at 3 h, 24 h, 7 day and 21 day after blast exposure. At 3 h after blast exposure the auditory brainstem response (ABR) threshold shifts were elevated by 60 dB in both treated and control groups. A partial recovery of to 35 dB was observed at 24 h in the controls, indicative of a temporary threshold shift (TTS) and there was essentially no further recovery by 21 days representing a permanent threshold shift (PTS) of about 30 dB. Antioxidant treatment increased the amount of both TTS and PTS recovery relative to controls by 10 and 20 dB respectively. Distortion product otoacoustic emission (DPOAE) reached a maximum level shift of 25-30 dB measured in both control and treated groups at 3 h after blast exposure. These levels did not change by day 21 in the control group but in the treatment group the level shifts began to decline at 24 h until by day 21 they were 10-20 dB below that of the controls. Loss of cochlear hair cells measured at 21 day after blast exposure was mostly in the outer hair cells (OHC) and broadly distributed across the basilar membrane, consistent with the distribution of loss of frequency responses as measured by ABR and DPOAE analysis and typical of blast-induced damage. OHC loss progressively increased after blast exposure reaching an average loss of 32% in the control group and 10% in the treated group at 21 days. These findings provide the first evidence that a combination of antioxidants, HPN-07 and NAC, can both enhance TTS recovery and prevent PTS by reducing damage to the mechanical and neural components of the auditory system when administered shortly after blast exposure. PMID: 22326291 [PubMed - indexed for MEDLINE]

Related Articles Pravastatin attenuates noise-induced cochlear injury in mice. Neuroscience. 2012 Apr 19;208:123-32 Authors: Park JS, Kim SW, Park K, Choung YH, Jou I, Park SM Abstract Noise-induced hearing loss (NIHL) is one of the most common forms of sensorineural hearing loss and a well-known contributor to presbycusis. Based on the generation of reactive oxygen species (ROS) in the pathogenesis of NIHL, augmentation of the antioxidative defense system is a major target for pharmacological prevention. In this study, we assessed whether administration of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of cholesterol synthesis, before noise exposure protects against cochlear injury in BALB/c mice. Noise exposure produced both compound threshold shift (CTS) and permanent threshold shift (PTS) over 40 dB at 16 and 32 kHz. Pretreatment with pravastatin (25 mg/kg) for 5 days significantly decreased both CTS and PTS. Pravastatin also reduced hair cell death after noise exposure in the cochlea, which was identified by surface preparation and scanning electron microscopy (SEM). It also reduced the formation of noise-induced 4-hydroxynonenal (4-HNE), a byproduct of lipid peroxidation. Activation of Rac1, one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which is a major superoxide generator in the cell membrane, was inhibited by the administration of pravastatin. These findings suggest that pravastatin can protect against cochlear acoustic injury by lowering ROS generation via inhibition of the formation of the NADPH oxidase complex. This study will be helpful for the development of new therapeutic strategies for NIHL and other hearing loss-related diseases caused by ROS overproduction. PMID: 22366511 [PubMed - indexed for MEDLINE]

Related Articles Hydrogen-rich saline alleviates experimental noise-induced hearing loss in guinea pigs. Neuroscience. 2012 May 3;209:47-53 Authors: Zhou Y, Zheng H, Ruan F, Chen X, Zheng G, Kang M, Zhang Q, Sun X Abstract OBJECTIVE: To examine the efficiency of hydrogen-rich saline in the treatment of intensive noise-induced cochlear injury. MATERIALS AND METHODS: Forty guinea pigs were assigned to one of four groups: HS+NOISE (i.p. injection hydrogen-rich saline), NS+NOISE (i.p. injection normal saline), NOISE ALONE (noise control), and NO TREATMENT (normal control) groups. The HS+NOISE, NS+NOISE, and NOISE ALONE groups were exposed to intensive noise (4 h at 115 dB SPL noise of 4000±100 Hz). The auditory brainstem response (ABR) was used to examine the hearing threshold in each group. Distortion product otoacoustic emission (DPOAE) was used to examine outer hair cell function. We also examined cochlear morphology to evaluate inner and outer hair cell trauma induced by noise exposure. Hydrogen-rich saline was administered twice daily for 6 days (2.5 ml/kg, i.p.) 24 h after noise exposure. RESULTS: Baseline ABR thresholds and DPOAE values were normal in all groups at the measured frequencies (2, 4, 8, and 16 kHz) before noise exposure. The ABR threshold shift was 50-55 dB across the frequencies tested, and average DPOAE declined in the NOISE ALONE, NS+NOISE, and HS+NOISE groups 24 h after noise exposure. However, the changes in cochlear parameters were different between groups. The HS+NOISE group showed a significantly decreased ABR threshold value as compared with the NS+NOISE or NOISE ALONE group (P

Related Articles Attitudes of the UK ear, nose and throat clinical community to the future potential use of stem cell therapies to treat deafness. Regen Med. 2012 Mar;7(2):179-86 Authors: Ali KH, Williams DJ, Jackson P, Pau HP Abstract AIMS: Hearing loss is commonly due to the degeneration and death of hair cells and their associated spiral ganglion neurons. A total of 250 million people are affected worldwide. Stem cell treatments offer new and powerful strategies to enable recovery from hearing loss. This study focuses on the translational process required to move stem cell therapy from the laboratory to clinical use as a novel treatment of deafness and an alternative to conventional therapy. In particular, this study aims to inform and enable the adoption process for such therapies, including understanding the awareness of and attitudes towards stem cell therapy for hearing loss among ear, nose and throat surgeons, physicians, audiologists and scientists, who are key stakeholders in the adoption process. METHODS: A structured questionnaire has been developed and applied to assess the knowledge and awareness of the clinical community with respect to the future potential use of stem cell therapies to treat deafness. RESULTS: Results showed >87% of the clinicians sampled have very little or no knowledge of stem cell therapy. A total of 11% have been asked by patients about the use of stem cell therapies to treat deafness, and 64% felt a new treatment is needed for deafness. Significantly, 40% felt that a stem cell therapy would be a good adjuvant to a cochlear implant. In total, 78% were supportive of investment in stem cell therapy research and manufacturing. This investment should be in work directed at those areas where clinicians favor adoption. CONCLUSION: Alignment is required between the scientific and clinical communities. This should not only take into account the likelihood of scientific success when pursuing the therapeutic alternatives, but should also consider the clinical trial requirements, regulatory landscape and reimbursement conditions for each option. PMID: 22397608 [PubMed - indexed for MEDLINE]

Related Articles Tracking the expression of excitatory and inhibitory neurotransmission-related proteins and neuroplasticity markers after noise induced hearing loss. PLoS One. 2012;7(3):e33272 Authors: Browne CJ, Morley JW, Parsons CH Abstract Excessive exposure to loud noise can damage the cochlea and create a hearing loss. These pathologies coincide with a range of CNS changes including reorganisation of frequency representation, alterations in the pattern of spontaneous activity and changed expression of excitatory and inhibitory neurotransmitters. Moreover, damage to the cochlea is often accompanied by acoustic disorders such as hyperacusis and tinnitus, suggesting that one or more of these neuronal changes may be involved in these disorders, although the mechanisms remain unknown. We tested the hypothesis that excessive noise exposure increases expression of markers of excitation and plasticity, and decreases expression of inhibitory markers over a 32-day recovery period. Adult rats (n = 25) were monaurally exposed to a loud noise (16 kHz, 1/10(th) octave band pass (115 dB SPL)) for 1-hour, or left as non-exposed controls (n = 5). Animals were euthanased at either 0, 4, 8, 16 or 32 days following acoustic trauma. We used Western Blots to quantify protein levels of GABA(A) receptor subunit α1 (GABA(A)α1), Glutamic-Acid Decarboxylase-67 (GAD-67), N-Methyl-D-Aspartate receptor subunit 2A (NR2A), Calbindin (Calb1) and Growth Associated Protein 43 (GAP-43) in the Auditory Cortex (AC), Inferior Colliculus (IC) and Dorsal Cochlear Nucleus (DCN). Compared to sham-exposed controls, noise-exposed animals had significantly (p

Related Articles Efficacy of different routes of administration for Coenzyme Q10 formulation in noise-induced hearing loss: systemic versus transtympanic modality. Acta Otolaryngol. 2012 Apr;132(4):391-9 Authors: Fetoni AR, Troiani D, Eramo SL, Rolesi R, Paludetti Troiani G Abstract CONCLUSION: The effectiveness of a coenzyme Q10 formulation, Q-ter, given via transtympanic injection is interesting for the future application of this minimally invasive procedure in the treatment of reactive oxygen species (ROS)-induced hearing loss. OBJECTIVE: We focused on antioxidant therapy in noise-induced hearing loss (NIHL). Our study was designed to evaluate the effectiveness of Q-ter for different schedules of drug administration to establish the best modality for treatment. METHODS: Rats were exposed to acoustic trauma (10 kHz at 120 dB for 60 min) and received Q-ter according to two modalities: systemic (Q-ter 100 mg/kg for 4 days 1 h before and 3 days post noise exposure) and transtympanic (Q-ter 20 and 40% concentration 1 h before noise exposure). Auditory brainstem response (ABR), immunohistochemical and morphological studies were performed. RESULTS: Q-ter administration significantly decreased NIHL at day 21 from noise exposure. The improvement of auditory function by Q-ter was paralleled by a significant reduction in oxidative stress. The transtympanic and systemic routes of drug administration showed a similar degree of protection. PMID: 22443854 [PubMed - indexed for MEDLINE]

Related Articles Stem cell therapy for the inner ear: recent advances and future directions. Trends Amplif. 2012 Mar;16(1):4-18 Authors: Okano T, Kelley MW Abstract In vertebrates, perception of sound, motion, and balance is mediated through mechanosensory hair cells located within the inner ear. In mammals, hair cells are only generated during a short period of embryonic development. As a result, loss of hair cells as a consequence of injury, disease, or genetic mutation, leads to permanent sensory deficits. At present, cochlear implantation is the only option for profound hearing loss. However, outcomes are still variable and even the best implant cannot provide the acuity of a biological ear. The recent emergence of stem cell technology has the potential to open new approaches for hair cell regeneration. The goal of this review is to summarize the current state of inner ear stem cell research from a viewpoint of its clinical application for inner ear disorders to illustrate how complementary studies have the potential to promote and refine stem cell therapies for inner ear diseases. The review initially discusses our current understanding of the genetic pathways that regulate hair cell formation from inner ear progenitors during normal development. Subsequent sections discuss the possible use of endogenous inner ear stem cells to induce repair as well as the initial studies aimed at transplanting stem cells into the ear. PMID: 22514095 [PubMed - indexed for MEDLINE]

Related Articles Functional interaction between mesenchymal stem cells and spiral ligament fibrocytes. J Neurosci Res. 2012 Sep;90(9):1713-22 Authors: Sun GW, Fujii M, Matsunaga T Abstract Spiral ligament fibrocytes (SLFs) play an important role in normal hearing as well as in several types of sensorineural hearing loss attributable to inner ear homeostasis disorders. Our previous study showed that transplantation of mesenchymal stem cells (MSCs) into the inner ear of rats with damaged SLFs significantly accelerates hearing recovery compared with rats without MSC transplantation. To elucidate this mechanism of SLF repair and to determine the contribution of transplanted MSCs in this model, we investigated the mutual effects on differentiation and proliferation between MSCs and SLFs in a coculture system. Factors secreted by SLFs had the ability to promote the transdifferentiation of MSCs into SLF-like cells, and the factors secreted by MSCs had a stimulatory effect on the proliferation of SLFs. Cytokine antibody array analysis revealed the involvement of transforming growth factor-β (TGF-β) in SLF proliferation induced by MSCs. In addition, a TGF-β inhibitor reduced SLF proliferation induced by MSC stimulation. Our results suggest that there are two mechanisms of hearing recovery following transplantation of MSCs into the inner ear: 1) MSCs transdifferentiate into SLF-like cells that compensate for lost SLFs, and 2) transplanted MSCs stimulate the regeneration of host SLFs. Both mechanisms contribute to the functional recovery of the damaged SLF network. PMID: 22535531 [PubMed - indexed for MEDLINE]

Related Articles Stemness of the organ of Corti relates to the epigenetic status of Sox2 enhancers. PLoS One. 2012;7(5):e36066 Authors: Waldhaus J, Cimerman J, Gohlke H, Ehrich M, Müller M, Löwenheim H Abstract In the adult mammalian auditory epithelium, the organ of Corti, loss of sensory hair cells results in permanent hearing loss. The underlying cause for the lack of regenerative response is the depletion of otic progenitors in the cell pool of the sensory epithelium. Here, we show that an increase in the sequence-specific methylation of the otic Sox2 enhancers NOP1 and NOP2 is correlated with a reduced self-renewal potential in vivo and in vitro; additionally, the degree of methylation of NOP1 and NOP2 is correlated with the dedifferentiation potential of postmitotic supporting cells into otic stem cells. Thus, the stemness the organ of Corti is related to the epigenetic status of the otic Sox2 enhancers. These observations validate the continued exploration of treatment strategies for dedifferentiating or reprogramming of differentiated supporting cells into progenitors to regenerate the damaged organ of Corti. PMID: 22570694 [PubMed - indexed for MEDLINE]

Related Articles Otologic safety of manuka honey. J Otolaryngol Head Neck Surg. 2012 Apr;41 Suppl 1:S21-30 Authors: Aron M, Victoria Akinpelu O, Dorion D, Daniel S Abstract OBJECTIVE: To investigate the possible ototoxic effects of a 50% concentration of manuka honey in a chinchilla animal model. STUDY DESIGN: A prospective, controlled animal study. SETTING: The Research Institute of the Montreal Children's Hospital, McGill University Health Centre. SUBJECTS AND METHODS: Eight animals had myringotomy incisions in both ears. One ear was randomly assigned to receive the 50% manuka honey solution. The contralateral ear received saline and served as the control ear. OUTCOME MEASURES: Auditory brainstem evoked responses (ABRs) were measured bilaterally for a wide range of frequencies (between 8 and 25 kHz) before and 2 weeks after transtympanic manuka honey and saline application. The animals were sacrificed, and all cochleae were dissected out and processed for light and scanning electron microscopy (SEM).Results:The measured ABR thresholds after the application of 50% concentration of manuka honey revealed severe ototoxicity in all honey-exposed ears. This was accompanied by gross physical changes and histologic evidence of hair cell toxicity on SEM and light microscopy. The control ears remained unchanged during the period of the experiment. CONCLUSION: Although 50% concentration of manuka honey is the proven concentration to have bactericidal properties against biofilms of Pseudomonas aeruginosa and Staphylococcus aureus, this concentration appeared to have caused severe or intense inflammatory changes that produced facial paralysis, vestibulotoxicity, and hearing loss. PMID: 22569046 [PubMed - indexed for MEDLINE]

Related Articles When inner ear stem cell therapy becomes a reality. Trends Amplif. 2012 Mar;16(1):3 Authors: Limb CJ PMID: 22593203 [PubMed - indexed for MEDLINE]

Related Articles Intravenous administration of human mesenchymal stem cells after noise- or drug-induced hearing loss in rats. Acta Otolaryngol. 2012 Jun;132 Suppl 1:S94-102 Authors: Choi BY, Song JJ, Chang SO, Kim SU, Oh SH Abstract CONCLUSION: Systemic application of human mesenchymal stem cells (hMSCs) may be another effective tool for stem cell supply to the inner ear. OBJECTIVES: Most researchers have used local application to provide the inner ear with stem cells. In spite of their efficacy, these methods can potentially cause irreversible damage to the inner ear. A homing phenomenon of systemically administered MSCs to the ischemic myocardium and brain was recently reported. Moreover, hMSCs have several advantages over conventional neural or embryonic stem cells. Thus we hypothesized that intense noise or ototoxic injury to the cochlea could induce the homing of hMSCs. METHODS: We harvested hMSCs from bone marrow of the iliac crest of five normal individuals. Then hMSCs at a dose of 4 × 10(6) cells were given via intravenous injection of cell suspension into rats with cochleae damaged by noise or ototoxic drugs. Histological analysis was undertaken 30 days later. RESULTS: Systemically delivered hMSCs were usually largely entrapped in the lungs. However, we documented the homing of some hMSCs to the cochlea with degenerated inner hair cells. The recruitment of hMSCs was limited to the spiral ganglion area only. The migration of donor cells into the cochlea was accompanied by the expression of brain-derived neurotrophic factor (BDNF). PMID: 22582790 [PubMed - indexed for MEDLINE]

Related Articles In vitro differentiation of mouse embryonic stem cells into inner ear hair cell-like cells using stromal cell conditioned medium. Cell Death Dis. 2012;3:e314 Authors: Ouji Y, Ishizaka S, Nakamura-Uchiyama F, Yoshikawa M Abstract Hearing loss is mainly caused by loss of sensory hair cells (HCs) in the organ of Corti or cochlea. Although embryonic stem (ES) cells are a promising source for cell therapy, little is known about the efficient generation of HC-like cells from ES cells. In the present study, we developed a single-medium culture method for growing embryoid bodies (EBs), in which conditioned medium (CM) from cultures of ST2 stromal cells (ST2-CM) was used for 14-day cultures of 4-day EBs. At the end of the 14-day cultures, up to 20% of the cells in EB outgrowths expressed HC-related markers, including Math1 (also known as Atoh1), myosin6, myosin7a, calretinin, α9AchR and Brn3c (also known as Pou4f3), and also showed formation of stereocilia-like structures. Further, we found that these cells were incorporated into the developing inner ear after transplantation into chick embryos. The present inner ear HC induction method using ST2-CM (HIST2 method) is quite simple and highly efficient to obtain ES-derived HC-like cells with a relatively short cultivation time. PMID: 22622133 [PubMed - in process]

Related Articles Potential roles of stem cells in the management of sensorineural hearing loss. J Laryngol Otol. 2012 Jul;126(7):653-7 Authors: Ibekwe TS, Ramma L, Chindo BA Abstract BACKGROUND: In the management of sensorineural hearing loss, effective therapy for degenerated hair cells, third order neurons, ganglions, dendrites and synaptic areas of the vestibulo-cochleo-cerebral pathway remains an enigma. Transplantation of stem and progenitor cells appears to be an emerging potential solution, and is the focus of this review. AIM: To review recent developments in the management of sensorineural hearing loss in the field of stem cell research. MATERIALS AND METHOD: A systematic review of the English language literature included all experimental and non-experimental studies with a Jadad score of three or more, published between 2000 and 2010 and included in the following databases: Cochrane Library Ear, Nose and Throat Disorders; Medline; Google Scholar; Hinari; and the Online Library of Toronto University. RESULTS: Of the 455 and 29 600 articles identified from Medline and Google Scholar, respectively, 48 met the inclusion criteria. These were independently reviewed and jointly analysed. CONCLUSION: Although there is not yet any evidence from successful human studies, stem cell and 'alternative stem cell' technology seems to represent the future of sensorineural hearing loss management. PMID: 22624825 [PubMed - indexed for MEDLINE]

Related Articles [A state of inner ear in patients, suffering diabetes mellitus and peculiarities of treatment of vestibular dysfunction]. Klin Khir. 2012 Feb;(2):57-9 Authors: Deeva IuV Abstract In patients, suffering diabetes mellitus and peripheral cochleovestibular syndrome a method of parameatal introduction of auto stem cells was applied for the treatment of vestibular dysfunction and sensoneural hearing loss. The clinical examination results have witnessed a positive dynamics of a hearing and vestibular functions changes in patients, to whom complex treatment was conducted. The method application have permitted to improve or restore a hearing and vestibular function, to reduce possibility of the disease progress and necessity to readmit the patients into the hospital. The method was recommended to use in the patients, suffering diabetes mellitus with vestibular dysfunction and sensoneural hearing loss. PMID: 22629809 [PubMed - indexed for MEDLINE]

Related Articles Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization. Int J Nanomedicine. 2012;7:2449-64 Authors: Meyer H, Stöver T, Fouchet F, Bastiat G, Saulnier P, Bäumer W, Lenarz T, Scheper V Abstract OBJECTIVE: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve-electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active. METHODS: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo. RESULTS: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results. CONCLUSION: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects. PMID: 22654517 [PubMed - indexed for MEDLINE]

Related Articles Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients. Eur J Pediatr. 2012 Oct;171(10):1527-31 Authors: Cağdaş D, Ozgür TT, Asal GT, Tezcan I, Metin A, Lambert N, de Saint Basile G, Sanal O Abstract Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. Three different types are caused by defects in three different genes. Patients with GS type 1 have primary central nervous system dysfunction, type 2 patients commonly develop hemophagocytic lymphohistiocytosis, and type 3 patients have only partial albinism. While hematopoietic stem cell transplantation is life saving in type 2, no specific therapy is required for types 1 and 3. Patients with GS types 1 and 3 are very rare. To date, only 2 patients with type 3 and about 20 GS type 1 patients, including the patients described as Elejalde syndrome, have been reported. The neurological deficits in Elejalde syndrome were reported as severe neurodevelopmental delay, seizures, hypotonia, and ophthalmological problems including nystagmus, diplopia, and retinal problems. However, none of these patients' clinical progresses were reported. We described here our two new type 1 and two type 3 patients along with the progresses of our previously diagnosed patients with GS types 1 and 3. Our previous patient with GS type I is alive at age 21 without any other problems except severe mental and motor retardation, patients with type 3 are healthy at ages 21 and 24 years having only pigmentary dilution; silvery gray hair, eye brows, and eyelashes. Since prognosis, treatment options, and genetic counseling markedly differ among different types, molecular characterization has utmost importance in GS. PMID: 22711375 [PubMed - indexed for MEDLINE]

Related Articles Trauma-specific insults to the cochlear nucleus in the rat. J Neurosci Res. 2012 Oct;90(10):1924-31 Authors: Sekiya T, Viberg A, Kojima K, Sakamoto T, Nakagawa T, Ito J, Canlon B Abstract The effect of acoustic overstimulation on the neuronal number of the cochlear nucleus (CN) was investigated by using unbiased stereological methods in rats. We found that, after 9 weeks of recovery, neurons in the anteroventral cochlear nucleus (AVCN) degenerated, whereas those in the posteroventral and dorsal cochlear nuclei (PVCN and DCN) were preserved. The noise trauma induced near complete loss of the outer hair cells throughout the cochlea, and the inner hair cells were preserved only in the more apical regions. This pattern of selective loss of AVCN neurons in this study was different from trauma induced by auditory deafferentation by mechanical compression of auditory neurons. In contrast to noise trauma, mechanical compression caused loss of neurons in the PVCN and DCN. After 5 weeks of recovery from mechanical compression, there was no loss of inner or outer hair cells. These findings indicate that auditory deprivation, induced by different experimental manipulations, can have strikingly different consequences for the central auditory system. We hypothesized that AVCN neuronal death was induced by excitotoxic mechanisms via AMPA-type glutamate receptors and that excitatory neuronal circuits developed after acoustic overstimulation protected the PVCN and DCN against neuronal death. The results of the present study demonstrate that hearing loss from different etiologies will cause different patterns of neuronal degeneration in the CN. These findings are important for enhancing the performance of cochlear implants and auditory brainstem implants, because diverse types of hearing loss can selectively affect neuronal degeneration of the CN. PMID: 22715005 [PubMed - indexed for MEDLINE]

Related Articles Changes in projections to the inferior colliculus following early hearing loss in rats. Hear Res. 2012 May;287(1-2):57-66 Authors: Hatano M, Ito M, Yoshizaki T, Kelly JB Abstract The purpose of this study was to investigate the effects of early hearing loss on the anatomy of the central auditory system, specifically, the ascending projections to the inferior colliculus (IC). We compared normal animals with animals deafened during early development by administration of amikacin, an ototoxic antibiotic that is known to destroy the hair cells in the inner ear. The amikacin was injected subcutaneously every day from postnatal days P7 to P16. A retrograde tract tracer, Fluoro-Gold (FG), was then injected unilaterally directly into the IC at either 4 weeks of age or 12 weeks of age. After axonal transport the animals were sacrificed and their brains were prepared for histology. The FG labeled neurons in the cochlear nucleus (CN) and the dorsal nucleus of lateral lemniscus (DNLL) were counted for each of the animals in the two age groups. For deaf animals sacrificed at 4 weeks of age there was a significant reduction in the number of FG labeled neurons that was limited to the ventral CN ipsilateral to the tracer injection. For deaf animals sacrificed at 12 weeks of age, however, there was a significant decrease in the number of labeled cells in both dorsal and ventral CN on both sides of the brain. In DNLL there was no change in the number or pattern of labeled neurons. The results show that neonatal deafness reduces the number of labeled neurons projecting from the CN to the IC with the effect being more evident during later stages of deafness. In contrast, there are no significant changes in the projections from DNLL to IC. PMID: 22726617 [PubMed - indexed for MEDLINE]

Related Articles Effect of low-level laser treatment on cochlea hair-cell recovery after acute acoustic trauma. J Biomed Opt. 2012 Jun;17(6):068002 Authors: Rhee CK, Bahk CW, Kim SH, Ahn JC, Jung JY, Chung PS, Suh MW Abstract We investigated the effect of low-level laser radiation on rescuing hair cells of the cochlea after acute acoustic trauma and hearing loss. Nine rats were exposed to noise. Starting the following day, the left ears (NL ears) of the rats were irradiated at an energy output of 100 to 165 mW/cm(2) for 60 min for 12 days in a row. The right ears (N ears) were considered as the control group. Frequency-specific hearing levels were measured before the noise exposure and also after the 1st, 3rd to 5th, 8th to 10th and 12th irradiations. After the 12th treatment, hair cells were observed using a scanning electron microscope. Compared to initial hearing levels at all frequencies, thresholds increased markedly after noise exposure. After the 12th irradiation, hearing threshold was significantly lower for the NL ears compared to the N ears. When observed using an electron microscope, the number of hair cells in the middle turn of the NL ears was significantly larger than that of the N ears. Our findings suggest that low-level laser irradiation promotes recovery of hearing thresholds after acute acoustic trauma. PMID: 22734788 [PubMed - indexed for MEDLINE]

Related Articles The mechanosensory structure of the hair cell requires clarin-1, a protein encoded by Usher syndrome III causative gene. J Neurosci. 2012 Jul 11;32(28):9485-98 Authors: Geng R, Melki S, Chen DH, Tian G, Furness DN, Oshima-Takago T, Neef J, Moser T, Askew C, Horwitz G, Holt JR, Imanishi Y, Alagramam KN Abstract Mutation in the clarin-1 gene (Clrn1) results in loss of hearing and vision in humans (Usher syndrome III), but the role of clarin-1 in the sensory hair cells is unknown. Clarin-1 is predicted to be a four transmembrane domain protein similar to members of the tetraspanin family. Mice carrying null mutation in the clarin-1 gene (Clrn1(-/-)) show loss of hair cell function and a possible defect in ribbon synapse. We investigated the role of clarin-1 using various in vitro and in vivo approaches. We show by immunohistochemistry and patch-clamp recordings of Ca(2+) currents and membrane capacitance from inner hair cells that clarin-1 is not essential for formation or function of ribbon synapse. However, reduced cochlear microphonic potentials, FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] loading, and transduction currents pointed to diminished cochlear hair bundle function in Clrn1(-/-) mice. Electron microscopy of cochlear hair cells revealed loss of some tall stereocilia and gaps in the v-shaped bundle, although tip links and staircase arrangement of stereocilia were not primarily affected by Clrn1(-/-) mutation. Human clarin-1 protein expressed in transfected mouse cochlear hair cells localized to the bundle; however, the pathogenic variant p.N48K failed to localize to the bundle. The mouse model generated to study the in vivo consequence of p.N48K in clarin-1 (Clrn1(N48K)) supports our in vitro and Clrn1(-/-) mouse data and the conclusion that CLRN1 is an essential hair bundle protein. Furthermore, the ear phenotype in the Clrn1(N48K) mouse suggests that it is a valuable model for ear disease in CLRN1(N48K), the most prevalent Usher syndrome III mutation in North America. PMID: 22787034 [PubMed - indexed for MEDLINE]

Related Articles An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect. Anticancer Drugs. 2013 Jan;24(1):43-51 Authors: Bielefeld EC, Tanaka C, Chen GD, Coling D, Li M, Henderson D, Fetoni AR Abstract Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability. PMID: 22828384 [PubMed - indexed for MEDLINE]

Related Articles Have you heard? Viral-mediated gene therapy restores hearing. Neuron. 2012 Jul 26;75(2):188-90 Authors: Martin DM, Raphael Y Abstract Genetic loss of VGLUT3 in cochlear inner hair cells results in profound deafness. In this issue of Neuron, Akil et al. (2012) show that AAV-mediated introduction of wild-type VGLUT3 in the genetically deaf mouse cochlea results in significantly improved hearing. PMID: 22841304 [PubMed - indexed for MEDLINE]

Related Articles Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron. 2012 Jul 26;75(2):283-93 Authors: Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, Edwards RH, Lustig LR Abstract Mice lacking the vesicular glutamate transporter-3 (VGLUT3) are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse. Cochlear delivery of VGLUT3 using adeno-associated virus type 1 (AAV1) leads to transgene expression in only inner hair cells (IHCs), despite broader viral uptake. Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response. Lastly, we demonstrate partial reversal of the morphologic changes seen within the afferent IHC ribbon synapse. These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness. PMID: 22841313 [PubMed - indexed for MEDLINE]

Related Articles Bilirubin induces auditory neuropathy in neonatal guinea pigs via auditory nerve fiber damage. J Neurosci Res. 2012 Nov;90(11):2201-13 Authors: Ye HB, Shi HB, Wang J, Ding DL, Yu DZ, Chen ZN, Li CY, Zhang WT, Yin SK Abstract Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin-induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy. PMID: 22847875 [PubMed - indexed for MEDLINE]

Related Articles Increased inner ear susceptibility to noise injury in mice with streptozotocin-induced diabetes. Diabetes. 2012 Nov;61(11):2980-6 Authors: Fujita T, Yamashita D, Katsunuma S, Hasegawa S, Tanimoto H, Nibu K Abstract We aimed to investigate the pathophysiology of diabetes-associated hearing impairment in type 1 diabetes using mice with streptozotocin-induced diabetes (C57BL/6J; male). Hearing function was evaluated 1, 3, and 5 months after induction of diabetes (five diabetic and five control animals per time point) using auditory-evoked brain stem responses (ABRs). Mice (four diabetic and four control) were exposed to loud noise (105 dB) 5 months after induction of diabetes. ABRs were measured before and after noise exposure. Cochlear blood flows were measured by laser-Doppler flowmeter. Spiral ganglion cells (SGCs) were counted. Vessel endothelial cells were observed by CD31 immunostaining. Chronologic changes in the ABR threshold shift were not significantly different between the diabetic and control groups. However, vessel walls in the modiolus of the cochleae were significantly thicker in the diabetic group than the control group. Additionally, recovery from noise-induced injury was significantly impaired in diabetic mice. Reduced cochlea blood flows and SGC loss were observed in diabetic mice cochleae after noise exposure. Our data suggest that diabetic cochleae are more susceptible than controls to loud noise exposure, and decreased cochlear blood flow due to sclerosis of the vessels and consequent loss of SGCs are possible mechanisms of hearing impairment in diabetic patients. PMID: 22851574 [PubMed - indexed for MEDLINE]

Related Articles Silvery-gray hair in a newborn. JAMA. 2012 Aug 8;308(6):617-8 Authors: Wong L, Yano S PMID: 22871872 [PubMed - indexed for MEDLINE]

Related Articles Exposure to low-dose barium by drinking water causes hearing loss in mice. Neurotoxicology. 2012 Oct;33(5):1276-83 Authors: Ohgami N, Hori S, Ohgami K, Tamura H, Tsuzuki T, Ohnuma S, Kato M Abstract PURPOSE: We continuously ingest barium as a general element by drinking water and foods in our daily life. Exposure to high-dose barium (>100mg/kg/day) has been shown to cause physiological impairments. Direct administration of barium to inner ears by vascular perfusion has been shown to cause physiological impairments in inner ears. However, the toxic influence of oral exposure to low-dose barium on hearing levels has not been clarified in vivo. We analyzed the toxic influence of oral exposure to low-dose barium on hearing levels and inner ears in mice. EXPERIMENTAL DESIGN: We orally administered barium at low doses of 0.14 and 1.4 mg/kg/day to wild-type ICR mice by drinking water. The doses are equivalent to and 10-fold higher than the limit level (0.7 mg/l) of WHO health-based guidelines for drinking water, respectively. After 2-week exposure, hearing levels were measured by auditory brain stem responses and inner ears were morphologically analyzed. After 2-month exposure, tissue distribution of barium was measured by inductively coupled plasma mass spectrometry. RESULTS: Low-dose barium in drinking water caused severe hearing loss in mice. Inner ears including inner and outer hair cells, stria vascularis and spiral ganglion neurons showed severe degeneration. The Barium-administered group showed significantly higher levels of barium in inner ears than those in the control group, while barium levels in bone did not show a significant difference between the two groups. Barium levels in other tissues including the cerebrum, cerebellum, heart, liver and kidney were undetectably low in both groups. CONCLUSIONS: Our results demonstrate for the first time that low-dose barium administered by drinking water specifically distributes to inner ears resulting in severe ototoxicity with degeneration of inner ears in mice. PMID: 22884792 [PubMed - indexed for MEDLINE]

Related Articles Auditory brainstem implants for neurofibromatosis type 2. Curr Opin Otolaryngol Head Neck Surg. 2012 Oct;20(5):353-7 Authors: Colletti L, Shannon R, Colletti V Abstract PURPOSE OF REVIEW: Neurofibromatosis type 2 (NF2) produces benign Schwann cell tumors on many cranial nerves, in particular on the vestibular portions of the VIIIn bilaterally. Removal of these vestibular schwannomas usually severs the auditory portion of the VIIIn, thus deafening the patients. The auditory brainstem implant (ABI) was designed to provide prosthetic electric stimulation of the cochlear nucleus in the brainstem to restore some hearing sensations to patients deafened by bilateral removal of vestibular schwannomas. This study will review the new developments and improving outcomes of the ABI. RECENT FINDINGS: From its initial application in 1979 until about 2005, the ABI provided modest but useful auditory sensations to NF2 patients. However, application of the ABI in non-NF2 populations and in children with congenital malformations demonstrated better results, showing that the ABI could provide high levels of speech recognition. Recent results show excellent speech recognition in NF2 patients as well. This study will discuss the potential causes of the variability in ABI outcomes. SUMMARY: ABIs activate neurons in the cochlear nucleus to recreate hearing sensations in people who have become deaf as a result of the loss of the auditory nerve. Most NF2 patients show functional hearing benefit from the ABI, with awareness and recognition of environmental sounds and enhancement of lipreading. It is now clear that ABIs can produce excellent speech recognition in some patients with NF2, allowing even conversational telephone use. Although the factors leading to this improved performance are not completely clear, these new results show that excellent hearing is possible for NF2 patients with the ABI. PMID: 22886036 [PubMed - indexed for MEDLINE]

Related Articles In vivo reversible regulation of dendritic patterning by afferent input in bipolar auditory neurons. J Neurosci. 2012 Aug 15;32(33):11495-504 Authors: Wang Y, Rubel EW Abstract Afferent input regulates neuronal dendritic patterning locally and globally through distinct mechanisms. To begin to understand these mechanisms, we differentially manipulate afferent input in vivo and assess effects on dendritic patterning of individual neurons in chicken nucleus laminaris (NL). Dendrites of NL neurons segregate into dorsal and ventral domains, receiving excitatory input from the ipsilateral and contralateral ears, respectively, via nucleus magnocellularis (NM). Blocking action potentials from one ear, by either cochlea removal or temporary treatment with tetrodotoxin (TTX), leads to rapid and significant retraction of affected NL dendrites (dorsal ipsilaterally and ventral contralaterally) within 8 h compared with the other dendrites of the same neurons. The degree of retraction is comparable with that induced by direct deafferentation resulting from transection of NM axons. Importantly, when inner ear activity is allowed to recover from TTX treatments, retracted NL dendrites regrow to their normal length within 48 h. The retraction and growth involve elimination of terminal branches and addition of new branches, respectively. Examination of changes in NL dendrites at 96 h after unilateral cochlea removal, a manipulation that induces cell loss in NM and persistent blockage of afferent excitatory action potentials, reveals a significant correlation between cell death in the ipsilateral NM and the degree of dendritic retraction in NL. These results demonstrate that presynaptic action potentials rapidly and reversibly regulate dendritic patterning of postsynaptic neurons in a compartment specific manner, whereas long-term dendritic maintenance may be regulated in a way that is correlated with the presence of silent presynaptic appositions. PMID: 22895732 [PubMed - indexed for MEDLINE]

Related Articles Long-term medical outcomes in survivors of extra-ocular retinoblastoma: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Pediatr Blood Cancer. 2013 Apr;60(4):694-9 Authors: Friedman DN, Sklar CA, Oeffinger KC, Kernan NA, Khakoo Y, Marr BP, Wolden SL, Abramson DH, Dunkel IJ Abstract BACKGROUND: Data on long-term outcomes of survivors of extra-ocular retinoblastoma are lacking. The authors sought to provide the first report characterizing long-term outcomes among survivors of extra-ocular retinoblastoma. PROCEDURE: Retrospective analysis of long-term medical outcomes in 19 survivors of extra-ocular retinoblastoma treated between 1992 and 2009. Severity of outcomes was graded using Common Terminology Criteria for Adverse Events. All patients received intensive multimodality therapy for their extra-ocular disease after management of their primary intra-ocular disease, including conventional chemotherapy (n = 19, 100%), radiotherapy (n = 15, 69%), and/or high-dose chemotherapy with autologous stem cell transplant (n = 17, 89%). RESULTS: The median follow-up was 7.8 years from diagnosis of extra-ocular retinoblastoma (range 2-17.8 years). The most common long-term non-visual outcomes were hearing loss (n = 15, 79%), short stature (n = 7, 37%), and secondary malignancies [SMN] (n = 6, 31%). Sixty-eight percent of survivors exhibited ≥2 non-visual long-term outcomes of any grade. Except short stature, which was not graded for severity, Grade 3-4 outcomes were limited to: ototoxicity (n = 8; n = 4 require hearing aids), SMNs (n = 6), and unequal limb length (n = 1). Five patients who developed SMNs carried a known RB1 mutation. SMNs developed at a median of 11.1 years after initial diagnosis; two patients died of their SMN. Long-term cardiac, pulmonary, hepatobiliary, or renal conditions were not identified in any survivors. CONCLUSION: Long-term outcomes are commonly seen in extra-ocular retinoblastoma survivors but the majority are mild-moderate in their severity. Longer comprehensive follow-up is needed to fully assess treatment-related outcomes but the information collected to date may affect management decisions for children with extra-ocular disease. PMID: 22911631 [PubMed - indexed for MEDLINE]

Related Articles Current strategies for the protection, regeneration, and replacement of cochlear hair cells. J Otolaryngol Head Neck Surg. 2012 Aug;41(4):227-39 Authors: Perde-Schrepler M, Maniu A, Cosgarea M Abstract Sensorineural hearing loss, which is often caused by degeneration of hair cells in the auditory epithelium, is permanent because lost hair cells cannot be replaced in mammals. In recent years, important progress has been made in understanding the mechanisms involved in hair cell damage and, more importantly, the reasons why hair cells cannot be regenerated spontaneously in mammals. The knowledge of the factors implicated in hair cell fate determination and of the mechanisms of hair cell regeneration in birds could help in the effort to find a treatment for hearing loss. Although cochlear implant technology is advanced, it still provides only moderate hearing capacity in sensorineural deaf individuals. Inducible stem cells and molecular therapies are appealing alternatives to the cochlear implant as they hold the promise of a cure. It is important to develop a safe and effective means to deliver stem cells or genes to the correct sites to stimulate regeneration in the right place. This review aims to synthesize the present knowledge in the field of sensorineural hearing loss, focusing on the mechanisms involved in hair cell development and regeneration, with the specific purpose of identifying new therapeutic strategies. Despite tremendous progress in this field, most of the concepts discussed in this review are still in the experimental stage. PMID: 22935173 [PubMed - indexed for MEDLINE]

Related Articles Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature. 2012 Oct 11;490(7419):278-82 Authors: Chen W, Jongkamonwiwat N, Abbas L, Eshtan SJ, Johnson SL, Kuhn S, Milo M, Thurlow JK, Andrews PW, Marcotti W, Moore HD, Rivolta MN Abstract Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness. PMID: 22972191 [PubMed - indexed for MEDLINE]

Related Articles Notch prosensory effects in the Mammalian cochlea are partially mediated by Fgf20. J Neurosci. 2012 Sep 12;32(37):12876-84 Authors: Munnamalai V, Hayashi T, Bermingham-McDonogh O Abstract Hearing loss is becoming an increasingly prevalent problem affecting more than 250 million people worldwide. During development, fibroblast growth factors (FGFs) are required for inner ear development as well as hair cell formation in the mammalian cochlea and thus make attractive therapeutic candidates for the regeneration of sensory cells. Previous findings showed that Fgfr1 conditional knock out mice exhibited hair cell and support cell formation defects. Immunoblocking with Fgf20 antibody in vitro produced a similar phenotype. While hair cell differentiation in mice starts at embryonic day (E)14.5, beginning with the inner hair cells, Fgf20 expression precedes hair cell differentiation at E13.5 in the cochlea. This suggests a potential role for Fgf20 in priming the sensory epithelium for hair cell formation. Treatment of explants with a gamma-secretase inhibitor, DAPT, decreased Fgf20 mRNA, suggesting that Notch is upstream of Fgf20. Notch signaling also plays an early role in prosensory formation during cochlear development. In this report we show that during development, Notch-mediated regulation of prosensory formation in the cochlea occurs via Fgf20. Addition of exogenous FGF20 compensated for the block in Notch signaling and rescued Sox2, a prosensory marker, and Gfi1, an early hair cell marker in explant cultures. We hypothesized that Fgf20 plays a role in specification, amplification, or maintenance of Sox2 expression in prosensory progenitors of the developing mammalian cochlea. PMID: 22973011 [PubMed - indexed for MEDLINE]

Related Articles Multi-sensory integration in brainstem and auditory cortex. Brain Res. 2012 Nov 16;1485:95-107 Authors: Basura GJ, Koehler SD, Shore SE Abstract Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to arise from aberrant neural activity within central auditory pathways that may be influenced by multiple brain centers, including the somatosensory system. Auditory-somatosensory (bimodal) integration occurs in the dorsal cochlear nucleus (DCN), where electrical activation of somatosensory regions alters pyramidal cell spike timing and rates of sound stimuli. Moreover, in conditions of tinnitus, bimodal integration in DCN is enhanced, producing greater spontaneous and sound-driven neural activity, which are neural correlates of tinnitus. In primary auditory cortex (A1), a similar auditory-somatosensory integration has been described in the normal system (Lakatos et al., 2007), where sub-threshold multisensory modulation may be a direct reflection of subcortical multisensory responses (Tyll et al., 2011). The present work utilized simultaneous recordings from both DCN and A1 to directly compare bimodal integration across these separate brain stations of the intact auditory pathway. Four-shank, 32-channel electrodes were placed in DCN and A1 to simultaneously record tone-evoked unit activity in the presence and absence of spinal trigeminal nucleus (Sp5) electrical activation. Bimodal stimulation led to long-lasting facilitation or suppression of single and multi-unit responses to subsequent sound in both DCN and A1. Immediate (bimodal response) and long-lasting (bimodal plasticity) effects of Sp5-tone stimulation were facilitation or suppression of tone-evoked firing rates in DCN and A1 at all Sp5-tone pairing intervals (10, 20, and 40 ms), and greater suppression at 20 ms pairing-intervals for single unit responses. Understanding the complex relationships between DCN and A1 bimodal processing in the normal animal provides the basis for studying its disruption in hearing loss and tinnitus models. This article is part of a Special Issue entitled: Tinnitus Neuroscience. PMID: 22995545 [PubMed - indexed for MEDLINE]

Related Articles Parvalbumin immunoreactivity in the auditory cortex of a mouse model of presbycusis. Hear Res. 2012 Dec;294(1-2):31-9 Authors: Martin del Campo HN, Measor KR, Razak KA Abstract Age-related hearing loss (presbycusis) affects ∼35% of humans older than sixty-five years. Symptoms of presbycusis include impaired discrimination of sounds with fast temporal features, such as those present in speech. Such symptoms likely arise because of central auditory system plasticity, but the underlying components are incompletely characterized. The rapid spiking inhibitory interneurons that co-express the calcium binding protein Parvalbumin (PV) are involved in shaping neural responses to fast spectrotemporal modulations. Here, we examined cortical PV expression in the C57bl/6 (C57) mouse, a strain commonly studied as a presbycusis model. We examined if PV expression showed auditory cortical field- and layer-specific susceptibilities with age. The percentage of PV-expressing cells relative to Nissl-stained cells was counted in the anterior auditory field (AAF) and primary auditory cortex (A1) in three age groups: young (1-2 months), middle-aged (6-8 months) and old (14-20 months). There were significant declines in the percentage of cells expressing PV at a detectable level in layers I-IV of both A1 and AAF in the old mice compared to young mice. In layers V-VI, there was an increase in the percentage of PV-expressing cells in the AAF of the old group. There were no changes in percentage of PV-expressing cells in layers V-VI of A1. These data suggest cortical layer(s)- and field-specific susceptibility of PV+ cells with presbycusis. The results are consistent with the hypothesis that a decline in inhibitory neurotransmission, particularly in the superficial cortical layers, occurs with presbycusis. PMID: 23010334 [PubMed - indexed for MEDLINE]

Related Articles Hearing restoration in a deaf animal model with intravenous transplantation of mesenchymal stem cells derived from human umbilical cord blood. Biochem Biophys Res Commun. 2012 Oct 26;427(3):629-36 Authors: Choi MY, Yeo SW, Park KH Abstract OBJECTIVE: This study was performed to confirm the effect of transplantation of human umbilical cord blood mesenchymal stem cells (UCB-MSCs) on hearing restoration in a sensorineural hearing loss (SNHL) animal model. MATERIAL AND METHODS: UCB was collected from pregnant women after obtaining consent, and mesenchymal stem cells (MSCs) were extracted. We established an SNHL model and transplanted UCB-MSCs through the brachial vein of the guinea pigs. The animals were divided into 4 groups: animals with normal hearing, animals with SNHL, animals with SNHL and injected with saline, and animals with SNHL and transplanted with UCB-MSCs. Hearing tests were conducted at 1, 3, and 5 weeks, and the results were compared by grading auditory brainstem response (ABR) recordings and distortion product otoacoustic emissions (DPOAEs) for each treatment. Lastly, cochlear pathological features were examined, and surface preparations and morphological changes in each animal model were compared using hematoxylin and eosin staining and light microscopy studies. RESULTS: In SNHL group, decreased DPOAEs and increased ABR threshold were noted. Furthermore, in the SNHL group, ABR hearing thresholds were unconverted and were similar to those observed in deafness. The transplanted UCB-MSC group showed a significant improvement in hearing threshold (40 dB) compared to that in all the SNHL group (80-90 dB). Examination of the SNHL animals' cochlear morphological features demonstrated a noticeable lack of spiral ganglion cells and also showed degenerated outer hair cells. However, the transplanted UCB-MSCs showed an increase in spiral ganglion and hair cells. CONCLUSION: Intravenous transplantation of UCB-MSCs can enhance hearing thresholds, outer-hair cells and increase the number of spiral ganglion neurons (SGNs). PMID: 23026045 [PubMed - indexed for MEDLINE]

Related Articles Regeneration of stereocilia of hair cells by forced Atoh1 expression in the adult mammalian cochlea. PLoS One. 2012;7(9):e46355 Authors: Yang SM, Chen W, Guo WW, Jia S, Sun JH, Liu HZ, Young WY, He DZ Abstract The hallmark of mechanosensory hair cells is the stereocilia, where mechanical stimuli are converted into electrical signals. These delicate stereocilia are susceptible to acoustic trauma and ototoxic drugs. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously regenerate lost stereocilia, mammalian cochlear hair cells no longer retain this capability. We explored the possibility of regenerating stereocilia in the noise-deafened guinea pig cochlea by cochlear inoculation of a viral vector carrying Atoh1, a gene critical for hair cell differentiation. Exposure to simulated gunfire resulted in a 60-70 dB hearing loss and extensive damage and loss of stereocilia bundles of both inner and outer hair cells along the entire cochlear length. However, most injured hair cells remained in the organ of Corti for up to 10 days after the trauma. A viral vector carrying an EGFP-labeled Atoh1 gene was inoculated into the cochlea through the round window on the seventh day after noise exposure. Auditory brainstem response measured one month after inoculation showed that hearing thresholds were substantially improved. Scanning electron microscopy revealed that the damaged/lost stereocilia bundles were repaired or regenerated after Atoh1 treatment, suggesting that Atoh1 was able to induce repair/regeneration of the damaged or lost stereocilia. Therefore, our studies revealed a new role of Atoh1 as a gene critical for promoting repair/regeneration of stereocilia and maintaining injured hair cells in the adult mammal cochlea. Atoh1-based gene therapy, therefore, has the potential to treat noise-induced hearing loss if the treatment is carried out before hair cells die. PMID: 23029493 [PubMed - indexed for MEDLINE]

Related Articles Human cochlea: anatomical characteristics and their relevance for cochlear implantation. Anat Rec (Hoboken). 2012 Nov;295(11):1791-811 Authors: Rask-Andersen H, Liu W, Erixon E, Kinnefors A, Pfaller K, Schrott-Fischer A, Glueckert R Abstract This is a review of the anatomical characteristics of human cochlea and the importance of variations in this anatomy to the process of cochlear implantation (CI). Studies of the human cochlea are essential to better comprehend the physiology and pathology of man's hearing. The human cochlea is difficult to explore due to its vulnerability and bordering capsule. Inner ear tissue undergoes quick autolytic changes making investigations of autopsy material difficult, even though excellent results have been presented over time. Important issues today are novel inner ear therapies including CI and new approaches for inner ear pharmacological treatments. Inner ear surgery is now a reality, and technical advancements in the design of electrode arrays and surgical approaches allow preservation of remaining structure/function in most cases. Surgeons should aim to conserve cochlear structures for future potential stem cell and gene therapies. Renewal interest of round window approaches necessitates further acquaintance of this complex anatomy and its variations. Rough cochleostomy drilling at the intricate "hook" region can generate intracochlear bone-dust-inducing fibrosis and new bone formation, which could negatively influence auditory nerve responses at a later time point. Here, we present macro- and microanatomic investigations of the human cochlea viewing the extensive anatomic variations that influence electrode insertion. In addition, electron microscopic (TEM and SEM) and immunohistochemical results, based on specimens removed at surgeries for life-threatening petroclival meningioma and some well-preserved postmortal tissues, are displayed. These give us new information about structure as well as protein and molecular expression in man. Our aim was not to formulate a complete description of the complex human anatomy but to focus on aspects clinically relevant for electric stimulation, predominantly, the sensory targets, and how surgical atraumaticity best could be reached. PMID: 23044521 [PubMed - indexed for MEDLINE]

Related Articles The cochlear implant: historical aspects and future prospects. Anat Rec (Hoboken). 2012 Nov;295(11):1967-80 Authors: Eshraghi AA, Nazarian R, Telischi FF, Rajguru SM, Truy E, Gupta C Abstract The cochlear implant (CI) is the first effective treatment for deafness and severe losses in hearing. As such, the CI is now widely regarded as one of the great advances in modern medicine. This article reviews the key events and discoveries that led up to the current CI systems, and we review and present some among the many possibilities for further improvements in device design and performance. The past achievements include: (1) development of reliable devices that can be used over the lifetime of a patient; (2) development of arrays of implanted electrodes that can stimulate more than one site in the cochlea; and (3) progressive and large improvements in sound processing strategies for CIs. In addition, cooperation between research organizations and companies greatly accelerated the widespread availability and use of safe and effective devices. Possibilities for the future include: (1) use of otoprotective drugs; (2) further improvements in electrode designs and placements; (3) further improvements in sound processing strategies; (4) use of stem cells to replace lost sensory hair cells and neural structures in the cochlea; (5) gene therapy; (6) further reductions in the trauma caused by insertions of electrodes and other manipulations during implant surgeries; and (7) optical rather electrical stimulation of the auditory nerve. Each of these possibilities is the subject of active research. Although great progress has been made to date in the development of the CI, including the first substantial restoration of a human sense, much more progress seems likely and certainly would not be a surprise. PMID: 23044644 [PubMed - indexed for MEDLINE]

Related Articles Auditory brainstem implants: how do they work? Anat Rec (Hoboken). 2012 Nov;295(11):1981-6 Authors: Vincent C Abstract This review covers the design, structure, and function of auditory brainstem implants. Auditory brainstem implants (ABIs) are auditory prostheses initially designed to treat deafness in patients with neurofibromatosis type 2 (NF2). NF2 typically results in deafness due to disruption of the cochlear nerves. When the tumors are removed the auditory nerve is usually cut or nonfunctional anymore. In these cases, patients cannot benefit from peripheral devices such as cochlear implants (CI). Another cause of VIII nerve loss is bilateral temporal bone fracture. Worldwide, more than 500 persons have received an ABI after removal of the tumors that occur with NF2. More recently, some extensions of indications have been proposed to include subjects who would not benefit enough from a cochlear implant (i.e. cochlear ossification). The ABI is similar in design and function to a CI, except that the electrode is placed on the first auditory relay station in the brainstem, the cochlear nucleus (CN). The ABI electrode array is a small paddle that contains plate electrode contacts. The CN has not a single linear tonotopic organization from base to apex like the cochlea but different tonotopic subunits. The CN comprises multiple neuron types that are characterized by specific properties (morphology, regional distribution and cell-membrane characteristics), synaptic input and responses to acoustic stimuli. As the ABI electrode array is placed along the surface of the CN, each electrode likely activates a variety of neuron types, possibly with different characteristic frequencies. Patients undergoing ABI have variable benefit with regard to sound and speech comprehension. For the majority of patients, this improvement is essentially obtained by an augmentation of lip reading performances. Speech comprehension without lip-reading is not as good as with cochlear implants. PMID: 23044901 [PubMed - indexed for MEDLINE]

Related Articles An in vitro model of developmental synaptogenesis using cocultures of human neural progenitors and cochlear explants. Stem Cells Dev. 2013 Mar 15;22(6):901-12 Authors: Nayagam BA, Edge AS, Needham K, Hyakumura T, Leung J, Nayagam DA, Dottori M Abstract In mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. To successfully replace auditory neurons, stem cell-derived neurons must be electrically active, capable of organized outgrowth of processes, and of making functional connections with appropriate tissues. We have developed an in vitro assay to test these parameters using cocultures of developing cochlear explants together with neural progenitors derived from human embryonic stem cells (hESCs). We found that these neural progenitors are electrically active and extend their neurites toward the sensory hair cells in cochlear explants. Importantly, this neurite extension was found to be significantly greater when neural progenitors were predifferentiated toward a neural crest-like lineage. When grown in coculture with hair cells only (denervated cochlear explants), stem cell-derived processes were capable of locating and growing along the hair cell rows in an en passant-like manner. Many presynaptic terminals (synapsin 1-positive) were observed between hair cells and stem cell-derived processes in vitro. These results suggest that differentiated hESC-derived neural progenitors may be useful for developing therapies directed at auditory nerve replacement, including complementing emerging hair cell regeneration therapies. PMID: 23078657 [PubMed - in process]

Related Articles Decellularized ear tissues as scaffolds for stem cell differentiation. J Assoc Res Otolaryngol. 2013 Feb;14(1):3-15 Authors: Santi PA, Johnson SB Abstract Permanent sensorineural hearing loss is a major medical problem and is due to the loss of hair cells and subsequently spiral ganglion neurons in the cochlea. Since these cells lack the capacity of renewal in mammals, their regeneration would be an optimal solution to reverse hearing loss. In other tissues, decellularized extracellular matrix (ECM) has been used as a mechanical and biochemical scaffold for the induction of stem and other cells toward a target tissue phenotype. Such induced cells have been used for tissue and organ transplants in preclinical animal and human clinical applications. This paper reports for the first time the decellularization of the cochlea and identification of remaining laminin and collagen type IV as a first step in preparing an ECM scaffold for directing stem cells toward an auditory lineage. Fresh ear tissues were removed from euthanized mice, a rat and a human and processed for decellularization using two different detergent extraction methods. Cochleas were imaged with scanning thin-sheet laser imaging microscopy (sTSLIM) and brightfield microscopy. Detergent treatment of fresh tissue removed all cells as evidenced by lack of H&E and DNA staining of the membranous labyrinth while preserving components of the ECM. The organ of Corti was completely removed, as were spiral ganglion neurons, which appeared as hollow sheaths and tubes of basal lamina (BL) material. Cells of the stria vascularis were removed and its only vestige left was its laterally linking network of capillary BL that appeared to "float" in the endolymphatic space. Laminin and type IV collagen were detected in the ECM after decellularization and were localized in vascular, neural and epithelial BL. Further work is necessary to attempt to seed neural and other stem cells into the decellularized ECM to hopefully induce differentiation and subsequent in vivo engraftment into damaged cochleas. PMID: 23085833 [PubMed - in process]

Related Articles Challenges for stem cells to functionally repair the damaged auditory nerve. Expert Opin Biol Ther. 2013 Jan;13(1):85-101 Authors: Needham K, Minter RL, Shepherd RK, Nayagam BA Abstract INTRODUCTION: In the auditory system, a specialized subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the brainstem after the loss of hair cells. This neural prosthesis therefore depends on a residual population of functional neurons in order to function effectively. AREAS COVERED: In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, the benefits derived from a cochlear implant may be minimal. One way in which to restore function to the auditory nerve is to replace these lost neurons using differentiated stem cells, thus re-establishing the neural circuit required for cochlear implant function. Such a therapy relies on producing an appropriate population of electrophysiologically functional neurons from stem cells, and on these cells integrating and reconnecting in an appropriate manner in the deaf cochlea. EXPERT OPINION: Here we review progress in the field to date, including some of the key functional features that stem cell-derived neurons would need to possess and how these might be enhanced using electrical stimulation from a cochlear implant. PMID: 23094991 [PubMed - in process]

Related Articles Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium. J Neurosci. 2012 Oct 24;32(43):14927-41 Authors: Hu BH, Cai Q, Hu Z, Patel M, Bard J, Jamison J, Coling D Abstract Matrix metalloproteinases (MMPs) and their related gene products regulate essential cellular functions. An imbalance in MMPs has been implicated in various neurological disorders, including traumatic injuries. Here, we report a role for MMPs and their related gene products in the modulation of cochlear responses to acoustic trauma in rats. The normal cochlea was shown to be enriched in MMP enzymatic activity, and this activity was reduced in a time-dependent manner after traumatic noise injury. The analysis of gene expression by RNA sequencing and qRT-PCR revealed the differential expression of MMPs and their related genes between functionally specialized regions of the sensory epithelium. The expression of these genes was dynamically regulated between the acute and chronic phases of noise-induced hearing loss. Moreover, noise-induced expression changes in two endogenous MMP inhibitors, Timp1 and Timp2, in sensory cells were dependent on the stage of nuclear condensation, suggesting a specific role for MMP activity in sensory cell apoptosis. A short-term application of doxycycline, a broad-spectrum inhibitor of MMPs, before noise exposure reduced noise-induced hearing loss and sensory cell death. In contrast, a 7 d treatment compromised hearing sensitivity and potentiated noise-induced hearing loss. This detrimental effect of the long-term inhibition of MMPs on noise-induced hearing loss was further confirmed using targeted Mmp7 knock-out mice. Together, these observations suggest that MMPs and their related genes participate in the regulation of cochlear responses to acoustic overstimulation and that the modulation of MMP activity can serve as a novel therapeutic target for the reduction of noise-induced cochlear damage. PMID: 23100416 [PubMed - indexed for MEDLINE]

Related Articles Identification of tympanic border cells as slow-cycling cells in the cochlea. PLoS One. 2012;7(10):e48544 Authors: Taniguchi M, Yamamoto N, Nakagawa T, Ogino E, Ito J Abstract Mammalian cochlear sensory epithelial cells are believed to possess minimal regenerative potential because they halt proliferation during late stage of embryogenesis and never regenerate after birth. This means that sensorineural hearing loss caused by the death of cochlear sensory epithelial cells is a permanent condition. However, stem cells were recently identified in neonatal mice following dissociation of their inner ear organs. This suggests that regenerative therapy for sensorineural hearing loss may be possible. Unfortunately, dissociation distorts the microanatomy of the inner ear, making it difficult to determine the precise location of stem cells in unaltered specimens. To develop new therapeutic approaches based on sensory epithelial cell regeneration, the location of these stem cells must be elucidated. Stem cells normally proliferate at a slow rate in adult organs. In fact, so-called label-retaining cells, or slow-cycling cells, of the brain and skin are recognized as stem cells. In this study, using the exogenous proliferation marker, 5'-bromo-2'-deoxyuridine (BrdU) in combination with the endogenous proliferation marker Ki-67, we identified tympanic border cells. These cells, which are located beneath the basilar membrane in vivo, represent slow-cycling cells of the murine cochlea. Immunohistochemically, these cells stained positive for the immature cell marker Nestin. But it will be difficult to achieve regeneration of the cochlear function because these slow-cycling cells disappear in the mature murine cochlea. PMID: 23119055 [PubMed - indexed for MEDLINE]

Related Articles Noise-induced changes in cochlear compression in the rat as indexed by forward masking of the auditory brainstem response. Hear Res. 2012 Dec;294(1-2):64-72 Authors: Bielefeld EC, Hoglund EM, Feth LL Abstract The current study was undertaken to investigate changes in forward masking patterns using on-frequency and off-frequency maskers of 7 and 10 kHz probes in the Sprague-Dawley rat. Off-frequency forward masking growth functions have been shown in humans to be non-linear, while on-frequency functions behave linearly. The non-linear nature of the off-frequency functions is attributable to active processing from the outer hair cells, and was therefore expected to be sensitive to noise-induced cochlear damage. For the study, nine Sprague-Dawley rats' auditory brainstem responses (ABRs) were recorded with and without forward maskers. Forward masker-induced changes in latency and amplitude of the initial positive peak of the rats' auditory brainstem responses were assessed with both off-frequency and on-frequency maskers. The rats were then exposed to a noise designed to induce 20-40 dB of permanent threshold shift. Twenty-one days after the noise exposure, the forward masking growth functions were measured to assess noise-induced changes in the off-frequency and on-frequency forward masking patterns. Pre-exposure results showed compressive non-linear masking effects of the off-frequency conditions on both latency and amplitude of the auditory brainstem response. The noise rendered the off-frequency forward masking patterns more linear, consistent with human behavioral findings. On- and off-frequency forward masking growth functions were calculated, and they displayed patterns consistent with human behavioral functions, both prior to noise and after the noise exposure. PMID: 23123219 [PubMed - indexed for MEDLINE]

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 - in process]

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]

Related Articles Long-term follow-up of children with high-risk neuroblastoma: The ENSG5 trial experience. Pediatr Blood Cancer. 2012 Dec 31; Authors: Moreno L, Vaidya SJ, Pinkerton CR, Lewis IJ, Imeson J, Machin D, Pearson AD, on behalf of the European Neuroblastoma Study Group and the 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

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]

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 - in process]

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]

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 - in process]

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]

Related Articles Mesenchymal stem cell transplantation to the mouse cochlea as a treatment for childhood sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2013 Apr 2; 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 - as supplied by publisher]

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 - in process]

Related Articles Possible Toxicity of Tuberculostatic Agents in a Patient With a Novel TYMP Mutation Leading to Mitochondrial Neurogastrointestinal Encephalomyopathy. J Neurogenet. 2013 Apr 16; 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 - as supplied by publisher]

Related Articles Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss. Neurobiol Dis. 2013 Apr 20;56C: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 - as supplied by publisher]

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 - in process]