Stem Cell Treatment Hearing Loss

Stem Cell Treatment Hearing Loss at SIRM

Two Types:

1. Conductive hearing loss

A conductive hearing impairment is present when the sound is not reaching the inner ear, the cochlea. This can be due to external ear canal malformation, dysfunction of the eardrum or malfunction of the bones of the middle ear. The ear drum may show defects from small to total resulting in hearing loss of different degree. Scar tissue after ear infections may also make the ear drum dysfunction as well as when it is retracted and adherent to the medial part of the middle ear.

Dysfunction of the three small bones of the middle ear; hammer, anvil and stapes may result in conductive hearing loss. The mobility of the ossicles may be impaired of different reasons and disruption of the ossicular chain due to trauma, infection or anchylosis may also result in hearing loss.

2. Sensorineural hearing loss

A sensorineural hearing loss is one resulting from dysfunction of the inner ear, the cochlea, the nerve that transmits the impulses from the cochlea to the hearing centre in the brain or damage in the brain. The most common reason for sensorineural hearing impairment is damage to the hair cells in the cochlea. As we grow older the hair cells degenerate and lose their function, and our hearing deteriorates. Depending on the definition it could be estimated that more than 50% of the population over the age of 70 has an impaired hearing. Impaired hearing is the most common physical handicap in the industrialized world.

Another common reason for hearing loss due to hair cell damage is noise-induced hearing loss. These types of hearing loss are often most pronounced in the high frequency range. This will often interfere with speech understanding, as it is in the high frequency range that we find the consonant sounds that are most important especially in noisy surroundings. Head trauma, ear infections, tumours and ototoxic drugs such as gentamyacin are other reasons for sensorineural hearing loss.

Mixed hearing loss

Mixed hearing loss is a combination of the two types discussed above. Chronic ear infection that is a fairly common diagnosis could result in a defect ear drum and/or middle ear ossicle damages.

Stem Cell Treatment for Hearing Loss

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Related Articles GeneReviews® Book. 1993 Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A Abstract CLINICAL CHARACTERISTICS: Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms. DIAGNOSIS/TESTING: The diagnosis of MLD is established in a proband with progressive neurologic dysfunction, MRI evidence of leukodystrophy, or ARSA enzyme deficiency and identification of biallelic ARSA pathogenic variants on molecular genetic testing, or identification of elevated urinary excretion of sulfatides, or less commonly, identification of metachromatic lipid deposits in nervous system tissue. MANAGEMENT: Treatment of manifestations: Physical therapy and an enriched environment to maximize intellect, neuromuscular function, and mobility; family support to enable parents and/or caregivers to anticipate decisions on walking aids, wheelchairs, feeding tubes, and other changing care needs; treatment of seizures using antiepileptic drugs in standard protocols; treatment of contractures with muscle relaxants. Standard treatments for gastroesophageal reflux, constipation, drooling, dental care, pulmonary function, and impaired vison. Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) is the only therapy for primary central nervous system manifestations. Outcomes depend on the clinical stage and the presence of neurologic symptoms. The best results are observed when HSCT is performed in pre- and very early symptomatic individuals with the juvenile or adult form of the disease. HSCT is not recommended for individuals with symptomatic, late-infantile MLD. Prevention of secondary complications: Therapies designed to prevent decline in mobility, cognitive ability, communication, or food intake; safety measures for movement limitations and seizure precautions. Surveillance: Regular monitoring by a neurologist or metabolic geneticist including evaluation for changes in motor function, development of seizures, contractions, feeding difficulties, and disease progression following anesthesia or fever; periodic brain MRI examination. GENETIC COUNSELING: MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member. PMID: 20301309
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Related Articles GeneReviews® Book. 1993 Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A Abstract CLINICAL CHARACTERISTICS: The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years. DIAGNOSIS/TESTING: The diagnosis of an ASAH1-related disorder is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in ASAH1 and/or decreased activity of the enzyme acid ceramidase in peripheral blood leukocytes or cultured skin fibroblasts. MANAGEMENT: Treatment of manifestations is symptomatic and multidisciplinary. For FD: Management may include gastrostomy tube placement, surgical removal of oral and airway granulomas, and treatment of seizures as per standard practice. Hematopoietic stem cell transplantation may be an option in affected individuals who do not have significant neurologic involvement. For SMA-PME: Management may include standard treatment for hearing loss, scoliosis, seizures, and tremor. Weakness can be mitigated with the use of orthotics, wheelchairs, or other assistive devices. Surveillance: For FD: At each visit assess growth with emphasis on feeding and nutritional status; airway, joint mobility, and developmental milestones. For SMA-PME: At each visit monitor growth with emphasis on feeding and nutritional status, pulmonary function, back for evidence of scoliosis, strength, seizure control, functional capacity (e.g., mobility, communication); assess hearing annually. GENETIC COUNSELING: ASAH1-related disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. Once the ASAH1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible. PMID: 29595935
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Related Articles GeneReviews® Book. 1993 Authors: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A Abstract CLINICAL CHARACTERISTICS: Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with early progressive disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing form of the disease. Additional findings in both forms of MPS II include: short stature; macrocephaly with or without communicating hydrocephalus; macroglossia; hoarse voice; conductive and sensorineural hearing loss; hepatosplenomegaly; dysostosis multiplex; spinal stenosis; and carpal tunnel syndrome. DIAGNOSIS/TESTING: The diagnosis of MPS II is established in a male proband by identification of deficient iduronate 2-sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase. Detection of a hemizygous pathogenic variant in IDS confirms the diagnosis in a male proband with an unusual phenotype or a phenotype that does not match the results of GAG testing. The diagnosis of MPS II is usually established in a female proband with suggestive clinical features by identification of a heterozygous IDS pathogenic variant on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Interventions commonly include: developmental, occupational, and physical therapy; shunting for hydrocephalus; tonsillectomy and adenoidectomy; positive pressure ventilation (CPAP or tracheostomy); carpal tunnel release; cardiac valve replacement; inguinal hernia repair; hip replacement. Prevention of primary manifestations: Weekly enzyme replacement therapy (ERT) with infusions of idursulfase (Elaprase®), a recombinant form of human iduronate 2-sulfatase, is approved to treat somatic manifestations and prolong survival. Pretreatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions. Hematopoietic stem cell transplantation (HSCT) (using umbilical cord blood or bone marrow) could provide sufficient enzyme activity to slow or stop the progression of the disease; however, no controlled clinical studies have been conducted in MPS II. Prevention of secondary complications: Anesthesia is best administered in centers familiar with the potential complications in persons with MPS II. Surveillance: Depends on organ system and disease severity and usually includes annual: cardiology evaluation and echocardiogram; pulmonary evaluation including pulmonary function testing; audiogram; ophthalmology examination; developmental assessment; neurologic examination. Additional studies may include: sleep study for obstructive apnea; nerve conduction velocity to assess for carpal tunnel syndrome; head/neck MRI to document ventricular size and cervicomedullary narrowing; opening pressure on lumbar puncture; and orthopedic evaluation to monitor hip disease. Evaluation of relatives at risk: While clinical experience suggests that early diagnosis of at-risk males allows initiation of ERT before the onset of irreversible changes and often before significant disease progression, it is unclear at present whether the potential benefits of early initiation of ERT justify early diagnosis by either newborn screening or testing of at-risk male relatives. GENETIC COUNSELING: MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has the pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Germline mosaicism has been observed. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known. PMID: 20301451
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Related Articles Molecular mechanisms underlying the protective effects of hydrogen-saturated saline on noise-induced hearing loss. Acta Otolaryngol. 2017 10;137(10):1063-1068 Authors: Chen L, Han M, Lu Y, Chen D, Sun X, Yang S, Sun W, Yu N, Zhai S Abstract OBJECTIVES: This study aimed to explore the molecular mechanism of the protective effects of hydrogen-saturated saline on NIHL. METHODS: Guinea pigs were divided into three groups: hydrogen-saturated saline; normal saline; and control. For saline administration, the guinea pigs were given daily abdominal injections 3 d before and 1 h before noise exposure. ABR were tested to examine cochlear physiology changes. The changes of 8-hydroxy-desoxyguanosine (8-HOdG), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1) and high mobility group box-1 protein (HMGB1) in the cochlea were also examined. RESULTS: The results showed that pre-treatment with hydrogen-saturated saline could significantly attenuate noise-induced hearing loss. The concentration of 8-HOdG was also significantly decreased in the hydrogen-saturated saline group compared with the normal saline group. After noise exposure, the concentrations of IL-1, IL-6, TNF-α, and ICAM-1 in the cochlea of guinea pigs in the hydrogen-saturated saline group were dramatically reduced compared to those in the normal saline group. The concentrations of HMGB-1 and IL-10 in the hydrogen-saturated saline group were significantly higher than in those in the normal saline group immediately and at 7 d after noise exposure. CONCLUSIONS: This study revealed for the first time the protective effects of hydrogen-saturated saline on noise-induced hearing loss (NIHL) are related to both the anti-oxidative activity and anti-inflammatory activity. PMID: 28549396 [PubMed - indexed for MEDLINE]
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Related Articles Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors. Pediatr Hematol Oncol. 2017 Mar;34(2):120-129 Authors: Clemens E, de Vries AC, Am Zehnhoff-Dinnesen A, Tissing WJ, Loonen JJ, Pluijm SF, van Dulmen-den Broeder E, Bresters D, Versluys B, Kremer LC, van der Pal HJ, Neggers SJ, van Grotel M, M van den Heuvel-Eibrink M Abstract Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Münster criteria (>20 dB at ≥4-8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m2 and median total cumulative dose carboplatin: 2520 mg/m2). Median follow-up time was 5.5 years (range: 1.0-28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Münster degrees was observed in five of 61 survivors after 1.6-19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale. PMID: 28590156 [PubMed - indexed for MEDLINE]
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Related Articles Evaluating the ototoxicity of an anti-MRSA peptide KR-12-a2. Braz J Otorhinolaryngol. 2018 Jul - Aug;84(4):441-447 Authors: Sung CM, Kim HC, Cho YB, Shin SY, Jang CH Abstract INTRODUCTION: Methicillin-resistant staphylococcus aureus is an emerging problem for the treatment of chronic suppurative otitis media, and also for pediatric tympanostomy tube otorrhea. To date, there are no effective topical antibiotic drugs to treat methicillin-resistant staphylococcus aureus otorrhea. OBJECTIVE: In this study, we evaluated the ototoxicity of topical KR-12-a2 solution on the cochlea when it is applied topically in the middle ear of guinea pigs. METHODS: The antimicrobial activity of KR-12-a2 against methicillin-resistant staphylococcus aureus strains was examined by using the inhibition zone test. Topical application of KR-12-a2 solution, gentamicin and phosphate buffered saline were applied in the middle ear of the guinea pigs after inserting ventilation tubes. Ototoxicity was assessed by auditory brainstem evoked response and scanning electron microscope examination. RESULTS: KR-12-a2 produced an inhibition zone against methicillin-resistant staphylococcus aureus from 6.25 μg. Hearing threshold in the KR-12-a2 and PBS groups were similar to that before ventilation tube insertion. However, the gentamicin group showed elevation of the hearing threshold and there were statistically significant differences compared to the phosphate buffered saline or the KR-12-a2 group. In the scanning electron microscope findings, the KR-12-a2 group showed intact outer hair cells. However, the gentamicin group showed total loss of outer hair cells. In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. CONCLUSION: In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. The KR-12-a2 solution can be used as ototopical drops for treating methicillin-resistant staphylococcus aureus otorrhea; however, further evaluations, such as the definition of optimal concentration and combination, are necessary. PMID: 28625810 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of mouse-induced pluripotent stem cells into the cochlea for the treatment of sensorineural hearing loss. Acta Otolaryngol. 2017 Nov;137(11):1136-1142 Authors: Chen J, Guan L, Zhu H, Xiong S, Zeng L, Jiang H Abstract CONCLUSION: Mouse-induced pluripotent stem cells (iPSCs) could differentiate into hair cell-like cells and spiral ganglion-like cells after transplantation into mouse cochleae, but it cannot improve the auditory brain response (ABR) thresholds in short term. OBJECTIVE: To evaluate the potential of iPSCs for use as a source of transplants for the treatment of sensorineural hearing loss (SNHL). METHODS: Establishing SNHL mice model, then injecting the iPSCs or equal volume DMEM basic medium into the cochleae, respectively. Immunofluorescence staining and reverse transcription-polymerase chain reaction (RT-PCR) were used to assess the survival, migration, differentiation of the transplanted iPSCs in cochleae and then recorded the ABR threshold in different time. Hematoxylin-eosin (HE) staining was used to observe the teratoma formation. RESULTS: Four weeks after transplantation, CM-Di1-labeled iPSCs could be found in the modiolus and Rosenthal's canal (RC), and some of them could expressed auditory hair cell markers or spiral ganglion neuron makers in group A, but not found in group B and C. As to the ABR threshold, no significance differences were found between pre- with postoperative in group A or B. In our study, no teratoma was observed in the cochleae. PMID: 28643534 [PubMed - indexed for MEDLINE]
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Related Articles Rhesus Cochlear and Vestibular Functions Are Preserved After Inner Ear Injection of Saline Volume Sufficient for Gene Therapy Delivery. J Assoc Res Otolaryngol. 2017 Aug;18(4):601-617 Authors: Dai C, Lehar M, Sun DQ, Rvt LS, Carey JP, MacLachlan T, Brough D, Staecker H, Della Santina AM, Hullar TE, Della Santina CC Abstract Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome. The primary goal of the present study was to assess that risk in rhesus monkeys, which closely approximates humans with regard to middle and inner ear anatomy. Secondary goals were to identify the best delivery route into the primate ear from among two common surgical approaches (i.e., via an oval window stapedotomy and via the round window) and to determine the relative volumes of rhesus, rodent, and human labyrinths for extrapolation of results to other species. We measured hearing and vestibular functions before and 2, 4, and 8 weeks after unilateral injection of phosphate-buffered saline vehicle (PBSV) into the perilymphatic space of normal rhesus monkeys at volumes sufficient to deliver an atoh1 gene therapy vector. To isolate effects of injection, PBSV without vector was used. Assays included behavioral observation, auditory brainstem responses, distortion product otoacoustic emissions, and scleral coil measurement of vestibulo-ocular reflexes during whole-body rotation in darkness. Three groups (N = 3 each) were studied. Group A received a 10 μL transmastoid/trans-stapes injection via a laser stapedotomy. Group B received a 10 μL transmastoid/trans-round window injection. Group C received a 30 μL transmastoid/trans-round window injection. We also measured inner ear fluid space volume via 3D reconstruction of computed tomography (CT) images of adult C57BL6 mouse, rat, rhesus macaque, and human temporal bones (N = 3 each). Injection was well tolerated by all animals, with eight of nine exhibiting no signs of disequilibrium and one animal exhibiting transient disequilibrium that resolved spontaneously by 24 h after surgery. Physiologic results at the final, 8-week post-injection measurement showed that injection was well tolerated. Compared to its pretreatment values, no treated ear's ABR threshold had worsened by more than 5 dB at any stimulus frequency; distortion product otoacoustic emissions remained detectable above the noise floor for every treated ear (mean, SD and maximum deviation from baseline: -1.3, 9.0, and -18 dB, respectively); and no animal exhibited a reduction of more than 3 % in vestibulo-ocular reflex gain during high-acceleration, whole-body, passive yaw rotations in darkness toward the treated side. All control ears and all operated ears with definite histologic evidence of injection through the intended site showed similar findings, with intact hair cells in all five inner ear sensory epithelia and intact auditory/vestibular neurons. The relative volumes of mouse, rat, rhesus, and human inner ears as measured by CT were (mean ± SD) 2.5 ± 0.1, 5.5 ± 0.4, 59.4 ± 4.7 and 191.1 ± 4.7 μL. These results indicate that injection of PBSV at volumes sufficient for gene therapy delivery can be accomplished without destruction of inner ear structures required for hearing and vestibular sensation. PMID: 28646272 [PubMed - indexed for MEDLINE]
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Related Articles Early hematopoietic stem cell transplantation in a patient with severe mucopolysaccharidosis II: A 7 years follow-up. Mol Genet Metab Rep. 2017 Sep;12:62-68 Authors: Barth AL, de Magalhães TSPC, Reis ABR, de Oliveira ML, Scalco FB, Cavalcanti NC, Silva DSE, Torres DA, Costa AAP, Bonfim C, Giugliani R, Llerena JC, Horovitz DDG Abstract Mucopolysaccharidosis type II (MPS II - Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2 sulfatase (I2S), leading to the accumulation of the glycosaminoglycans, affecting multiple organs and systems. Enzyme replacement therapy does not cross the blood brain barrier, limiting results in neurological forms of the disease. Another option of treatment for severe MPS, hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for the severe form of MPS type I, since it can preserve neurocognition when performed early in the course of the disease. To date, only few studies have examined the long-term outcomes of HSCT in patients with MPS II. We describe the seven-year follow-up of a prenatally diagnosed MPS II boy with positive family history of severe MPS form, submitted to HSCT with umbilical cord blood cells at 70 days of age. Engraftment after 30 days revealed mixed chimerism with 79% donor cells; after 7 years engraftment remains at 80%. I2S activity 30 days post-transplant was low in plasma and normal in leukocytes and the same pattern is observed to date. At age 7 years growth charts are normal and he is very healthy, although mild signs of dysostosis multiplex are present, as well as hearing loss. The neuropsychological evaluation (Wechsler Intelligence Scale for Children - Fourth Edition - WISC-IV), disclosed an IQ of 47. Despite this low measured IQ, the patient continues to show improvements in cognitive, language and motor skills, being quite functional. We believe that HSCT is a therapeutic option for MPS II patients with the severe phenotype, as it could preserve neurocognition or even halt neurodegeneration, provided strict selection criteria are followed. PMID: 28649514 [PubMed]
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Related Articles Nanofibrous scaffolds for the guidance of stem cell-derived neurons for auditory nerve regeneration. PLoS One. 2017;12(7):e0180427 Authors: Hackelberg S, Tuck SJ, He L, Rastogi A, White C, Liu L, Prieskorn DM, Miller RJ, Chan C, Loomis BR, Corey JM, Miller JM, Duncan RK Abstract Impairment of spiral ganglion neurons (SGNs) of the auditory nerve is a major cause for hearing loss occurring independently or in addition to sensory hair cell damage. Unfortunately, mammalian SGNs lack the potential for autonomous regeneration. Stem cell based therapy is a promising approach for auditory nerve regeneration, but proper integration of exogenous cells into the auditory circuit remains a fundamental challenge. Here, we present novel nanofibrous scaffolds designed to guide the integration of human stem cell-derived neurons in the internal auditory meatus (IAM), the foramen allowing passage of the spiral ganglion to the auditory brainstem. Human embryonic stem cells (hESC) were differentiated into neural precursor cells (NPCs) and seeded onto aligned nanofiber mats. The NPCs terminally differentiated into glutamatergic neurons with high efficiency, and neurite projections aligned with nanofibers in vitro. Scaffolds were assembled by seeding GFP-labeled NPCs on nanofibers integrated in a polymer sheath. Biocompatibility and functionality of the NPC-seeded scaffolds were evaluated in vivo in deafened guinea pigs (Cavia porcellus). To this end, we established an ouabain-based deafening procedure that depleted an average 72% of SGNs from apex to base of the cochleae and caused profound hearing loss. Further, we developed a surgical procedure to implant seeded scaffolds directly into the guinea pig IAM. No evidence of an inflammatory response was observed, but post-surgery tissue repair appeared to be facilitated by infiltrating Schwann cells. While NPC survival was found to be poor, both subjects implanted with NPC-seeded and cell-free control scaffolds showed partial recovery of electrically-evoked auditory brainstem thresholds. Thus, while future studies must address cell survival, nanofibrous scaffolds pose a promising strategy for auditory nerve regeneration. PMID: 28672008 [PubMed - indexed for MEDLINE]
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Related Articles Adenomatous Tumors of the Middle Ear: A Literature Review. Int Arch Otorhinolaryngol. 2017 Jul;21(3):308-312 Authors: Cardoso FA, Monteiro EMR, Lopes LB, Avila MNDC, Scarioli BO Abstract Introduction  Neuroendocrine adenomas of the middle ear (NAME) are uncommon causes of middle ear masses. Mostly limited to case reports and small series, the literature is poor in providing an overall assessment of these tumors. Objective  To review the current literature about all aspects of the disease, including its etiology, clinical manifestations, diagnosis, and treatment. Data Synthesis  The pathogenesis of adenomatous tumors of the middle ear is not clear yet. One potential explanation is that an undifferentiated pluripotent endodermal stem cell may still be present in the middle ear mucosal surface, and may be the origin of the tumors. It typically appears as a nonspecific retrotympanic mass. The average age of onset for the disease is the fifth decade, and the most common clinical symptom is conductive hearing loss. Malign behavior is rare. There are numerous differential diagnoses of NAME. The final diagnosis depends on microscopic findings. The preoperative evaluation should include the use of computed tomography and magnetic resonance imaging. The adjunctive therapy of middle ear adenomatous tumors with radiotherapy, chemotherapy or somatostatin analogs is generally not recommended. Conclusion  There is still much debate on pathogenesis and classification of NAME. Saliba's classification is currently the most complete and preferable one. Aggressive surgical procedure with ossicular chain excision is the gold standard treatment. Follow-up with physical and radiological exams is mandatory, particularly if the first procedure was conservative, without the removal of the encased ossicles. PMID: 28680503 [PubMed]
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Related Articles Hearing Restoration: A Step Closer? JAMA. 2017 Jul 25;318(4):319-320 Authors: Lyon J PMID: 28687841 [PubMed - indexed for MEDLINE]
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Related Articles Brief Stimulus Exposure Fully Remediates Temporal Processing Deficits Induced by Early Hearing Loss. J Neurosci. 2017 08 09;37(32):7759-7771 Authors: Green DB, Mattingly MM, Ye Y, Gay JD, Rosen MJ Abstract In childhood, partial hearing loss can produce prolonged deficits in speech perception and temporal processing. However, early therapeutic interventions targeting temporal processing may improve later speech-related outcomes. Gap detection is a measure of auditory temporal resolution that relies on the auditory cortex (ACx), and early auditory deprivation alters intrinsic and synaptic properties in the ACx. Thus, early deprivation should induce deficits in gap detection, which should be reflected in ACx gap sensitivity. We tested whether earplugging-induced, early transient auditory deprivation in male and female Mongolian gerbils caused correlated deficits in behavioral and cortical gap detection, and whether these could be rescued by a novel therapeutic approach: brief exposure to gaps in background noise. Two weeks after earplug removal, animals that had been earplugged from hearing onset throughout auditory critical periods displayed impaired behavioral gap detection thresholds (GDTs), but this deficit was fully reversed by three 1 h sessions of exposure to gaps in noise. In parallel, after earplugging, cortical GDTs increased because fewer cells were sensitive to short gaps, and gap exposure normalized this pattern. Furthermore, in deprived animals, both first-spike latency and first-spike latency jitter increased, while spontaneous and evoked firing rates decreased, suggesting that deprivation causes a wider range of perceptual problems than measured here. These cortical changes all returned to control levels after gap exposure. Thus, brief stimulus exposure, perhaps in a salient context such as the unfamiliar placement into a testing apparatus, rescued impaired gap detection and may have potential as a remediation tool for general auditory processing deficits.SIGNIFICANCE STATEMENT Hearing loss in early childhood leads to impairments in auditory perception and language processing that can last well beyond the restoration of hearing sensitivity. Perceptual deficits can be improved by training, or by acoustic enrichment in animal models, but both approaches involve extended time and effort. Here, we used a novel remediation technique, brief periods of auditory stimulus exposure, to fully remediate cortical and perceptual deficits in gap detection induced by early transient hearing loss. This technique also improved multiple cortical response properties. Rescue by this efficient exposure regime may have potential as a therapeutic tool to remediate general auditory processing deficits in children with perceptual challenges arising from early hearing loss. PMID: 28706081 [PubMed - indexed for MEDLINE]
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Related Articles Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta). Hear Res. 2017 09;353:213-223 Authors: Valero MD, Burton JA, Hauser SN, Hackett TA, Ramachandran R, Liberman MC Abstract Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12-27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50-75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents. PMID: 28712672 [PubMed - indexed for MEDLINE]
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Related Articles Absence of Relationship between Mitochondrial DNA Haplogroups and Cisplatin-Induced Hearing Loss. Int J Otolaryngol. 2017;2017:5185268 Authors: Graterol D, Mir C, Garcia-Vaquero C, Braña I, Pardo AN, Rochera-Villach MI, Lyakhovich A, LLeonart ME, Lorente J Abstract BACKGROUND: Many drugs used for cancer chemotherapy produce reactive oxygen species, thus leading to various complications including nephrotoxicity, cardiotoxicity, and ototoxicity. OBJECTIVE: We have provided a haplogroup analysis of a cohort of cancer patients treated with chemotherapy and compared factors associated with associated hearing loss. STUDY DESIGN AND METHODS: This observational cohort study includes a pure-tone audiometry of the patients who underwent chemotherapeutic treatment. Medical history, presence of risk factors for hearing loss, toxic habits, and association with haplogroups have been determined. RESULTS: 40% of patients developed hearing loss after administration of cisplatin, which was bilateral and symmetrical and of high frequencies. The most frequent haplogroup was H with a slight overexpression of groups V and K and a low frequency of groups J and T. No association of the haplogroup types with the hearing loss has been found; however age was revealed as an important determining factor. CONCLUSIONS: Ototoxicity caused by cisplatin is manifested as bilateral, symmetrical, and predominantly high frequency hearing loss. Although we did not find a strong correlation of haplogroups with ototoxicity, our results revealed the existence of a risk group of elderly patients over 60, which are more susceptible to hearing loss induced by cisplatin, than young adults, regardless of preexisting hearing loss. PMID: 28757873 [PubMed]
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Related Articles Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures. J Assoc Res Otolaryngol. 2017 Dec;18(6):731-750 Authors: Pfingst BE, Colesa DJ, Swiderski DL, Hughes AP, Strahl SB, Sinan M, Raphael Y Abstract Because cochlear implants function by stimulating the auditory nerve, it is assumed that the condition of the nerve plays an important role in the efficacy of the prosthesis. Thus, considerable research has been devoted to methods of preserving the nerve following deafness. Neurotrophins have been identified as a potential contributor to neural health, but most of the research to date has been done in young animals and for short periods (less than 3 to 6 months) after the onset of treatment. The first objective of the current experiment was to examine the effects of a neurotrophin gene therapy delivery method on spiral ganglion neuron (SGN) preservation and function in the long term (5 to 14 months) in mature guinea pigs with cochlear implants. The second objective was to examine several potential non-invasive monitors of auditory nerve health following the neurotrophin gene therapy procedure. Eighteen mature adult male guinea pigs were deafened by cochlear perfusion of neomycin and then one ear was inoculated with an adeno-associated viral vector with an Nft3-gene insert (AAV.Ntf3) and implanted with a cochlear implant electrode array. Five control animals were deafened and inoculated with an empty AAV and implanted. Data from 43 other guinea pig ears from this and previous experiments were used for comparison: 24 animals implanted in a hearing ear, nine animals deafened and implanted with no inoculation, and ten normal-hearing non-implanted ears. After 4 to 21 months of psychophysical and electrophysiological testing, the animals were prepared for histological examination of SGN densities and inner hair cell (IHC) survival. Seventy-eight percent of the ears deafened and inoculated with AAV.Ntf3 showed better SGN survival than the 14 deafened-control ears. The degree of SGN preservation following the gene therapy procedure was variable across animals and across cochlear turns. Slopes of psychophysical multipulse integration (MPI) functions were predictive of SGN density, but only in animals with preserved IHCs. MPI was not affected by the AAV.Ntf3 treatment, but there was a minor improvement in temporal integration (TI). AAV.Ntf3 treatment had significant effects on ECAP and EABR amplitude growth func-tion (AGF) slopes; the reduction in slope in deafened ears was ameliorated by the AAV.Ntf3 treatment. Slopes of the ECAP and EABR AGFs were predictive of SGN density in a broad area near and just apical to the implant. The highest ensemble spontaneous activity (ESA) values were seen in animals with surviving IHCs, but AAV.Ntf3 treatment in deafened ears resulted in slightly higher ESA values compared to deafened untreated ears. Overall, a combination of the psychophysical and electrophysiological measures can be useful for monitoring the health of the implanted cochlea in guinea pigs. These measures should be applicable for assessing cochlear health in human subjects. PMID: 28776202 [PubMed - indexed for MEDLINE]
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Related Articles Retracted: Exogenous IL-4-Expressing Bone Marrow Mesenchymal Stem Cells for the Treatment of Autoimmune Sensorineural Hearing Loss in a Guinea Pig Model. Biomed Res Int. 2017;2017:9539385 Authors: International BR Abstract [This retracts the article DOI: 10.1155/2014/856019.]. PMID: 28785593 [PubMed]
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Related Articles Oral Administration of Clinical Stage Drug Candidate SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in Rats. Otol Neurotol. 2017 10;38(9):1355-1361 Authors: Petremann M, Tran Van Ba C, Broussy A, Romanet C, Dyhrfjeld-Johnsen J Abstract HYPOTHESIS: SENS-401, an oral clinical-stage drug, may reduce cisplatin-induced hearing loss and cochlear damage in an in vivo model. BACKGROUND: Cisplatin is commonly associated with hearing loss, causing significant learning and behavioral difficulties in the pediatric cancer population, and for which there are currently no clinical solutions. SENS-401 has previously been shown to improve acoustic trauma-induced hearing loss in vivo. METHODS: The effect of SENS-401 (R-azasetron besylate) on cisplatin IC50 values was evaluated in a panel of cisplatin-sensitive cell lines (NIH:OVCAR-3, SK-N-AS, NCI-H460, FaDu). Auditory brainstem response and distortion product otoacoustic emission tests were performed in a rat model of cisplatin-induced hearing-loss (8 mg/kg, day 1) at baseline, and after 14 days of SENS-401 (6.6, 13.2, 26.4 mg/kg/d). Cochlear outer hair cells were counted after immunolabeling for myosin-VIIa. RESULTS: Cisplatin cytotoxicity was not impacted by the addition of SENS-401 (up to 10 μM) in any of the cell types evaluated. In vivo, all SENS-401 doses significantly improved auditory brainstem response threshold shift (up to 30 dB) and distortion product otoacoustic emission amplitude loss (up to 19 dB) over placebo. Body weight and survival were not significantly different between rats receiving placebo and those receiving 26.4 mg/kg SENS-401. Significantly more surviving outer hair cells were present after SENS-401 treatment compared with placebo (p < 0.001), with up to 11-fold more in the basal turn of the cochlea. CONCLUSION: In vivo and in vitro data support the otoprotective potential and tolerability of SENS-401 without impacting chemotherapeutic potential. Oral SENS-401 is a promising candidate for treating cisplatin-induced ototoxicity. PMID: 28796092 [PubMed - indexed for MEDLINE]
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Related Articles Musashi-1 is the candidate of the regulator of hair cell progenitors during inner ear regeneration. BMC Neurosci. 2017 08 16;18(1):64 Authors: Wakasaki T, Niiro H, Jabbarzadeh-Tabrizi S, Ohashi M, Kimitsuki T, Nakagawa T, Komune S, Akashi K Abstract BACKGROUND: Hair cell loss in the cochlea is caused by ototoxic drugs, aging, and environmental stresses and could potentially lead to devastating pathophysiological effects. In adult mammals, hair cell loss is irreversible and may result in hearing and balance deficits. In contrast, nonmammalian vertebrates, including birds, can regenerate hair cells through differentiation of supporting cells and restore inner ear function, suggesting that hair cell progenitors are present in the population of supporting cells. RESULTS: In the present study, we aimed to identify novel genes related to regeneration in the chicken utricle by gene expression profiling of supporting cell and hair cell populations obtained by laser capture microdissection. The volcano plot identified 408 differentially expressed genes (twofold change, p = 0.05, Benjamini-Hochberg multiple testing correction), 175 of which were well annotated. Among these genes, we focused on Musashi-1 (MSI1), a marker of neural stem cells involved in Notch signaling, and the downstream genes in the Notch pathway. Higher expression of these genes in supporting cells compared with that in hair cells was confirmed by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry analysis demonstrated that MSI1 was mainly localized at the basal side of the supporting cell layer in normal chick utricles. During the regeneration period following aminoglycoside antibiotic-induced damage of chicken utricles, the expression levels of MSI1, hairy and enhancer of split-5, and cyclin D1 were increased, and BrdU labeling indicated that cell proliferation was enhanced. CONCLUSIONS: The findings of this study suggested that MSI1 played an important role in the proliferation of supporting cells in the inner ear during normal and damaged conditions and could be a potential therapeutic target in the treatment of vestibular defects. PMID: 28814279 [PubMed - indexed for MEDLINE]
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Related Articles Recent Advancements in the Regeneration of Auditory Hair Cells and Hearing Restoration. Front Mol Neurosci. 2017;10:236 Authors: Mittal R, Nguyen D, Patel AP, Debs LH, Mittal J, Yan D, Eshraghi AA, Van De Water TR, Liu XZ Abstract Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepithelial sensory cells. Any disruption of the biochemical and molecular pathways that facilitate these responses can result in severe deficits, including hearing loss and vestibular dysfunction. Hearing is affected by both environmental and genetic factors, with impairment of auditory function being the most common neurosensory disorder affecting 1 in 500 newborns, as well as having an impact on the majority of elderly population. Damage to auditory sensory cells is not reversible, and if sufficient damage and cell death have taken place, the resultant deficit may lead to permanent deafness. Cochlear implants are considered to be one of the most successful and consistent treatments for deaf patients, but only offer limited recovery at the expense of loss of residual hearing. Recently there has been an increased interest in the auditory research community to explore the regeneration of mammalian auditory hair cells and restoration of their function. In this review article, we examine a variety of recent therapies, including genetic, stem cell and molecular therapies as well as discussing progress being made in genome editing strategies as applied to the restoration of hearing function. PMID: 28824370 [PubMed]
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Related Articles Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G. Proc Natl Acad Sci U S A. 2017 09 05;114(36):9695-9700 Authors: Emptoz A, Michel V, Lelli A, Akil O, Boutet de Monvel J, Lahlou G, Meyer A, Dupont T, Nouaille S, Ey E, Franca de Barros F, Beraneck M, Dulon D, Hardelin JP, Lustig L, Avan P, Petit C, Safieddine S Abstract Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected. PMID: 28835534 [PubMed - indexed for MEDLINE]
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Related Articles Renal, auricular, and ocular outcomes of Alport syndrome and their current management. Pediatr Nephrol. 2018 Aug;33(8):1309-1316 Authors: Zhang Y, Ding J Abstract Alport syndrome is a hereditary glomerular basement membrane disease caused by mutations in the COL4A3/4/5 genes encoding the type IV collagen alpha 3-5 chains. Most cases of Alport syndrome are inherited as X-linked dominant, and some as autosomal recessive or autosomal dominant. The primary manifestations are hematuria, proteinuria, and progressive renal failure, whereas some patients present with sensorineural hearing loss and ocular abnormalities. Renin-angiotensin-aldosterone system blockade is proven to delay the onset of renal failure by reducing proteinuria. Renal transplantation is a curative treatment for patients who have progressed to end-stage renal disease. However, only supportive measures can be used to improve hearing loss and visual loss. Although both stem cell therapy and gene therapy aim to repair the basement membrane defects, technical difficulties require more research in Alport mice before clinical studies. Here, we review the renal, auricular, and ocular manifestations and outcomes of Alport syndrome and their current management. PMID: 28864840 [PubMed - in process]
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Related Articles Ferulic acid promotes survival and differentiation of neural stem cells to prevent gentamicin-induced neuronal hearing loss. Exp Cell Res. 2017 11 15;360(2):257-263 Authors: Gu L, Cui X, Wei W, Yang J, Li X Abstract Neural stem cells (NSCs) have exhibited promising potential in therapies against neuronal hearing loss. Ferulic acid (FA) has been widely reported to enhance neurogenic differentiation of different stem cells. We investigated the role of FA in promoting NSC transplant therapy to prevent gentamicin-induced neuronal hearing loss. NSCs were isolated from mouse cochlear tissues to establish in vitro culture, which were then treated with FA. The survival and differentiation of NSCs were evaluated. Subsequently, neurite outgrowth and excitability of the in vitro neuronal network were assessed. Gentamicin was used to induce neuronal hearing loss in mice, in the presence and absence of FA, followed by assessments of auditory brainstem response (ABR) and distortion product optoacoustic emissions (DPOAE) amplitude. FA promoted survival, neurosphere formation and differentiation of NSCs, as well as neurite outgrowth and excitability of in vitro neuronal network. Furthermore, FA restored ABR threshold shifts and DPOAE in gentamicin-induced neuronal hearing loss mouse model in vivo. Our data, for the first time, support potential therapeutic efficacy of FA in promoting survival and differentiation of NSCs to prevent gentamicin-induced neuronal hearing loss. PMID: 28916193 [PubMed - indexed for MEDLINE]
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Related Articles Role of BDNF and neurotrophic receptors in human inner ear development. Cell Tissue Res. 2017 12;370(3):347-363 Authors: Johnson Chacko L, Blumer MJF, Pechriggl E, Rask-Andersen H, Dietl W, Haim A, Fritsch H, Glueckert R, Dudas J, Schrott-Fischer A Abstract The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons. PMID: 28924861 [PubMed - indexed for MEDLINE]
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Related Articles The histone deacetylase inhibitor sodium butyrate protects against noise-induced hearing loss in Guinea pigs. Neurosci Lett. 2017 Nov 01;660:140-146 Authors: Yang DH, Xie J, Liu K, Peng Z, Guo JY, Yu SK, Wang GP, Gong SS Abstract Noise-induced hearing loss (NIHL) severely impacts the quality of life of affected individuals. Oxidative stress resulting from noise exposure is a significant cause of NIHL. Although histone deacetylase (HDAC) inhibitors were shown to protect against NIHL, the underlying mechanism remains unclear, and it is not known how they act on noise-induced oxidative stress. In the current study, we investigated the expression levels of acetyl-histone H3 (Lys9) (H3-AcK9), histone deacetylase 1 (HDAC1), and 3-nitrotyrosine (3-NT), an oxidative stress marker, in a guinea pig model of NIHL using immunohistology and Western blotting. We then assessed the effects of systemic administration of the HDAC inhibitor, sodium butyrate (SB), on noise-induced permanent threshold shifts (PTS), hair cell (HC) loss, and changes in the above mentioned markers. The results showed that SB attenuated noise-induced PTS and outer hair cell loss. SB treatment promoted H3-AcK9 expression and repressed HDAC1 expression in the nuclei of HCs and Hensen's cells after noise exposure. Furthermore, SB attenuated the noise-induced increase of 3-NT expression in HCs and Hensen's cells. These findings suggest that SB protects against NIHL by reversing the noise-induced histone acetylation imbalance and inhibiting oxidative stress in cochlear HCs and Hensen's cells. SB treatment may represent a potential strategy to prevent and treat NIHL. PMID: 28928030 [PubMed - indexed for MEDLINE]
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Related Articles Macrophage recruitment, but not interleukin 1 beta activation, enhances noise-induced hearing damage. Biochem Biophys Res Commun. 2017 11 18;493(2):894-900 Authors: Mizushima Y, Fujimoto C, Kashio A, Kondo K, Yamasoba T Abstract It has been suggested that macrophages or inflammatory monocytes participate in the pathology of noise-induced hearing loss (NIHL), but it is unclear how extensively these cells contribute to the development of temporary and/or permanent NIHL. To address this question, we used clodronate liposomes to deplete macrophages and monocytes. After clodronate liposome injection, mice were exposed to 4-kHz octave band noise at 121 dB for 4 h. Compared to vehicle-injected controls, clodronate-treated mice exhibited significantly reduced permanent threshold shifts at 4 and 8 kHz and significantly smaller outer hair cell losses in the lower-apical cochlear turn. Following noise exposure, the stria vascularis had significantly more cells expressing the macrophage-specific protein F4/80, and this effect was significantly suppressed by clodronate treatment. These F4/80-positive cells expressed interleukin 1 beta (IL-1β), which noise exposure activated. However, IL-1β deficient mice did not exhibit significant resistance to intense noise when compared to wild-type mice. These findings suggest that macrophages that enter the cochlea after noise exposure are involved in NIHL, whereas IL-1β inhibition does not reverse this cochlear damage. Therefore, macrophages may be a promising therapeutic target in human sensorineural hearing losses such as NIHL. PMID: 28951212 [PubMed - indexed for MEDLINE]
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Related Articles Long-term cognitive and somatic outcomes of enzyme replacement therapy in untransplanted Hurler syndrome. Mol Genet Metab Rep. 2017 Dec;13:64-68 Authors: Eisengart JB, Jarnes J, Ahmed A, Nestrasil I, Ziegler R, Delaney K, Shapiro E, Whitley C Abstract Mucopolysaccharidosis type I (MPS I) was added to the Recommended Uniform Screening Panel for newborn screening in 2016, highlighting recognition that early treatment of MPS I is critical to stem progressive, irreversible disease manifestations. Enzyme replacement therapy (ERT) is an approved treatment for all MPS I phenotypes, but because the severe form (MPS IH, Hurler syndrome) involves rapid neurocognitive decline, the impermeable blood-brain-barrier is considered an obstacle for ERT. Instead, hematopoietic cell transplantation (HCT) has long been recommended, as it is believed to be the only therapy that arrests neurocognitive decline. Yet ERT monotherapy has never been compared to HCT, because it is unethically unacceptable to evaluate a therapeutic alternative to one shown to treat Central Nervous System (CNS) disease. An unusual opportunity to address this question is presented with this clinical report of a 16-year-old female with MPS IH treated only with ERT since her diagnosis at age 2. Neurological functioning was stable until cervical spinal cord compression at age 8, hydrocephalus at age 11, and neurocognitive declines beginning at age 10. Somatic disease burden is significant for first degree AV block, restrictive lung disease, bilateral hearing loss, severe corneal clouding, joint pain/limitations requiring mobility assistance, and short stature. This patient's extended survival and prolonged intact neurocognitive functioning depart from the untreated natural history of MPS IH. Disease burden typically controlled by HCT emerged. Although not anticipated to provide benefit for CNS disease, ERT may have provided some amelioration or slowing of neurocognitive deterioration. PMID: 28983455 [PubMed]
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Related Articles Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment. J Assoc Res Otolaryngol. 2018 02;19(1):1-16 Authors: Ponnath A, Depreux FF, Jodelka FM, Rigo F, Farris HE, Hastings ML, Lentz JJ Abstract The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show that Ush1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and high-frequency tone pairs. This OHC deficit is rescued by treatment with an ASO that corrects expression of Ush1c c.216G>A. Interestingly, although rescue of inner hairs cells, as measured by ABR, is achieved by ASO treatment as late as 7 days after birth, rescue of outer hair cells, measured by DPOAE, requires treatment before post-natal day 5. These results suggest that ASO-mediated rescue of both IHC and OHC function is age dependent and that the treatment window is different for the different cell types. The timing of treatment for congenital hearing disorders is of critical importance for the development of drugs such ASO-29 for hearing rescue. PMID: 29027038 [PubMed - indexed for MEDLINE]
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Related Articles Neuronal differentiation of hair-follicle-bulge-derived stem cells co-cultured with mouse cochlear modiolus explants. PLoS One. 2017;12(10):e0187183 Authors: Schomann T, Mezzanotte L, De Groot JCMJ, Rivolta MN, Hendriks SH, Frijns JHM, Huisman MA Abstract Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs) are promising candidates for this type of therapy, because they (1) have migratory properties, enabling migration after transplantation, (2) can differentiate into sensory neurons and glial cells, and (3) can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose. We hypothesized that HFBSCs can be used for cell-based repair of the auditory nerve and we have examined their migration and incorporation into cochlear modiolus explants and their subsequent differentiation. Modiolus explants obtained from adult wild-type mice were cultured in the presence of EF1α-copGFP-transduced HFBSCs, constitutively expressing copepod green fluorescent protein (copGFP). Also, modiolus explants without hair cells were co-cultured with DCX-copGFP-transduced HFBSCs, which demonstrate copGFP upon doublecortin expression during neuronal differentiation. Velocity of HFBSC migration towards modiolus explants was calculated, and after two weeks, co-cultures were fixed and processed for immunohistochemical staining. EF1α-copGFP HFBSC migration velocity was fast: 80.5 ± 6.1 μm/h. After arrival in the explant, the cells formed a fascicular pattern and changed their phenotype into an ATOH1-positive neuronal cell type. DCX-copGFP HFBSCs became green-fluorescent after integration into the explants, confirming neuronal differentiation of the cells. These results show that HFBSC-derived neuronal progenitors are migratory and can integrate into cochlear modiolus explants, while adapting their phenotype depending on this micro-environment. Thus, HFBSCs show potential to be employed in cell-based therapies for auditory nerve repair. PMID: 29084289 [PubMed - indexed for MEDLINE]
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Related Articles Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis. Hum Genet. 2017 11;136(11-12):1463-1475 Authors: Hai T, Guo W, Yao J, Cao C, Luo A, Qi M, Wang X, Wang X, Huang J, Zhang Y, Zhang H, Wang D, Shang H, Hong Q, Zhang R, Jia Q, Zheng Q, Qin G, Li Y, Zhang T, Jin W, Chen ZY, Wang H, Zhou Q, Meng A, Wei H, Yang S, Zhao J Abstract Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. In mouse models with MITF mutations, WS2A is transmitted in a recessive pattern, which limits the study of hearing loss (HL) pathology. In the current study, we performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A. The heterozygous mutant pig (MITF +/L247S) exhibits a dominant form of profound HL and hypopigmentation in skin, hair, and iris, accompanied by degeneration of stria vascularis (SV), fused hair cells, and the absence of endocochlear potential, which indicate the pathology of human WS2A. Besides hypopigmentation and bilateral HL, the homozygous mutant pig (MITF L247S/L247S) and CRISPR/Cas9-mediated MITF bi-allelic knockout pigs both exhibited anophthalmia. Three WS2 patients carrying MITF mutations adjacent to the corresponding region were also identified. The pig models resemble the clinical symptom and molecular pathology of human WS2A patients perfectly, which will provide new clues for better understanding the etiology and development of novel treatment strategies for human HL. PMID: 29094203 [PubMed - indexed for MEDLINE]
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Related Articles Trigonelline promotes auditory function through nerve growth factor signaling on diabetic animal models. Phytomedicine. 2017 Dec 01;36:128-136 Authors: Castañeda R, Rodriguez I, Nam YH, Hong BN, Kang TH Abstract BACKGROUND: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM). PURPOSE: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker. METHOD: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks. RESULTS: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to-noise ratio in TEOAE (P < .05). CONCLUSIONS: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss. PMID: 29157806 [PubMed - indexed for MEDLINE]
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Related Articles Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II. J Inherit Metab Dis. 2018 03;41(2):221-229 Authors: Rybová J, Ledvinová J, Sikora J, Kuchař L, Dobrovolný R Abstract Mucopolysaccharidosis type II (MPSII) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene (IDS, Xq28). MPSII is characterized by skeletal deformities, hearing loss, airway obstruction, hepatosplenomegaly, cardiac valvular disease, and progressive neurological impairment. At the cellular level, IDS deficiency leads to lysosomal storage of glycosaminoglycans (GAGs), dominated by accumulation of dermatan and heparan sulfates. Human induced pluripotent stem cells (iPSC) represent an alternative system that complements the available MPSII murine model. Herein we report on the reprogramming of peripheral white blood cells from male and female MPSII patients into iPSC using a non-integrating protocol based on the Sendai virus vector system. We differentiated the iPSC lines into IDS deficient and GAG accumulating β-Tubulin III+ neurons, GFAP+ astrocytes, and CNPase+ oligodendrocytes. The lysosomal system in these cells displayed structural abnormalities reminiscent of those previously found in patient tissues and murine IDS deficient neuronal stem cells. Furthermore, quantitative determination of GAGs revealed a moderate increase in GAG levels in IDS deficient neurons and glia. We also tested the effects of recombinant IDS and found that the exogenous enzyme was internalized from the culture media and partially decreased the intracellular GAG levels in iPSC-derived neural cells; however, it failed to completely prevent accumulation of GAGs. In summary, we demonstrate that this human iPSC based model expresses the cellular and biochemical features of MPSII, and thus represents a useful experimental tool for further pathogenesis studies as well as therapy development and testing. PMID: 29168031 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of Mitoquinone for Protecting Against Amikacin-Induced Ototoxicity in Guinea Pigs. Otol Neurotol. 2018 01;39(1):111-118 Authors: Dirain CO, Ng MRAV, Milne-Davies B, Joseph JK, Antonelli PJ Abstract HYPOTHESIS: Mitoquinone (MitoQ) attenuates amikacin ototoxicity in guinea pigs. BACKGROUND: MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, has improved bioavailability and demonstrated safety in humans. Thus, MitoQ is a promising therapeutic approach for protecting against amikacin-induced ototoxicity. METHODS: Both oral and subcutaneous administrations of MitoQ were tested. Amikacin-treated guinea pigs (n = 12-18 per group) received water alone (control) or MitoQ 30 mg/l-supplemented drinking water; or injected subcutaneously with 3 to 5 mg/kg MitoQ or saline (control). Auditory brainstem responses and distortion product otoacoustic emissions were measured before MitoQ or control solution administration and after amikacin injections. Cochlear hair cell damage was assessed using scanning electron microscopy and Western blotting. RESULTS: With oral administration, animals that received 30 mg/l MitoQ had better hearing than controls at only 24 kHz at 3-week (p = 0.017) and 6-week (p = 0.027) post-amikacin. With subcutaneous administration, MitoQ-injected guinea pigs had better hearing than controls at only 24 kHz, 2-week post-amikacin (p = 0.013). Distortion product otoacoustic emission (DPOAE) amplitudes were decreased after amikacin injections, but were not different between treatments (p > 0.05). Electron microscopy showed minor difference in outer hair cell loss between treatments. Western blotting demonstrated limited attenuation of oxidative stress in the cochlea of MitoQ-supplemented guinea pigs. CONCLUSIONS: Oral or subcutaneous MitoQ provided limited protection against amikacin-induced hearing loss and cochlear damage in guinea pigs. Other strategies for attenuating aminoglycoside-induced ototoxicity should be explored. PMID: 29194212 [PubMed - indexed for MEDLINE]
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Related Articles Prevention of ischemia-induced hearing loss by intravenous administration of hydrogen-rich saline in gerbil. Neurosci Lett. 2018 02 05;665:195-199 Authors: Ogawa H, Okada M, Shudou M, Gyo K, Hato N Abstract OBJECTIVE: Hydrogen-rich water, which is a potent antioxidant agent, was investigated for its protective effects against ischemic damage of the cochlea in gerbils. METHODS: The animals were subjected to transient cochlear ischemia by occluding the bilateral vertebral arteries for l5min. Five milliliters of hydrogen-rich saline was then intravenously administered immediately after the insult. Saline without hydrogen was used as a control. Effects of hydrogen were evaluated using the auditory brainstem response (ABR) and histological studies of the inner ear. RESULTS: In non-ischemia animals, ABR thresholds and histological findings of the cochlea did not change by administration of saline or hydrogen-rich saline. In contrast, transient cochlear ischemia caused a 24.2±3.8dB increase in the ABR threshold at 8kHz, and a decrease of 14.1%±1.8% in the number of inner hair cells (IHCs) at the basal turn on day 7. Ischemic damage was more severe at 16 and 32kHz. When the animals were treated with hydrogen-rich saline, cochlear damage was significantly reduced: the increase in ABR threshold was 11.7±2.6dB at 8kHz and the IHC loss was 7.5%±2.1% at the basal turn on day 7. The effects of hydrogen-rich saline were more prominent at higher frequencies. CONCLUSIONS: Intravenous administration of hydrogen-rich saline was effective in preventing acute hearing loss due to transient cochlear ischemia. PMID: 29223865 [PubMed - indexed for MEDLINE]
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Related Articles Human mesenchymal stromal cell therapy for damaged cochlea repair in nod-scid mice deafened with kanamycin. Cytotherapy. 2018 02;20(2):189-203 Authors: Bettini S, Franceschini V, Astolfi L, Simoni E, Mazzanti B, Martini A, Revoltella RP Abstract BACKGROUND: Kanamycin, mainly used in the treatment of drug-resistant-tuberculosis, is known to cause irreversible hearing loss. Using the xeno-transplant model, we compared both in vitro and in vivo characteristics of human mesenchymal stromal cells (MSCs) derived from adult tissues, bone marrow (BM-MSCs) and adipose tissue (ADSCs). These tissues were selected for their availability, in vitro multipotency and regenerative potential in vivo in kanamycin-deafened nod-scid mice. METHODS: MSCs were isolated from informed donors and expanded ex vivo. We evaluated their proliferation capacity in vitro using the hexosaminidase assay, the phenotypic profile using flow-cytometry of a panel of surface antigens, the osteogenic potential using alkaline phosphatase activity and the adipogenic potential using oil-red-O staining. MSCs were intravenously injected in deafened mice and cochleae, liver, spleen and kidney were sampled 7 and 30 days after transplantation. The dissected organs were analyzed using lectin histochemistry, immunohistochemistry, polymerase chain reaction (PCR) and dual color fluorescence in situ hybridization (DC-FISH). RESULTS: MSCs showed similar in vitro characteristics, but ADSCs appeared to be more efficient after prolonged expansion. Both cell types engrafted in the cochlea of damaged mice, inducing regeneration of the damaged sensory structures. Several hybrid cells were detected in engrafted tissues. DISCUSSION: BM-MSCs and ADSCs showed in vitro characteristics suitable for tissue regeneration and fused with resident cells in engrafted tissues. The data suggest that paracrine effect is the prevalent mechanism inducing tissue recovery. Overall, BM-MSCs and ADSCs appear to be valuable tools in regenerative medicine for hearing loss recovery. PMID: 29246648 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018 01 11;553(7687):217-221 Authors: Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, Hu YJ, Hu JH, Thompson DB, Shu Y, Li Y, Wang H, Yang S, Xu Q, Polley DB, Liberman MC, Kong WJ, Holt JR, Chen ZY, Liu DR Abstract Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss. PMID: 29258297 [PubMed - indexed for MEDLINE]
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Related Articles The feasibility of an encapsulated cell approach in an animal deafness model. J Control Release. 2018 01 28;270:275-281 Authors: Fransson A, Tornøe J, Wahlberg LU, Ulfendahl M Abstract For patients with profound hearing loss a cochlear implant (CI) is the only treatment today. The function of a CI depends in part of the function and survival of the remaining spiral ganglion neurons (SGN). It is well known from animal models that inner ear infusion of neurotrophic factors prevents SGN degeneration and maintains electrical responsiveness in deafened animals. The purpose with this study was to investigate the effects of a novel encapsulated cell (EC) device releasing neurotrophic factors in the deafened guinea pig. The results showed that an EC device releasing glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) implanted for four weeks in deafened guinea pigs significantly preserved the SGNs and maintained their electrical responsiveness. There was a significant difference between BDNF and GDNF in favour of GDNF. This study, demonstrating positive structural and functional effects in the deafened inner ear, suggests that an implanted EC device releasing biologically protective substances offers a feasible approach for treating progressive hearing impairment. PMID: 29269144 [PubMed - indexed for MEDLINE]
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Related Articles Paeoniflorin reduces neomycin-induced ototoxicity in hair cells by suppression of reactive oxygen species generation and extracellularly regulated kinase signalization. Toxicol Lett. 2018 Mar 15;285:9-19 Authors: Yu X, Fan Z, Han Y, Zhang D, Xu L, Wang M, Yang Q, Li H, Zhou M, Zhang L, Sun G, Bai X, Li J, Wang H Abstract The present study was designed to investigate the effect of paeoniflorin (PF) on neomycin-induced ototoxicity in hair cells (HCs). Here, we took advantage of C57BL/6 mice and cochlear explants culture to determine the role of PF in vivo and in vitro. We demonstrated that neomycin exposure induced severe hearing loss and HC damage, which was mediated by activated mitochondrial apoptosis pathway, promoted extracellular signal-regulated kinase (ERK) signaling as well as enhanced reactive oxygen species (ROS) generation in HCs. Interestingly, we found that PF pretreatment significantly alleviated neomycin-induced hearing loss, attenuated HC injury and decreased HC apoptosis caused by neomycin. Mechanistic studies revealed that PF could decrease cellular ROS levels, suppress the activation of ERK signaling and, subsequently, mitigate the imbalance of mitochondrial apoptotic pathway, thus protecting HCs from neomycin-induced apoptosis. This study indicates that PF may serve as an antioxidative and anti-apoptotic agent to prevent hearing loss caused by neomycin. PMID: 29292089 [PubMed - indexed for MEDLINE]
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Related Articles Clinical Safety and Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell Transplantation in Sensorineural Hearing Loss Patients. J Audiol Otol. 2018 Apr;22(2):105-109 Authors: Lee HS, Kim WJ, Gong JS, Park KH Abstract Stem cell transplantation represents a promising therapy for several degenerating and necrotic diseases. In several animal studies, we could find hearing restoration after inoculation of the mesenchymal stem cells' as well as mesenchymal stem cells' differentiation of hair cells and spiral ganglion. But until now, no clinical study has been reported directly for the human being. In this pilot studies, we applied mesenchymal stem cells to human beings trans-venously. Although we verified the safety of the autologous bone marrow stem cell transplantation in sensorineural hearing loss patients but we could not achieve significant improvement in hearing. PMID: 29301392 [PubMed]
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Related Articles Strategies for a regenerative therapy of hearing loss. HNO. 2018 Jan;66(Suppl 1):39-46 Authors: Diensthuber M, Stöver T Abstract Despite impressive technical progress in the field of conventional hearing aids and implantable hearing systems, the hopes for the treatment of inner ear diseases such as hearing loss and tinnitus have become increasingly directed toward regenerative therapeutic approaches. This review discusses the currently most promising strategies for hair cell regeneration in the inner ear to treat hearing loss, including stem cell-based, gene transfer-based, and pharmacological interventions. Furthermore, previous milestones and ground-breaking work in this scientific field are identified. After many years of basic research, the first clinical trials with a regenerative therapeutic approach for hearing-impaired patients were recently initiated. Although there is still a long and bumpy road ahead until a true breakthrough is achieved, it seems more realistic than ever that regenerative therapies for the inner ear will find their way into clinical practice. PMID: 29318324 [PubMed - in process]
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Related Articles Auditory Neural Activity in Congenitally Deaf Mice Induced by Infrared Neural Stimulation. Sci Rep. 2018 01 10;8(1):388 Authors: Tan X, Jahan I, Xu Y, Stock S, Kwan CC, Soriano C, Xiao X, García-Añoveros J, Fritzsch B, Richter CP Abstract To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3 -/-) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100-500 µs. No auditory responses to acoustic stimuli could be evoked in any of these animals. INS could not evoke auditory brainstem responses in Atoh1 CKO mice but could in Neurog1 KI and Vglut3 -/- mice. X-ray micro-computed tomography of the cochleae showed that responses correlated with the presence of SGNs and hair cells. Results in Neurog1 KI mice do not support a mechanical stimulation through the vibration of the basilar membrane, but cannot rule out the direct activation of the inner hair cells. Results in Vglut3 -/- mice, which have no synaptic transmission between inner hair cells and SGNs, suggested that hair cells are not required. PMID: 29321651 [PubMed - indexed for MEDLINE]
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Related Articles Acquired sensorineural hearing loss in children: current research and therapeutic perspectives. Acta Otorhinolaryngol Ital. 2017 Dec;37(6):500-508 Authors: Ralli M, Rolesi R, Anzivino R, Turchetta R, Fetoni AR Abstract The knowledge of mechanisms responsible for acquired sensorineural hearing loss in children, such as viral and bacterial infections, noise exposure, aminoglycoside and cisplatin ototoxicity, is increasing and progressively changing the clinical management of affected patients. Viral infections are by far the most relevant cause of acquired hearing loss, followed by aminoglycoside and platinum derivative ototoxicity; moreover, cochlear damage induced by noise overexposure, mainly in adolescents, is an emerging topic. Pharmacological approaches are still challenging to develop a truly effective cochlear protection; however, the use of steroids, antioxidants, antiviral drugs and other small molecules is encouraging for clinical practice. Most of evidence on the effectiveness of antioxidants is still limited to experimental models, while the use of corticosteroids and antiviral drugs has a wide correspondence in literature but with controversial safety. Future therapeutic perspectives include innovative strategies to transport drugs into the cochlea, such as molecules incorporated in nanoparticles that can be delivered to a specific target. Innovative approaches also include the gene therapy designed to compensate for abnormal genes or to make proteins by introducing genetic material into cells; finally, regenerative medicine (including stem cell approaches) may play a central role in the upcoming years in hearing preservation and restoration even if its role in the inner ear is still debated. PMID: 29327735 [PubMed - indexed for MEDLINE]
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Related Articles Comparison of Three Types of Mesenchymal Stem Cells (Bone Marrow, Adipose Tissue, and Umbilical Cord-Derived) as Potential Sources for Inner Ear Regeneration. Int Tinnitus J. 2017 Dec 01;21(2):122-127 Authors: Mahmoudian-Sani MR, Mehri-Ghahfarrokhi A, Hashemzadeh-Chaleshtori M, Saidijam M, Jami MS Abstract In this review, we compared the potential of mesenchymal stem cells derived from bone marrow, adipose tissue and umbilical cord as suitable sources for regeneration of inner ear hair cells and auditory neurons. Our intensive literature search indicates that stem cells in some of adult mammalian tissues, such as bone marrow, can generate new cells under physiological and pathological conditions. Among various types of stem cells, bone marrow-derived mesenchymal stem cells are one of the most promising candidates for cell replacement therapy. Mesenchymal stem cells have been reported to invade the damaged area, contribute to the structural reorganization of the damaged cochlea and improve incomplete hearing recovery. We suggest that bone marrow-derived mesenchymal stem cells would be more beneficial than other mesenchymal stem cells. PMID: 29336130 [PubMed - in process]
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Related Articles Deferoxamine promotes mesenchymal stem cell homing in noise-induced injured cochlea through PI3K/AKT pathway. Cell Prolif. 2018 Apr;51(2):e12434 Authors: Peyvandi AA, Abbaszadeh HA, Roozbahany NA, Pourbakht A, Khoshsirat S, Niri HH, Peyvandi H, Niknazar S Abstract OBJECTIVE: Over 5% of the world's population suffers from disabling hearing loss. Stem cell homing in target tissue is an important aspect of cell-based therapy, which its augmentation increases cell therapy efficiency. Deferoxamine (DFO) can induce the Akt activation, and phosphorylation status of AKT (p-AKT) upregulates CXC chemokine receptor-4 (CXCR4) expression. We examined whether DFO can enhance mesenchymal stem cells (MSCs) homing in noise-induced damaged cochlea by PI3K/AKT dependent mechanism. MATERIALS AND METHODS: Mesenchymal stem cells were treated with DFO. AKT, p-AKT protein and hypoxia inducible factor 1- α (HIF-1α) and CXCR4 gene and protein expression was evaluated by RT- PCR and Western blot analysis. For in vivo assay, rats were assigned to control, sham, noise exposure groups without any treatment or receiving normal, DFO-treated and DFO +LY294002 (The PI3K inhibitor)-treated MSCs. Following chronic exposure to 115 dB white noise, MSCs were injected into the rat cochlea through the round window. Number of Hoechst- labelled cells was determined in the endolymph after 24 hours. RESULTS: Deferoxamine increased P-AKT, HIF-1α and CXCR4 expression in MSCs compared to non-treated cells. DFO pre-conditioning significantly increased the homing ability of MSCs into injured ear compared to normal MSCs. These effects of DFO were blocked by LY294002. CONCLUSIONS: Pre-conditioning of MSCs by DFO before transplantation can improve stem cell homing in the damaged cochlea through PI3K/AKT pathway activation. PMID: 29341316 [PubMed - indexed for MEDLINE]
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Related Articles Engraftment of Human Pluripotent Stem Cell-derived Progenitors in the Inner Ear of Prenatal Mice. Sci Rep. 2018 01 31;8(1):1941 Authors: Takeda H, Hosoya M, Fujioka M, Saegusa C, Saeki T, Miwa T, Okano H, Minoda R Abstract There is, at present, no curative treatment for genetic hearing loss. We have previously reported that transuterine gene transfer of wild type CONNEXIN30 (CX30) genes into otocysts in CX30-deleted mice could restore hearing. Cell transplantation therapy might be another therapeutic option, although it is still unknown whether stem cell-derived progenitor cells could migrate into mouse otocysts. Here, we show successful cell transplantation of progenitors of outer sulcus cell-like cells derived from human-derived induced pluripotent stem cells into mouse otocysts on embryonic day 11.5. The delivered cells engrafted more frequently in the non-sensory region in the inner ear of CX30-deleted mice than in wild type mice and survived for up to 1 week after transplantation. Some of the engrafted cells expressed CX30 proteins in the non-sensory region. This is the first report that demonstrates successful engraftment of exogenous cells in prenatal developing otocysts in mice. Future studies using this mouse otocystic injection model in vivo will provide further clues for developing treatment modalities for congenital hearing loss in humans. PMID: 29386634 [PubMed - indexed for MEDLINE]
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Related Articles The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats. FASEB J. 2018 06;32(6):3005-3019 Authors: Singer W, Kasini K, Manthey M, Eckert P, Armbruster P, Vogt MA, Jaumann M, Dotta M, Yamahara K, Harasztosi C, Zimmermann U, Knipper M, Rüttiger L Abstract Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats. PMID: 29401591 [PubMed - indexed for MEDLINE]
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Related Articles Differentiation of stem cells from human deciduous and permanent teeth into spiral ganglion neuron-like cells. Arch Oral Biol. 2018 Apr;88:34-41 Authors: Gonmanee T, Thonabulsombat C, Vongsavan K, Sritanaudomchai H Abstract OBJECTIVE: Stem cells from pulp tissue are a promising cell-based therapy for neurodegenerative patients based on their origin in the neural crest. The aim of this study was to differentiate and evaluate the ability of human dental pulp stem cells from permanent teeth (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) to differentiate into spiral ganglion neurons. DESIGN: After isolation and characterization of mesenchymal stem cell properties, DPSC and SHED were treated with the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell-derived neurotrophic factor (GDNF). The differentiation was identified by immunostaining and qRT-PCR analysis of neuronal markers and measuring intracellular calcium activity. RESULTS: After 2 weeks of induction, morphological changes were observed in both DPSC and SHED. The differentiated cells expressed neuron-specific class III beta-tubulin, GATA binding protein 3 (GATA3) and tropomyosin receptor kinase B, protein markers of spiral ganglion neurons. These cells also showed upregulation of the genes encoding these proteins, namely GATA3 and neurotrophic receptor tyrosine kinase 2. Intracellular calcium dynamics that reflect neurotransmitter release were observed in differentiated DPSC and SHED. CONCLUSION: These results demonstrate that dental pulp stem cells from permanent and deciduous teeth can differentiate into spiral ganglion neuron-like cells. PMID: 29407749 [PubMed - indexed for MEDLINE]
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Related Articles Barhl1 is required for the differentiation of inner ear hair cell-like cells from mouse embryonic stem cells. Int J Biochem Cell Biol. 2018 03;96:79-89 Authors: Zhong C, Chen Z, Luo X, Wang C, Jiang H, Shao J, Guan M, Huang L, Huang X, Wang J Abstract Inner ear hair cells are mechanoreceptors responsible for hearing. Pathogenic defects of hair cell-specific genes are one of the major causes of deafness. The BarH class homeobox gene Barhl1 is a deafness gene expressed in developing hair cells, yet the role of Barhl1 during hair cell development remains poorly understood. In the present study, we first established an in vitro differentiation system to efficiently obtain mouse embryonic stem cell (mESC)-derived hair cell-like cells. Subsequently, a mESC line carrying a targeted disruption of Barhl1 was generated using CRISPR/Cas9 technology and subjected to the established in vitro hair cell differentiation protocol. Targeted disruption of Barhl1 does not affect the induction of mESCs toward early primitive ectoderm-like (EPL) cells and otic progenitors but strongly inhibits the differentiation of hair cell-like cells. Using RNA-sequencing and bioinformatics, we further unravel the molecular mechanism underlying Barhl1-mediated hair cell development. Our data demonstrate the essential role of Barhl1 during hair cell development and provide a basis for the treatment of Barhl1 mutation-based deafness. PMID: 29413750 [PubMed - indexed for MEDLINE]
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Related Articles High-dose Chemotherapy is Efficacious and Well Tolerated in a Toddler With Aicardi Syndrome and Malignant Sacrococcygeal Teratoma. J Pediatr Hematol Oncol. 2018 Oct;40(7):e467-e469 Authors: Wharton JD, Johnson S, Connelly JA, Hills T, Gingles L, Wood M, Crane GL, Katzenstein HM Abstract Aicardi syndrome (AS) is a rare neurodevelopmental disorder, predominantly seen in female individuals, which appears to have an increased risk of both benign and malignant neoplasia. We report the case of a child with AS who presented with metastatic malignant sacrococcygeal tumor (with yolk sac elements) which recurred and then was treated with 3 cycles of high-dose chemotherapy with autologous stem cell rescue. The patient tolerated therapy with acceptable toxicity and remains in clinical remission 3 months after the completion of therapy. Her neurological status remains similar to that before diagnosis with the exception of chemotherapy induced hearing loss. This is the first description a sacrococcygeal teratoma in a patient with Aicardi, as well as the first use of intensified consolidation chemotherapy in a patient with Aicardi, which was well tolerated and resulted in remission. The use of chemotherapy should be considered for all patients with AS and malignancy. PMID: 29420371 [PubMed - in process]
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Related Articles Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. Mol Ther. 2018 03 07;26(3):917-931 Authors: Cicalese MP, Ferrua F, Castagnaro L, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Roncarolo MG, Aiuti A Abstract Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired. Gene therapy (GT) with an autologous CD34+-enriched cell fraction that contains CD34+ cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients. Here, we report short- and medium-term safety analyses from 18 patients enrolled as part of single-arm, open-label studies or compassionate use programs. Survival was 100% with a median of 6.9 years follow-up (range, 2.3 to 13.4 years). Adverse events were mostly grade 1 or grade 2 and were reported by all 18 patients following GT. Thirty-nine serious adverse events (SAEs) were reported by 15 of 18 patients; no SAEs were considered related to GT. The most common adverse events reported post-GT include upper respiratory tract infection, gastroenteritis, rhinitis, bronchitis, oral candidiasis, cough, neutropenia, diarrhea, and pyrexia. Incidence rates for all of these events were highest during pre-treatment, treatment, and/or 3-month follow-up and then declined over medium-term follow-up. GT did not impact the incidence of neurologic/hearing impairments. No event indicative of leukemic transformation was reported. PMID: 29433935 [PubMed - indexed for MEDLINE]
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Related Articles [Strategies for a regenerative therapy of hearing loss. German version]. HNO. 2018 Mar;66(3):179-187 Authors: Diensthuber M, Stöver T Abstract Despite impressive technical progress in the field of conventional hearing aids and implantable hearing systems, the hopes for the treatment of inner ear diseases such as hearing loss and tinnitus have become increasingly directed toward regenerative therapeutic approaches. This review discusses the currently most promising strategies for hair cell regeneration in the inner ear to treat hearing loss, including stem cell-based, gene transfer-based, and pharmacological interventions. Furthermore, previous milestones and ground-breaking work in this scientific field are identified. After many years of basic research, the first clinical trials with a regenerative therapeutic approach for hearing-impaired patients were recently initiated. Although there is still a long and bumpy road ahead until a true breakthrough is achieved, it seems more realistic than ever that regenerative therapies for the inner ear will find their way into clinical practice. PMID: 29450596 [PubMed - in process]
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Related Articles Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super-Resolution Immunohistochemistry. Front Immunol. 2018;9:223 Authors: Liu W, Molnar M, Garnham C, Benav H, Rask-Andersen H Abstract The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with "synapse-like" specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human's auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration. PMID: 29487598 [PubMed - indexed for MEDLINE]
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Related Articles Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity. Brain Struct Funct. 2018 Jun;223(5):2343-2360 Authors: Muca A, Standafer E, Apawu AK, Ahmad F, Ghoddoussi F, Hali M, Warila J, Berkowitz BA, Holt AG Abstract Loud noise frequently results in hyperacusis or hearing loss (i.e., increased or decreased sensitivity to sound). These conditions are often accompanied by tinnitus (ringing in the ears) and changes in spontaneous neuronal activity (SNA). The ability to differentiate the contributions of hyperacusis and hearing loss to neural correlates of tinnitus has yet to be achieved. Towards this purpose, we used a combination of behavior, electrophysiology, and imaging tools to investigate two models of noise-induced tinnitus (either with temporary hearing loss or with permanent hearing loss). Manganese (Mn2+) uptake was used as a measure of calcium channel function and as an index of SNA. Manganese uptake was examined in vivo with manganese-enhanced magnetic resonance imaging (MEMRI) in key auditory brain regions implicated in tinnitus. Following acoustic trauma, MEMRI, the SNA index, showed evidence of spatially dependent rearrangement of Mn2+ uptake within specific brain nuclei (i.e., reorganization). Reorganization of Mn2+ uptake in the superior olivary complex and cochlear nucleus was dependent upon tinnitus status. However, reorganization of Mn2+ uptake in the inferior colliculus was dependent upon hearing sensitivity. Furthermore, following permanent hearing loss, reduced Mn2+ uptake was observed. Overall, by combining testing for hearing sensitivity, tinnitus, and SNA, our data move forward the possibility of discriminating the contributions of hyperacusis and hearing loss to tinnitus. PMID: 29488007 [PubMed - indexed for MEDLINE]
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Related Articles Cochlear implant - state of the art. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2017;16:Doc04 Authors: Lenarz T Abstract Cochlear implants are the treatment of choice for auditory rehabilitation of patients with sensory deafness. They restore the missing function of inner hair cells by transforming the acoustic signal into electrical stimuli for activation of auditory nerve fibers. Due to the very fast technology development, cochlear implants provide open-set speech understanding in the majority of patients including the use of the telephone. Children can achieve a near to normal speech and language development provided their deafness is detected early after onset and implantation is performed quickly thereafter. The diagnostic procedure as well as the surgical technique have been standardized and can be adapted to the individual anatomical and physiological needs both in children and adults. Special cases such as cochlear obliteration might require special measures and re-implantation, which can be done in most cases in a straight forward way. Technology upgrades count for better performance. Future developments will focus on better electrode-nerve interfaces by improving electrode technology. An increased number of electrical contacts as well as the biological treatment with regeneration of the dendrites growing onto the electrode will increase the number of electrical channels. This will give room for improved speech coding strategies in order to create the bionic ear, i.e. to restore the process of natural hearing by means of technology. The robot-assisted surgery will allow for high precision surgery and reliable hearing preservation. Biological therapies will support the bionic ear. Methods are bio-hybrid electrodes, which are coded by stem cells transplanted into the inner ear to enhance auto-production of neurotrophins. Local drug delivery will focus on suppression of trauma reaction and local regeneration. Gene therapy by nanoparticles will hopefully lead to the preservation of residual hearing in patients being affected by genetic hearing loss. Overall the cochlear implant is a very powerful tool to rehabilitate patients with sensory deafness. More than 1 million of candidates in Germany today could benefit from this high technology auditory implant. Only 50,000 are implanted so far. In the future, the procedure can be done under local anesthesia, will be minimally invasive and straight forward. Hearing preservation will be routine. PMID: 29503669 [PubMed]
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Related Articles CXCR4: A new player in vestibular schwannoma pathogenesis. Oncotarget. 2018 Feb 09;9(11):9940-9950 Authors: Breun M, Schwerdtfeger A, Martellotta DD, Kessler AF, Perez JM, Monoranu CM, Ernestus RI, Matthies C, Löhr M, Hagemann C Abstract Background: CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients' clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy. Results: Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss. Materials and Methods: CXCR4 mRNA and protein levels were determined in VS samples (n = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters. Conclusions: CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS. PMID: 29515781 [PubMed]
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Related Articles The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. Biol Sex Differ. 2018 03 12;9(1):12 Authors: Milon B, Mitra S, Song Y, Margulies Z, Casserly R, Drake V, Mong JA, Depireux DA, Hertzano R Abstract BACKGROUND: Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. Among the suggested therapeutics tested in rodents, suberoylanilide hydroxamic acid (SAHA) has been shown to be otoprotective from NIHL; however, these results were limited to male mice. METHODS: Here we tested the effect of SAHA on the hearing of 10-week-old B6CBAF1/J mice of both sexes, which were exposed to 2 h of octave-band noise (101 dB SPL centered at 11.3 kHz). Hearing was assessed by measuring auditory brainstem responses (ABR) at 8, 16, 24, and 32 kHz, 1 week before, as well as at 24 h and 15-21 days following exposure (baseline, compound threshold shift (CTS) and permanent threshold shift (PTS), respectively), followed by histologic analyses. RESULTS: We found significant differences in the CTS and PTS of the control (vehicle injected) mice to noise, where females had a significantly smaller CTS at 16 and 24 kHz (p < 0.0001) and PTS at 16, 24, and 32 kHz (16 and 24 kHz p < 0.001, 32 kHz p < 0.01). This sexual dimorphic effect could not be explained by a differential loss of sensory cells or synapses but was reflected in the amplitude and amplitude progression of wave I of the ABR, which correlates with outer hair cell (OHC) function. Finally, the frequency of the protective effect of SAHA differed significantly between males (PTS, 24 kHz, p = 0.002) and females (PTS, 16 kHz, p = 0.003), and the magnitude of the protection was smaller in females than in males. Importantly, the magnitude of the protection by SAHA was smaller than the effect of sex as a biological factor in the vehicle-injected mice. CONCLUSIONS: These results indicate that female mice are significantly protected from NIHL in comparison to males and that therapeutics for NIHL may have a different effect in males and females. The data highlight the importance of analyzing NIHL experiments from males and females, separately. Finally, these data also raise the possibility of effectors in the estrogen signaling pathway as novel therapeutics for NIHL. PMID: 29530094 [PubMed - indexed for MEDLINE]
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Related Articles Toward a true cure for hearing impairment. Science. 2018 Mar 09;359(6380):1113 Authors: McLean W PMID: 29590039 [PubMed - indexed for MEDLINE]
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Related Articles Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice. Toxicol Lett. 2018 Jul;291:121-128 Authors: Bächinger D, Horvath L, Eckhard A, Goosmann MM, Honegger T, Gassmann M, Vogel J, Naldi AM Abstract Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss. Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycoside-induced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain. PMID: 29654830 [PubMed - indexed for MEDLINE]
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Related Articles Transient Abnormalities in Masking Tuning Curve in Early Progressive Hearing Loss Mouse Model. Biomed Res Int. 2018;2018:6280969 Authors: Souchal M, Labanca L, Alves da Silva Carvalho S, Macedo de Resende L, Blavignac C, Avan P, Giraudet F Abstract Damage to cochlear outer hair cells (OHCs) usually affects frequency selectivity in proportion to hearing threshold increase. However, the current clinical heuristics that attributes poor hearing performance despite near-normal auditory sensitivity to auditory neuropathy or "hidden" synaptopathy overlooks possible underlying OHC impairment. Here, we document the part played by OHCs in influencing suprathreshold auditory performance in the presence of noise in a mouse model of progressive hair cell degeneration, the CD1 strain, at postnatal day 18-30 stages when high-frequency auditory thresholds remained near-normal. Nonetheless, total loss of high-frequency distortion product otoacoustic emissions pointed to nonfunctioning basal OHCs. This "discordant profile" came with a huge low-frequency shift of masking tuning curves that plot the level of interfering sound necessary to mask the response to a probe tone, against interfering frequency. Histology revealed intense OHC hair bundle abnormalities in the basal cochlea uncharacteristically associated with OHC survival and preserved coupling with the tectorial membrane. This pattern dismisses the superficial diagnosis of "hidden" neuropathy while underpinning a disorganization of cochlear frequency mapping with optimistic high-frequency auditory thresholds perhaps because responses to high frequencies are apically shifted. The audiometric advantage of frequency transposition is offset by enhanced masking by low-frequency sounds, a finding essential for guiding rehabilitation. PMID: 29662891 [PubMed - indexed for MEDLINE]
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Related Articles Impact of hematopoietic stem cell transplant on VEP and ABR values of the patients with malignant infantile osteopetrosis. Eur J Paediatr Neurol. 2018 Jul;22(4):718-724 Authors: Badv RS, Dehghani SS, Behfar M, Ahadi B, Tabasi A, Hamidieh AA Abstract OBJECTIVES: Malignant Infantile Osteopetrosis (MIOP) is a rare inherited disorder with neurological complications, notably visual impairment and decrease of hearing level. Although Hematopoietic Stem Cell Transplantation (HSCT) has been approved as the only curative treatment for these patients, the exact impact of it on visual and hearing level is still unclear. STUDY DESIGN: We analyzed the P2 latency and amplitude from Visual Evoked Potentials (VEP) of 10 patients (20 eyes) and the threshold of wave V from Auditory Brainstem Response (ABR) of 15 patients (30 ears) with MIOP before, 6 and 12 months after HSCT. RESULTS: Before the HSCT, 10/30 ears demonstrated some degree of hearing loss; while only 3/20 eyes had P2 wave latencies in normal range for age. Using GEE models, it was shown that 12 months after HSCT, wave V threshold of ABR of the patients was significantly lower compared to its value from before the transplant (p value: 0.04). The analysis of latency and amplitude of P2 wave of VEPs showed no significant difference between before and after the transplant. CONCLUSION: This study clearly showed that HSCT can improve the hearing level of the patients in terms of ABR threshold. Although HSCT made no significant improvement in latency of P2 in VEP of the patients, it can be concluded that transplant can halt visual regression in these patients. Early diagnosis of MIOP with this objective tools and subsequently early HSCT in these patients can decrease the rate of neurological complications of MIOP and improve the quality of life in them. PMID: 29730165 [PubMed - indexed for MEDLINE]
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Related Articles Cochlear hair cell regeneration: an emerging opportunity to cure noise-induced sensorineural hearing loss. Drug Discov Today. 2018 Aug;23(8):1564-1569 Authors: Youm I, Li W Abstract In mammals, cochlear hair cells have a pivotal role in transducing mechanical energy into electrical signals. Cochlear hair cells are sensitive to acoustic trauma, drug insults, aging, and environmental or genetic influences that can cause permanent hearing loss. Currently, many researchers have focused on noise-induced sensorineural hearing loss (SNHL). Noise-induced SNHL is primarily caused by damage to hair cells of the cochlear sensory epithelium. Here, we summarize recent progress in restoring the sensory epithelium after SNHL resulting from noise exposure. The prevalent strategy to regenerate cochlear hair cells is through transdifferentiation of the supporting cells via the inhibition of the NOTCH 1 pathway. PMID: 29733894 [PubMed - indexed for MEDLINE]
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Related Articles ATOH1/RFX1/RFX3 transcription factors facilitate the differentiation and characterisation of inner ear hair cell-like cells from patient-specific induced pluripotent stem cells harbouring A8344G mutation of mitochondrial DNA. Cell Death Dis. 2018 04 01;9(4):437 Authors: Chen YC, Tsai CL, Wei YH, Wu YT, Hsu WT, Lin HC, Hsu YC Abstract Degeneration or loss of inner ear hair cells (HCs) is irreversible and results in sensorineural hearing loss (SHL). Human-induced pluripotent stem cells (hiPSCs) have been employed in disease modelling and cell therapy. Here, we propose a transcription factor (TF)-driven approach using ATOH1 and regulatory factor of x-box (RFX) genes to generate HC-like cells from hiPSCs. Our results suggest that ATOH1/RFX1/RFX3 could significantly increase the differentiation capacity of iPSCs into MYO7AmCherry-positive cells, upregulate the mRNA expression levels of HC-related genes and promote the differentiation of HCs with more mature stereociliary bundles. To model the molecular and stereociliary structural changes involved in HC dysfunction in SHL, we further used ATOH1/RFX1/RFX3 to differentiate HC-like cells from the iPSCs from patients with myoclonus epilepsy associated with ragged-red fibres (MERRF) syndrome, which is caused by A8344G mutation of mitochondrial DNA (mtDNA), and characterised by myoclonus epilepsy, ataxia and SHL. Compared with isogenic iPSCs, MERRF-iPSCs possessed ~42-44% mtDNA with A8344G mutation and exhibited significantly elevated reactive oxygen species (ROS) production and CAT gene expression. Furthermore, MERRF-iPSC-differentiated HC-like cells exhibited significantly elevated ROS levels and MnSOD and CAT gene expression. These MERRF-HCs that had more single cilia with a shorter length could be observed only by using a non-TF method, but those with fewer stereociliary bundle-like protrusions than isogenic iPSCs-differentiated-HC-like cells could be further observed using ATOH1/RFX1/RFX3 TFs. We further analysed and compared the whole transcriptome of M1ctrl-HCs and M1-HCs after treatment with ATOH1 or ATOH1/RFX1/RFX3. We revealed that the HC-related gene transcripts in M1ctrl-iPSCs had a significantly higher tendency to be activated by ATOH1/RFX1/RFX3 than M1-iPSCs. The ATOH1/RFX1/RFX3 TF-driven approach for the differentiation of HC-like cells from iPSCs is an efficient and promising strategy for the disease modelling of SHL and can be employed in future therapeutic strategies to treat SHL patients. PMID: 29740017 [PubMed - in process]
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Related Articles Low-Frequency Sensorineural Hearing Loss in Familial Hemophagocytic Lymphohistiocytosis Type 5. Ann Otol Rhinol Laryngol. 2018 Jun;127(6):409-413 Authors: Bezdjian A, Bruijnzeel H, Pagel J, Daniel SJ, Thomeer HGXM Abstract INTRODUCTION: Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease affecting the cytotoxic pathway. Due to the recent advances in molecular diagnosis, immuno-chemo therapy, and hematopoietic stem cell transplantation treatment, FHL survival rates have drastically increased. CASE PRESENTATION: Herein, we describe a case of FHL type 5 presenting with low-frequency sensorineural hearing loss. Alongside our reported case, 6 additional patients were identified in the literature. Management and Outcome: The progressive nature of FHL disorder may cause bilateral, low-frequency, irreversible sensorineural hearing loss. This type of hearing loss should be considered among the long-term sequelea presenting with FHL5. DISCUSSION: We recommend audiological evaluation at initial FHL5 diagnosis to assess for hearing functions. Follow-up in audiology should be part of the long-term monitoring of patients with FHL5 as hearing loss could develop long after diagnosis. PMID: 29776323 [PubMed - indexed for MEDLINE]
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Related Articles Potential Application of Electrical Stimulation in Stem Cell-Based Treatment against Hearing Loss. Neural Plast. 2018;2018:9506387 Authors: Tang M, Yan X, Tang Q, Guo R, Da P, Li D Abstract Deafness is a common human disease, which is mainly caused by irreversible damage to hair cells and spiral ganglion neurons (SGNs) in the mammalian cochlea. At present, replacement of damaged or missing hair cells and SGNs by stem cell transplantation therapy is an effective treatment. However, the survival rate of stem cell transplantation is low, with uncontrollable differentiation hindering its application. Most researchers have focused on biochemical factors to regulate the growth and differentiation of stem cells, whereas little study has been performed using physical factors. This review intends to illustrate the current problems in stem cell-based treatment against deafness and to introduce electric field stimulation as a physical factor to regulate stem cell behavior and facilitate stem cell therapy to treat hearing loss in the future. PMID: 29853854 [PubMed - indexed for MEDLINE]
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Related Articles Association between age‑related hearing loss and cognitive decline in C57BL/6J mice. Mol Med Rep. 2018 Aug;18(2):1726-1732 Authors: Dong Y, Guo CR, Chen D, Chen SM, Peng Y, Song H, Shi JR Abstract Accumulating evidence has revealed the link between age‑related hearing loss (presbycusis) and cognitive decline; however, their exact association remains unclear. The present study aimed to investigate the association between age‑related hearing loss and cognitive decline, and to explore the underlying mechanisms. Briefly, three groups of C57BL/6J mice were evaluated, based on their age, as follows: Young group, 3 months; adult group, 6 months; and middle‑aged group, 15 months. The results of an auditory brainstem response (ABR) test demonstrated that the hearing threshold levels of the mice were increased in those aged 6 and 15 months compared with those aged 3 months, thus suggesting that significant hearing loss occurred at 6 months, and worsened at 15 months. The results of a Morris water maze test demonstrated that spatial learning and memory function was significantly decreased in 15‑month‑old mice, but not in 6‑month‑old mice. Pearson analysis indicated that the escape latency was positively correlated with hearing threshold at 16 kHz and percentage of time in the target quadrant was negatively correlated with hearing threshold at 16 kHz, thus suggesting a correlation between age‑related hearing loss and cognitive decline. The auditory cortex and hippocampal CA1 region in 15‑month‑old mice exhibited significantly decreased cell numbers, abnormal arrangement and morphological alterations. Transmission electron microscopy revealed reduced synapse numbers and synaptic vesicle density in mice aged 15 months. Furthermore, the protein expression levels of matrix metalloproteinase (MMP)‑9 in the auditory cortex and hippocampus in the 15‑month‑old mice were significantly higher than in the 3‑month‑old mice. In conclusion, these findings support the correlation between age‑related hearing loss and cognitive decline in C57BL/6J mice, and indicated that MMP‑9 expression in the auditory cortex and hippocampus may be associated with the underlying mechanisms. PMID: 29901198 [PubMed - indexed for MEDLINE]
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Related Articles Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells. Organogenesis. 2018;14(2):82-93 Authors: Han Z, Gu YY, Cong N, Ma R, Chi FL Abstract We aimed to investigate the beneficial effect of Celastrol on inner ear stem cells and potential therapeutic value for hearing loss. The inner ear stem cells were isolated and characterized from utricular sensory epithelium of adult mice. The stemness was evaluated by sphere formation assay. The relative expressions of Atoh1, MAP-2 and Myosin VI were measured by RT-PCR and immunoblotting. The up-regulation of MAP-2 was also analysed with immunofluorescence. The in vitro neuronal excitability was interrogated by calcium oscillation. The electrophysiological property was determined by inward current recorded on patch clamp. Our results demonstrated that Celastrol treatment significantly improved the viability and proliferation of mouse inner ear stem cells, and facilitated sphere formation. Moreover, Celastrol stimulated differentiation of mouse inner ear stem cells to neuronal-like cells and enhanced neural excitability. Celastrol also enhanced neuronal-like cell identity in the inner ear stem cell derived neurons, as well as their electrophysiological function. Most notably, these effects were apparently associated with the upregulation of Atoh1 in response to Celastrol treatment. Celastrol showed beneficial effect on inner ear stem cells and held therapeutic promise against hearing loss. PMID: 29902110 [PubMed - in process]
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Related Articles Potential of Gene and Cell Therapy for Inner Ear Hair Cells. Biomed Res Int. 2018;2018:8137614 Authors: Lee MY, Park YH Abstract Sensorineural hearing loss is caused by the loss of sensory hair cells (HCs) or a damaged afferent nerve pathway to the auditory cortex. The most common option for the treatment of sensorineural hearing loss is hearing rehabilitation using hearing devices. Various kinds of hearing devices are available but, despite recent advancements, their perceived sound quality does not mimic that of the "naïve" cochlea. Damage to crucial cochlear structures is mostly irreversible and results in permanent hearing loss. Cochlear HC regeneration has long been an important goal in the field of hearing research. However, it remains challenging because, thus far, no medical treatment has successfully regenerated cochlear HCs. Recent advances in genetic modulation and developmental techniques have led to novel approaches to generating HCs or protecting against HC loss, to preserve hearing. In this review, we present and review the current status of two different approaches to restoring or protecting hearing, gene therapy, including the newly introduced CRISPR/Cas9 genome editing, and stem cell therapy, and suggest the future direction. PMID: 30009175 [PubMed - indexed for MEDLINE]
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Related Articles The first successful application of preimplantation genetic diagnosis for hearing loss in Iran. Cell Mol Biol (Noisy-le-grand). 2018 Jun 30;64(9):1718 Authors: Karimi Yazdi A, Davoudi-Dehaghani E, Rabbani Anari M, Fouladi P, Ebrahimi E, Sabeghi S, Eftekharian A, Fatemi KS, Emami H, Sharifi Z, Ramezanzadeh F, Tajdini A, Zeinali S, Amanpour S Abstract Hearing impairment (HI) caused by mutations in the connexin-26 gene (GJB2) accounts for the majority of cases with inherited, nonsyndromic sensorineural hearing loss. Due to the illegality of the abortion of deaf fetuses in Islamic countries, preimplantation genetic diagnosis (PGD) is a possible solution for afflicted families to have a healthy offspring. This study describes the first use of PGD for GJB2 associated non-syndromic deafness in Iran. GJB2 donor splicing site IVS1+1G&gt;A mutation analysis was performed using Sanger sequencing for a total of 71 Iranian families with at least 1 deaf child diagnosed with non-syndromic deafness. In Vitro Fertilization (IVF) was performed, followed by PGD for a cousin couple with a 50% chance of having an affected child. Bi-allelic pathogenic mutations were found in a total of 12 families (~17 %); of which a couple was a PGD volunteer. The deaf woman in this family was homozygous and her husband was a carrier of the IVS1+1G&gt;A gene mutation. Among 8 biopsied embryos, two healthy embryos were implanted which resulted in a single pregnancy and subsequent birth of a healthy baby boy. This is the first report of a successful application of PGD for hearing loss in Iran. Having a baby with a severe hearing impairment often imposes families with long-term disease burden and heavy therapy costs. Today PGD has provided an opportunity for high-risk individuals to avoid the birth of a deaf child. PMID: 30030956 [PubMed - indexed for MEDLINE]
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Related Articles [Thiamine-responsive megaloblastic anemia or Rogers syndrome: A literature review]. Rev Med Interne. 2019 Jan;40(1):20-27 Authors: Lu H, Lu H, Vaucher J, Tran C, Vollenweider P, Castioni J Abstract Thiamine-responsive megaloblastic anemia (TRMA), also known as Rogers syndrome, is a rare autosomal recessive disease characterized by three main components: megaloblastic anemia, diabetes mellitus and sensorineural deafness. Those features occur in infancy but may arise during adolescence. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreatic beta cells and inner ear cells, explaining the clinical manifestations of the disease. Based on a multidisciplinary approach, treatment resides on lifelong thiamine oral supplementation at pharmacological doses, which reverses anemia and may delay development of diabetes. However, thiamine supplementation does not alleviate already existing hearing defects. PMID: 30031565 [PubMed - in process]
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Related Articles Little evidence for a chronotolerance effect for impulse noise exposure in the C57BL/6J mouse. Neurosci Lett. 2018 09 25;684:127-131 Authors: Harrison RT, Bielefeld EC Abstract Noise-induced hearing loss affects a large number of adults and children worldwide, and continues to be a major public health problem. The cochlea is an organ that maintains delicate metabolic homeostasis and precise mechanical architecture. Disruption of either can cause temporary or permanent injury. Impulse noises, which are short-duration, high-level bursts of sound caused by explosions, such as gunfire, can injure the cochlea through combinations of mechanical and metabolic injury. Susceptibility to the metabolic component of noise injury may vary with the circadian rhythm, a phenomenon known as chronotolerance. Chronotolerance to noise injury has been demonstrated for a one-hour noise exposure at a fixed level, but chronotolerance for impulse noise-induced hearing loss has never been studied. Forty-four mice were exposed to 500 short-duration clicks at 137 dB peSPL at one of four hours after light onset: 2, 8, 14, or 20. Auditory brainstem response threshold shifts were measured at 3, 7, and 21 days after the exposure to measure hearing loss, and post mortem outer hair cell counts were used to confirm cochlear injury. The testing revealed no significant differences between the four exposure times for hearing threshold shifts, but did detect a small, but statistically significant, difference in outer hair cell loss, in which the loss was greatest for the mice exposed two hours after light offset. Therefore, a weak chronotolerance effect for impulse noise was detected, though the functional significance of the effect is low. Further investigation is required to more fully understand the relationship between circadian rhythm and hearing loss from different types of noise exposure. PMID: 30031734 [PubMed - indexed for MEDLINE]
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Related Articles Challenges in Cell-Based Therapies for the Treatment of Hearing Loss. Trends Neurosci. 2018 11;41(11):823-837 Authors: Takeda H, Dondzillo A, Randall JA, Gubbels SP Abstract Hearing loss in mammals is an irreversible process caused by degeneration of the hair cells of the inner ear. Current therapies for hearing loss include hearing aids and cochlear implants that provide substantial benefits to most patients, but also have several shortcomings. There is great interest in the development of regenerative therapies to treat deafness in the future. Cell-based therapies, based either on adult, multipotent stem, or other types of pluripotent cells, offer promise for generating differentiated cell types to replace lost or damaged hair cells of the inner ear. In this review, we focus on the methods proposed and avenues for research that seem the most promising for stem cell-based auditory sensory cell regeneration, from work collected over the past 15 years. PMID: 30033182 [PubMed - indexed for MEDLINE]
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Related Articles Mimic Cochlear Implant Surgery-Induced Cochlear Infection Fails to Further Damage Auditory Pathway in Deafened Guinea Pigs. Med Sci Monit. 2018 Aug 06;24:5448-5456 Authors: Han Z, Wang C, Gu Y, Cong N, Ma R, Chi F Abstract BACKGROUND Kanamycin and subsequent furosemide administration was applied to the healthy guinea pigs to induce deafness. MATERIAL AND METHODS Of the deafened guinea pigs, 10 were further infused with anti-infection procedures (Group B) and the other 10 animals did not undergo anti-infection procedures (Group C). In Group B, the deafened animals were able to restore cochlear and middle ear functions following the anti-infection procedure. In Group C, all animals developed cochlear and middle ear infections. RESULTS Compared to the healthy guinea pigs, hair cells and spiral ganglion neurons (SGN) of deafened animals (in Group B and Group C) were severely damaged. SGN density of deafened animals was significantly lower than that of healthy control animals in all ear turns except the basal turn. There was no significant difference between Group B and Group C in SGN density. The average optical density value of neurofilaments of deafened animals was also significantly decreased after the ototoxic drug administration. Notably, the density of the neurons in the cochlear nucleus region (CNR) of the brainstem were not significantly different between the healthy control guinea pigs and deafened animals. CONCLUSIONS Mimic cochlear implant surgery-induced cochlear infection caused no significant damage to the auditory pathway in ototoxic drug-induced deafened guinea pigs. PMID: 30078839 [PubMed - indexed for MEDLINE]
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Related Articles Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model. PLoS One. 2018;13(8):e0201022 Authors: Schiavon E, Smalley JL, Newton S, Greig NH, Forsythe ID Abstract Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia. PMID: 30106954 [PubMed - indexed for MEDLINE]
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Related Articles The olfactory mucosa: a potential source of stem cells for hearing regeneration. Regen Med. 2018 07 01;13(5):581-593 Authors: Young E, Westerberg B, Yanai A, Gregory-Evans K Abstract The olfactory mucosa contains cells that enable it to generate new neurons and other supporting cells throughout life, allowing it to replace cells of the mucosa that have been damaged by exposure to various insults. In this article, we discuss the different types of stem cell found within the olfactory mucosa and their properties. In particular, the mesenchymal-like cells found within the lamina propria will be reviewed in detail. In addition, we discuss potential applications of olfactory-derived stem cells toward hearing regeneration secondary to either inner hair cell loss or primary or secondary auditory nerve degeneration. PMID: 30113240 [PubMed - indexed for MEDLINE]
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Related Articles Valproic acid promotes the neuronal differentiation of spiral ganglion neural stem cells with robust axonal growth. Biochem Biophys Res Commun. 2018 09 18;503(4):2728-2735 Authors: Moon BS, Lu W, Park HJ Abstract Hearing loss occurs with the loss of hair cells of the cochlea and subsequent degeneration of spiral ganglion neurons (SGNs). Regeneration of SGNs is a potentially promising therapeutic approach to hearing loss in addition to the use of a cochlear implant (CI), because this device stimulates SGNs directly to restore hearing bypassing the missing hair cells. The presence of SGN-neural stem cells (NSCs) has been reported in adult human and mice. These cells have the potential to become SGNs and thus represent a cellular foundation for regeneration therapies for hearing loss. Valproic acid (VPA) has been shown to influence the neural differentiation of NSCs through multiple signaling pathways involving glycogen synthase kinase3β (GSK3β). Our present study therefore aimed to modulate the neural differentiation potential of SGN-NSCs by treatment with VPA. We here report that a clinically relevant concentration of 1 mM VPA induced the differentiation of basic fibroblast growth factor (bFGF)-treated P1- and P14-SGN-NSCs into neuronal and glial cells, confirmed by neuronal marker (Tuj1 and MAP2) and glial cell marker (GFAP and S100β) detection. VPA-treated cells also promoted much longer neurite outgrowth compared to differentiated cells cultured without bFGF. The effects of VPA on the regulation of differentiation may be related to the activation of the Wnt/β-catenin signaling pathway, but not the inhibition of histone deacetylases (HDACs). We propose that VPA has the potential to convert SGN-NSCs into SGNs and thereby restore hearing when combined with a CI. PMID: 30119886 [PubMed - indexed for MEDLINE]
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Related Articles N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells. Neural Plast. 2018;2018:3989201 Authors: Hong J, Chen Y, Zhang Y, Li J, Ren L, Yang L, Shi L, Li A, Zhang T, Li H, Dai P Abstract Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses. PMID: 30123246 [PubMed - indexed for MEDLINE]
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Related Articles Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear. Neural Plast. 2018;2018:4372913 Authors: Li P, Wen Z, Zhang G, Zhang A, Fu X, Gao J Abstract Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans. PMID: 30123247 [PubMed - indexed for MEDLINE]
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Related Articles Safety of Autologous Umbilical Cord Blood Therapy for Acquired Sensorineural Hearing Loss in Children. J Audiol Otol. 2018 Oct;22(4):209-222 Authors: Baumgartner LS, Moore E, Shook D, Messina S, Day MC, Green J, Nandy R, Seidman M, Baumgartner JE Abstract BACKGROUND AND OBJECTIVES: Sensorineural hearing loss (SNHL) in children is associated with neurocognitive morbidity. The cause of SNHL is a loss of hair cells in the organ of Corti. There are currently no reparative treatments for SNHL. Numerous studies suggest that cord blood mononuclear cells (human umbilical cord blood, hUCB) allow at least partial restoration of SNHL by enabling repair of a damaged organ of Corti. Our objective is to determine if hUCB is a safe treatment for moderate to severe acquired SNHL in children. Subjects and. METHODS: Eleven children aged 6 months to 6 years with moderate to severe acquired SNHL were treated with intravenous autologous hUCB. The cell dose ranged from 8 to 30 million cells/kg body weight. Safety was assessed by measuring systemic hemodynamics during hUCB infusion. Infusion-related toxicity was evaluated by measuring neurologic, hepatic, renal and pulmonary function before and after infusion. Auditory function, auditory verbal language assessments and MRI with diffusion tensor imaging (DTI) were obtained before and after treatment. RESULTS: All patients survived, and there were no adverse events. No infusionrelated changes in hemodynamics occurred. No infusion-related toxicity was recorded. Five subjects experienced a reduction in auditory brainstem response (ABR) thresholds. Four of those 5 subjects also experienced an improvement in cochlear nerve latencies. Comparison of MRI with DTI sequences obtained before and after treatment revealed increased fractional anisotropy in the primary auditory cortex in three of five subjects with reduced ABR thresholds. Statistically significant (p<0.05) reductions in ABR thresholds were identified. CONCLUSIONS: TIntravenous hUCB is feasible and safe in children with SNHL. PMID: 30126263 [PubMed]
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Related Articles Ouabain Does Not Induce Selective Spiral Ganglion Cell Degeneration in Guinea Pigs. Biomed Res Int. 2018;2018:1568414 Authors: Schomann T, Ramekers D, de Groot JCMJ, van der Ploeg CH, Hendriksen FGJ, Böhringer S, Klis SFL, Frijns JHM, Huisman MA Abstract Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea. PMID: 30151372 [PubMed - indexed for MEDLINE]
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Related Articles Late effects in high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell rescue. Pediatr Blood Cancer. 2019 Jan;66(1):e27421 Authors: Elzembely MM, Dahlberg AE, Pinto N, Leger KJ, Chow EJ, Park JR, Carpenter PA, Baker KS Abstract BACKGROUND: Current treatment strategies have improved the outcome of high-risk neuroblastoma (HRNB) at the cost of increasing acute and late effects of treatment. Although high-dose chemotherapy with stem cell rescue (HDC-SCR) has replaced total body irradiation (TBI) based HRNB therapy, late effects of therapy remain a significant concern. OBJECTIVES: To describe late effects prevalence, severity, and risks after HDC-SCR. METHODS: Retrospective chart review of relapse-free HRNB survivors ≥1 year after single HDC-SCR between 2000 and 2015 at Fred Hutchinson Cancer Research Center. RESULTS: Sixty-one survivors (30 males) were eligible. Median age (years) at SCR was 3.5 years (range 0.7-27 years) and median posttransplant follow-up was 5.4 years (1.2-16.3 years) . Fifty-three (86.9%) survivors developed late effects that increased over time (P < 0.001) and varied in severity from grade 1 (35) to grade 5 (1). These were unrelated to gender or age. High-frequency hearing loss seen in 82% of survivors was the most common abnormality present and 43% of those required hearing aids. Seventeen (27.9%) survivors developed dental late effects and these were most common in children <2 years of age at transplant (P = 0.008). Other toxicities included endocrine (18%), orthopedic (14.8 %), renal (3.9%), melanotic nevi (8.2%), neuropsychological impairments (8.2%), subsequent malignancies (4.9%), pulmonary (4.9%), cardiac (4.9%), and focal nodular liver hyperplasia (3.3%). At 9 years posttransplant, the median height and weight Z-scores were significantly lower than Z-scores at the time of HDC-SCR (-0.01/-1.08, P < 0.001; -0.14/-0.78, P = 0.005). CONCLUSION: Avoidance of TBI does not mitigate the need to provide diligent, ongoing surveillance for late effects. PMID: 30151986 [PubMed - in process]
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Related Articles Differentiation and transplantation of human induced pluripotent stem cell-derived otic epithelial progenitors in mouse cochlea. Stem Cell Res Ther. 2018 08 29;9(1):230 Authors: Chen J, Hong F, Zhang C, Li L, Wang C, Shi H, Fu Y, Wang J Abstract BACKGROUND: Inner ear hair cells as mechanoreceptors are extremely important for hearing. Defects in hair cells are a major cause of deafness. Induced pluripotent stem cells (iPSCs) are promising for regenerating inner ear hair cells and treating hearing loss. Here, we investigated migration, differentiation, and synaptic connections of transplanted otic epithelial progenitors (OEPs) derived from human iPSCs in mouse cochlea. METHODS: Human urinary cells isolated from a healthy donor were reprogramed to form iPSCs that were induced to differentiate into OEPs and hair cell-like cells. Immunocytochemistry, electrophysiological examination, and scanning electron microscopy were used to examine characteristics of induced hair cell-like cells. OEP-derived hair cell-like cells were cocultured with spiral ganglion neurons (SGNs), and the markers of synaptic connections were detected using immunocytochemistry and transmission electron microscope. In vivo, OEPs derived from iPSCs were transplanted into the cochlea of mice by injection through the round window. Migration, differentiation, and synaptic connections of transplanted cells were also examined by thin cochlear sectioning and immunohistochemistry. RESULTS: The induced hair cell-like cells displayed typical morphological characteristics and electrophysiological properties specific to inner hair cells. In vitro, OEP-derived hair cell-like cells formed synaptic connections with SGNs in coculture. In vivo, some of the transplanted cells migrated to the site of the resident hair cells in the organ of Corti, differentiated into hair cell-like cells, and formed synaptic connections with native SGNs. CONCLUSIONS: We conclude that the transplantation of OEPs is feasible for the regeneration of hair cells. These results present a substantial reference for a cell-based therapy for the loss of hair cells. PMID: 30157937 [PubMed - indexed for MEDLINE]
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Related Articles Gene Delivery into the Inner Ear and Its Clinical Implications for Hearing and Balance. Molecules. 2018 Sep 30;23(10): Authors: Kanzaki S Abstract The inner ear contains many types of cell, including sensory hair cells and neurons. If these cells are damaged, they do not regenerate. Inner ear disorders have various etiologies. Some are related to aging or are idiopathic, as in sudden deafness. Others occur due to acoustic trauma, exposure to ototoxic drugs, viral infections, immune responses, or endolymphatic hydrops (Meniere's disease). For these disorders, inner ear regeneration therapy is expected to be a feasible alternative to cochlear implants for hearing recovery. Recently, the mechanisms underlying inner ear regeneration have been gradually clarified. Inner ear cell progenitors or stem cells have been identified. Factors necessary for regeneration have also been elucidated from the mechanism of hair cell generation. Inducing differentiation of endogenous stem cells or inner ear stem cell transplantation is expected. In this paper, we discuss recent approaches to hair cell proliferation and differentiation for inner ear regeneration. We discuss the future road map for clinical application. The therapies mentioned above require topical administration of transgenes or drug onto progenitors of sensory cells. Developing efficient and safe modes of administration is clinically important. In this regard, we also discuss our development of an inner ear endoscope to facilitate topical administration. PMID: 30274337 [PubMed - indexed for MEDLINE]
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Related Articles Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review. Front Oncol. 2018;8:363 Authors: Prayuenyong P, Taylor JA, Pearson SE, Gomez R, Patel PM, Hall DA, Kasbekar AV, Baguley DM Abstract Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer. Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized. Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin. Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed. PMID: 30319960 [PubMed]
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Related Articles Pluripotent stem cell-derived cochlear cells: a challenge in constant progress. Cell Mol Life Sci. 2019 Feb;76(4):627-635 Authors: Czajkowski A, Mounier A, Delacroix L, Malgrange B Abstract Hearing loss is a common affection mainly resulting from irreversible loss of the sensory hair cells of the cochlea; therefore, developing therapies to replace missing hair cells is essential. Understanding the mechanisms that drive their formation will not only help to unravel the molecular basis of deafness, but also give a roadmap for recapitulating hair cells development from cultured pluripotent stem cells. In this review, we provide an overview of the molecular mechanisms involved in hair cell production from both human and mouse embryonic stem cells. We then provide insights how this knowledge has been applied to differentiate induced pluripotent stem cells into otic progenitors and hair cells. Finally, we discuss the current limitations for properly obtaining functional hair cell in a Petri dish, as well as the difficulties that have to be overcome prior to consider stem cell therapy as a potential treatment for hearing loss. PMID: 30341460 [PubMed - indexed for MEDLINE]
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Related Articles Combined Growth Factor and Gene Therapy: An Approach for Hair Cell Regeneration and Hearing Recovery. ORL J Otorhinolaryngol Relat Spec. 2018;80(5-6):326-337 Authors: Mahmoudian-Sani MR, Jamshidi M, Asgharzade S Abstract INTRODUCTION: Fibroblast growth factor, nerve growth factor neurotrophins, and insulin-like growth factor 1 are considered 3 families of growth factors that can be involved in the process of otic neurogenesis. In this respect, otic neurons can also be connected with mechanoreceptors in the ear, the hair cells (HCs), as well as the central nervous system. As a growth factor is combined with gene transfer technology, it can be used for hair cell regeneration. Gene therapy can be similarly employed to introduce genes into a system in order to induce the expression of genes for therapeutic agents, to replace defective genes, or to re-program supporting or surrounding cells to acquire the phenotype of lost or damaged cells in order to repair or regenerate the damaged tissue. OBJECTIVE: The purpose of this review article was to investigate the epigenetic and growth factors involved in the differentiation pathway of embryonic stem cells (ESCs) into HCs and auditory neurons (ANs). METHODS: To this end, the databases of Directory of Open Access Journals, Google Scholar, PubMed (NLM), LISTA (EBSCO), as well as Web of Science were searched. RESULTS: Given the results available in the related literature, the differentiation efficacy of ESCs toward the ANs and the HCs, the important role of growth factors, and 3 different strategies of application of miRNA, epigenetic regulation, and preparation of three-dimensional (3D) environments were suggested to be taken into consideration in order to improve these studies in the future. Furthermore, the role of epige-netic mechanisms and miRNA in this differentiation process became quite obvious; hence, the utilization of such procedures in the near future would be significant. CONCLUSION: Combining several techniques with a synergic effect (such as growth factor gene therapy and 3D environments) seemed to lead to obtaining the best results as a therapeutic strategy. PMID: 30359973 [PubMed - in process]
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Related Articles The Effect of the MicroRNA-183 Family on Hair Cell-Specific Markers of Human Bone Marrow-Derived Mesenchymal Stem Cells. Audiol Neurootol. 2018;23(4):208-215 Authors: Mahmoudian-Sani MR, Jami MS, Mahdavinezhad A, Amini R, Farnoosh G, Saidijam M Abstract Hearing loss is considered the most common sensory disorder across the world. Nowadays, a cochlear implant can be an effective treatment for patients. Moreover, it is often believed that sensorineural hearing loss in humans is caused by loss or disruption of the function of hair cells in the cochlea. In this respect, mesenchymal cells can be a good candidate for cell-based therapeutic approaches. To this end, the potential of human bone marrow-derived mesenchymal stem cells to differentiate into hair cells with the help of transfection of microRNA in vitro was investigated. MicroRNA mimics (miRNA-96, 182, and 183) were transfected to human bone marrow-derived mesenchymal stem cells using Lipofec-tamine as a common transfection reagent following the manufacturer's instructions at 50 nM for microRNA mimics and 50 nM for the scramble. The changes in cell morphology were also observed under an inverted microscope. Then, the relative expression levels of SOX2, POU4F3, MYO7A, and calretinin were assayed using real-time polymerase chain reaction according to the ΔΔCt method. The ATOH1 level was similarly measured via real-time polymerase chain reaction and Western blotting. The results showed that increased expression of miRNA-182, but neither miRNA-96 nor miRNA-183, could lead to higher expression levels in some hair cell markers. The morphology of the cells also did not change in this respect, but the evaluation of gene expression at the levels of mRNA could promote the expression of the ATOH1, SOX2, and POU4F3 markers. Furthermore, miRNA-182 could enhance the expression of ATOH1 at the protein level. According to the results of this study, it was concluded that miRNA-182 could serve as a crucial function in hair cell differentiation by the upregulation of SOX2, POU4F3, and ATOH1 to promote a hair cell's fate. PMID: 30380528 [PubMed - in process]
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Related Articles Otologic, audiometric and speech findings in patients undergoing surgery for cleft palate. BMC Pediatr. 2018 Nov 08;18(1):350 Authors: Garcia-Vaquero C, Mir C, Graterol D, Ortiz N, Rochera-Villach MI, LLeonart ME, Lorente J Abstract BACKGROUND: Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. METHODS: Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d'Hebron Hospital, Barcelona from 2000 to 2014. RESULTS: The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. CONCLUSION: Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes. PMID: 30409226 [PubMed - in process]
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Related Articles DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium. Sci Rep. 2018 Nov 26;8(1):17348 Authors: Yizhar-Barnea O, Valensisi C, Jayavelu ND, Kishore K, Andrus C, Koffler-Brill T, Ushakov K, Perl K, Noy Y, Bhonker Y, Pelizzola M, Hawkins RD, Avraham KB Abstract The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system. PMID: 30478432 [PubMed - in process]
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Related Articles Transplantation of human limbus-derived mesenchymal stromal cells via occipital approach improves hearing in animal auditory neuropathy. Int J Pediatr Otorhinolaryngol. 2019 Feb;117:67-72 Authors: Chen HC, Liang CM, Wang CH, Huang MY, Lin YY, Shih CP, Kuo CY, Lin YC, Chen HK Abstract OBJECTIVE: To develop a surgical approach for cell transplantation into mouse cochlear nerves via an intracranial route and investigate whether transplantation of human limbus-derived mesenchymal stromal cells (HL-MSCs) can improve hearing in this model of auditory neuropathy. METHODS: We used 8-week-old CBA/CaJ male mice and created ouabain-induced auditory neuropathy. The surgical approach passed through the cerebellum to reveal the superior semicircular canal and brainstem, allowing access to the auditory nerve. Then HL-MSCs were injected around the cochlear nerve trunk using a micropipette driven by a micropump. Hearing thresholds in the mice were determined by auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). RESULTS: We produced ouabain-induced neuropathy in mice with an elevated hearing threshold but normal DPOAE. Using immunohistological staining, we detected HL-MSCs were localized in the cochlear nerve trunk 2 days after cell transplantation via this occipital approach. More spiral ganglion neurons were detected in ouabain-treated cochleae 3 months after HL-MSCs transplantation compared to those without HL-MSCs transplantation. The ABR showed significant hearing improvement 3 months after HL-MSCs transplantation. CONCLUSIONS: We successfully established a mouse model for cell transplantation into the intracranial cochlear nerve trunk and showed that HL-MSCs potentially can be applied as cell therapy to treat sensorineural hearing loss. PMID: 30579092 [PubMed - indexed for MEDLINE]
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Related Articles Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome. Regen Ther. 2019 Jun;10:54-63 Authors: Hosoya M, Saeki T, Saegusa C, Matsunaga T, Okano H, Fujioka M, Ogawa K Abstract Introduction: Pendred syndrome is an autosomal-recessive disease characterized by congenital hearing loss and thyroid goiter. Previously, cell stress susceptibilities were shown to increase in patient-derived cells with intracellular aggregation using an in vitro acute cochlear cell model derived from patient-specific pluripotent stem (iPS) cells. Moreover, we showed that rapamycin can relieve cell death. However, studies regarding long-term cell survival without cell stressors that mimic the natural course of disease or the rational minimum concentration of rapamycin that prevents cell death are missing. Methods: In this report, we first investigated the rational minimum concentration of rapamycin using patient-specific iPS cells derived-cochlear cells with three different conditions of acute stress. We next confirmed the effects of rapamycin in long-term cell survival and phenotypes by using cochlear cells derived from three different patient-derived iPS cells. Results: We found that inner ear cells derived from Pendred syndrome patients are more vulnerable than those from healthy individuals during long-term culturing; however, this susceptibility was relieved via treatment with low-dose rapamycin. The slow progression of hearing loss in patients may be explained, in part, by the vulnerability observed in patient cells during long-term culturing. We successfully evaluated the rational minimum concentration of rapamycin for treatment of Pendred syndrome. Conclusion: Our results suggest that low-dose rapamycin not only decreases acute symptoms but may prevent progression of hearing loss in Pendred syndrome patients. PMID: 30581897 [PubMed]
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Related Articles Malignant progression of an extraventricular neurocytoma arising from the VIIIth cranial nerve: A case report and literature review. Neuropathology. 2019 Apr;39(2):120-126 Authors: Sugita Y, Furuta T, Komaki S, Ohshima K, Sakata K, Morioka M Abstract A rare case of extraventricular neurocytoma (EVN) arising from the VIIIth cranial nerve in a 34-year-old woman is reported. The patient had a 20-year history of hearing loss and facial palsy. Computed tomography showed a 3-cm enhancing lesion in the left cerebellopontine angle (CPA). At operation, the tumor was seen to originate from the cochlear and vestibular nerves. The tumor was subtotally resected. Histologically, the tumor consisted of uniform cells with oval to round nuclei and scant cytoplasm. Immunohistochemically, the tumor cells were positive for synaptophysin, but negative for glial fibrillary acid protein and S-100 protein. The Ki-67 labeling index was 0%. Twelve years after the operation, magnetic resonance imaging (MRI) showed tumor recurrence at the left CPA. The tumor was subtotally resected, and radiation therapy was given. Histologically, the tumor consisted of round cells with mild atypia and one mitosis/20 high-power fields (HPF). Immunohistochemically, tumor cells showed the same findings as the first operation sample, except for the Ki-67 labeling index (3%). Twelve years after the second operation, MRI showed a second tumor recurrence at the left CPA and surroundings of the brain stem. The tumor was subtotally resected. Histologically, the tumor consisted of anaplastic short spindle cells and five mitoses/10 HPF. The immunohistochemical findings were almost the same as the earlier operation samples. However, the Ki-67 labeling index was 20%. In addition, tumor cells from the third specimen were more strongly and more diffusely positive for GAB1 (growth factor receptor-bound protein 2-associated binding protein 1) compared to those of the earlier specimens. Electron microscopy showed the presence of numerous cell processes with a dense core and clear vesicles and microtubules. GAB1 immunostaining also indicated that malignant progression might be associated with the sonic hedgehog signaling pathways. To the best of our knowledge, this is the first report of an EVN arising from the VIIIth cranial nerve with malignant progression. PMID: 30588667 [PubMed - in process]
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Related Articles Spontaneous Otoacoustic Emissions in TectaY1870C/+ Mice Reflect Changes in Cochlear Amplification and How It Is Controlled by the Tectorial Membrane. eNeuro. 2018 Nov-Dec;5(6): Authors: Cheatham MA, Zhou Y, Goodyear RJ, Dallos P, Richardson GP Abstract Spontaneous otoacoustic emissions (SOAEs) recorded from the ear canal in the absence of sound reflect cochlear amplification, an outer hair cell (OHC) process required for the extraordinary sensitivity and frequency selectivity of mammalian hearing. Although wild-type mice rarely emit, those with mutations that influence the tectorial membrane (TM) show an incidence of SOAEs similar to that in humans. In this report, we characterized mice with a missense mutation in Tecta, a gene required for the formation of the striated-sheet matrix within the core of the TM. Mice heterozygous for the Y1870C mutation (TectaY1870C/+ ) are prolific emitters, despite a moderate hearing loss. Additionally, Kimura's membrane, into which the OHC stereocilia insert, separates from the main body of the TM, except at apical cochlear locations. Multimodal SOAEs are also observed in TectaY1870C/+ mice where energy is present at frequencies that are integer multiples of a lower-frequency SOAE (the primary). Second-harmonic SOAEs, at twice the frequency of a lower-frequency primary, are the most frequently observed. These secondary SOAEs are found in spatial regions where stimulus-evoked OAEs are small or in the noise floor. Introduction of high-level suppressors just above the primary SOAE frequency reduce or eliminate both primary and second-harmonic SOAEs. In contrast, second-harmonic SOAEs are not affected by suppressors, either above or below the second-harmonic SOAE frequency, even when they are much larger in amplitude. Hence, second-harmonic SOAEs do not appear to be spatially separated from their primaries, a finding that has implications for cochlear mechanics and the consequences of changes to TM structure. PMID: 30627650 [PubMed - indexed for MEDLINE]
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Related Articles Bone Marrow Stromal Cells Accelerate Hearing Recovery via Regeneration or Maintenance of Cochlear Fibrocytes in Mouse Spiral Ligaments. Anat Rec (Hoboken). 2019 Jan 11;: Authors: Kada S, Hamaguchi K, Ito J, Omori K, Nakagawa T Abstract Mammalian cochleae have limited capacity for regeneration, which is one of the major difficulties in the treatment of sensorineural hearing loss. In the current study, we examined the potential of bone marrow-derived stromal cells (BMSCs) for functional restoration of mouse cochleae through regeneration or maintenance of cochlear fibrocytes in the spiral ligament (SL). We used a mouse model of degeneration of cochlear fibrocytes in the SL using local application of 3-nitropropionic acid (3-NP), in which disruption of the gap junction network in the SL resulted in the reduction of the endocochlear potential (EP). Mouse BMSCs were infused into the posterior semicircular canal 7 days after 3-NP application. Transplanted BMSCs were frequently observed in the cochlear fluid space 4 weeks after transplantation, although a few transplants had migrated into the cochlear tissues including the SL. BMSC-treated cochleae exhibited higher cell densities in the SL and greater EP levels than the control ones. Immunohistochemistry further demonstrated the restoration of functional proteins in the SL. Significant recovery in thresholds of auditory brainstem responses following BMSC transplantation was found only at 40 kHz in a mild degeneration model. Our cumulative findings indicated that BMSCs accelerated regeneration or maintenance of fibrocytes in damaged SLs, leading to partial functional restoration of the mouse cochleae. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. PMID: 30632312 [PubMed - as supplied by publisher]
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Related Articles Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Cochlear Function in an Experimental Rat Model. Anat Rec (Hoboken). 2019 Jan 11;: Authors: Mittal R, Ocak E, Zhu A, Perdomo MM, Pena SA, Mittal J, Bohorquez J, Eshraghi AA Abstract Mesenchymal stem cell (MSC) therapy is an emerging treatment modality for various human diseases. Although induced pluripotent stem cells have been explored for the restoration of hearing, the potential of MSCs as a therapeutic strategy for various cochlear insults is not precisely known. MSCs possess anti-inflammatory, anti-apoptotic and neuroprotective properties, making them an attractive target for the treatment of inner ear disorders such as hair cell damage in response to inflammation. Most of the previous studies have used immunosuppression or the complex surgical techniques to deliver stem cells into the cochlea. However, no information is available regarding the biocompatibility and safety of MSCs in the inner ear in immunocompetent cochlea. The aim of the present study was to determine the effect of non-surgical administration of rodent bone marrow derived MSCs (BM-MSCs) through transtympanic delivery on the cochlear function and to assess any adverse effects on the auditory system employing a rat model without immunosuppression. We observed that the transtympanic administration of BM-MSCs has no significant effect on the hearing thresholds as determined by auditory brainstem response and distortion product otoacoustic emissions. Histopathological examination revealed no recruitment of inflammatory leukocytes and edema in the cochlea of BM-MSCs administrated rats. The results of this study suggest that transtympanic administration of BM-MSCs is safe and can be explored in providing otoprotection against cochlear insults. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. PMID: 30632683 [PubMed - as supplied by publisher]
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Related Articles Imaging Bioluminescent Exogenous Stem Cells in the Intact Guinea Pig Cochlea. Anat Rec (Hoboken). 2019 Jan 11;: Authors: Schomann T, Mezzanotte L, de Groot JCMJ, Löwik CWGM, Frijns JHM, Huisman MA Abstract Stem-cell-based therapy may be used to replace damaged or lost neurons in the cochlear nerve of patients suffering from severe-to-profound sensorineural hearing loss. In order to achieve functional recovery in future clinical trials, knowledge about survival of grafted cells and their differentiation into functional neurons is a prerequisite. This calls for non-invasive in vivo visualization of cells and long-term monitoring of their survival and fate after cochlear transplantation. We have investigated if molecular optical imaging enables visualization of exogenous cells in the intact cochlea of guinea pig cadaver heads. Transduced (stem) cells, stably co-expressing fluorescent (copGFP) and bioluminescent (Luc2) reporter molecules, were injected into the internal auditory meatus or directly into the cochlea through the round window. After injection of the cells into the internal auditory meatus, a bright bioluminescent signal was observed in the cavum conchae of the auricle, indicating that light generated by Luc2 is passing through the tympanic membrane and the external auditory meatus. Similar results were obtained after injection of the cells through the round window membrane, either directly into the scala tympani or in Rosenthal's canal within the modiolus of the basal cochlear turn. Imaging of the auditory bulla demonstrated that the bioluminescent signal passes through the tympanic membrane and crevices in the bony wall of the bulla. After opening the auditory bulla, the bioluminescent signal was emanating from the round window. This is the first study demonstrating that bioluminescence imaging enables visualization of luciferase-expressing cells injected into the intact guinea pig cochlea. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. PMID: 30635981 [PubMed - as supplied by publisher]
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Related Articles Acid stimulation-induced semi-pluripotent characteristics in human somatic cells. Acta Otolaryngol. 2019 Feb;139(2):146-152 Authors: Xu QQ, Guo WW, Wang X, Zhai S, Yang S Abstract BACKGROUND: Clinical trials of cell-based therapies using induced pluripotent stem (iPS) cells have already been started for several neurological diseases. OBJECTIVE: The purpose of the present study was to explore the characteristics and differentiation of somatic cells in vitro undergoing a low pH treatment, so as to provide new therapeutic strategies for treating sensorineural hearing loss. METHODS: Somatic cells were treated with low pH solution to alter their characteristics. In addition, a mouse model of the cochlear lesion was constructed using bilirubin. Subsequently, the characteristics and therapeutic effect of somatic cells undergoing low pH treatment were examined by morphology, alkaline phosphatase (AKP) activity, immunofluorescence assay and q-PCR. RESULTS: The cells in the experimental group grew better than those in the control group. The AKP activity in the experimental group was higher than that in the control group. The expression of Nanog and Oct4 was both positive in the two groups. When the cells were changed to neurobasal medium, the marker of nestin was positive. CONCLUSION: The human somatic cells undergoing a low pH treatment showed the similar characteristics as those of iPS cells, although the functions and therapeutic effect of these altered human somatic cells need to be further studied. PMID: 30734622 [PubMed - in process]
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Related Articles Recent Advancements in Gene and Stem Cell-Based Treatment Modalities: Potential Implications in Noise-Induced Hearing Loss. Anat Rec (Hoboken). 2019 Mar 11;: Authors: Eshraghi AA, Jung HD, Mittal R Abstract Noise-induced hearing loss (NIHL) poses a significant burden on not only the economics of health care but also the quality of life of an individual, as we approach an unprecedented age of longevity. In this article, we will delineate the current landscape of management of NIHL. We discuss the most recent results from in vitro and in vivo studies that determine the effectiveness of established pharmacotherapy such as corticosteroid and potential emerging therapies like N-acetyl cysteine and neurotrophins (NTs), as well as highlight ongoing clinical trials for these therapeutic agents. We present an overview of how the recent advancements in the field of gene-based and stem cell-based therapies can help in developing effective therapeutic strategies for NIHL. Gene-based therapies have shown exciting results demonstrating cochlear cellular regeneration using Atoh1, NRF2 as well as NT gene therapy employing viral vectors. In addition, we will discuss the recent advancements in genome-editing technologies, such as CRISPR/Cas9, and its potential role in NIHL therapy. We will further discuss the current state of stem cell therapy as it pertains to treating neurodegenerative conditions including NIHL. Embryonic stem cells, adult-derived stem cells, and induced pluripotent stem cells all represent an enticing reservoir of replacing damaged cells as a result of NIHL. Finally, we will discuss the barriers that need to be overcome to translate these promising treatment modalities to the clinical practice in pursuit of improving quality of life of patients having NIHL. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. PMID: 30859735 [PubMed - as supplied by publisher]
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Related Articles Exploring the Experiences of Cancer Patients With Chemotherapy-Induced Ototoxicity: Qualitative Study Using Online Health Care Forums. JMIR Cancer. 2019 Mar 14;5(1):e10883 Authors: Pearson SE, Taylor J, Hoare DJ, Patel P, Baguley DM Abstract BACKGROUND: Many cancer patients and survivors experience permanent and life-debilitating effects, such as ototoxicity, from treatment. Ototoxicity manifests as high-frequency hearing loss and tinnitus, which can have a detrimental effect on the quality of life (QoL) of those affected. Currently, there is little information and support offered to these patients who experience ototoxicity, potentially leading to many being undiagnosed and untreated. OBJECTIVE: The aim of this study was to explore the extent of ototoxic side effects, such as hearing loss and tinnitus, and their impact on cancer patients following chemotherapy treatment. Secondary objectives included detecting the time periods of onset and duration of the ototoxicity and identifying what support was available to this population. METHODS: Posts from publicly available online forums were thematically analyzed using the guidelines by Braun and Clarke. A coding manual was iteratively developed to create a framework for the analysis of the ototoxicity experience among the cancer population. RESULTS: A total of 9 relevant online forums were identified, consisting of 86 threads and 570 posts from 377 members. Following the bottom-up thematic analysis, 6 major themes were identified: nature of ototoxicity, time of experienced ototoxicity, information on ototoxicity, quality of life, therapies, and online social support. CONCLUSIONS: There was a significant number of reports expressing concerns about the lack of information on the risk of ototoxicity. More support for those suffering is needed; for example, improved interdepartmental communication between oncology and audiology services could optimize patient care. Patients should also be encouraged to communicate with their health care professionals about their ototoxicity and relay how their QoL is impacted by ototoxicity when accessing support. Tinnitus was the most common concern and was associated with distress. Hearing loss was less common; however, it was associated with fear and employment issues. Those who reported preexisting conditions were fearful about worsening their condition as their QoL was already impacted. PMID: 30869640 [PubMed]
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Stem Cells: A New Hope for Hearing Loss Therapy. Adv Exp Med Biol. 2019;1130:165-180 Authors: Qiu Y, Qiu J Abstract Permanent hearing loss was considered which cannot be cured since cochlear hair cells and primary afferent neurons cannot be regenerated. In recent years, due to the in-depth study of stem cell and its therapeutic potential, regenerating auditory sensory cells is made possible. By using two strategies of endogenous stem cell activation and exogenous stem cell transplantation, researchers hope to find methods to restore hearing function. However, there are complex factors that need to be considered in the in vivo application of stem cell therapy, such as stem cell-type choice, signaling pathway regulations, transplantation approaches, internal environment of the cochlea, and external stimulation. After years of investigations, some theoretic progress has been made in the treatment of hearing loss using stem cells, but there are also many problems which limited its application that need to be solved. Understanding the future perspective of stem cell therapy in hearing loss, solving the encountered problems, and promoting its development are the common goals of audiological researchers. In this review, we present critical experimental findings of stem cell therapy on treatment of hearing loss and intend to bring hope to researchers and patients. PMID: 30915707 [PubMed - in process]
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Related Articles The use of animal models to study cell transplantation in neuropathic hearing loss. Hear Res. 2019 Mar 19;377:72-87 Authors: Abbas L, Rivolta MN Abstract Auditory neuropathy (AN) is a form of sensorineural deafness specifically affecting the conduction of the nerve impulse from the cochlear hair cells to the auditory centres of the brain. As such, the condition is a potential clinical target for 'cell replacement therapy', in which a functioning auditory nerve is regenerated by transplanting an appropriated neural progenitor. In this review, we survey the current literature and examine possible experimental models for this condition, with particular reference to their compatibility as suitable hosts for transplantation. The use of exogenous neurotoxic agents such as ouabain or β-bungarotoxin is discussed, as are ageing and noise-induced synaptopathy models. Lesioning of the nerve by mechanical damage during surgery and the neuropathy resulting from infectious diseases may be very relevant clinically, and we discuss whether there are good models for these situations. We also address genetic models for AN, examining whether the phenotypes truly model the clinical situation in their human counterpart syndromes - we use the example of the hyperbilirubinaemic Gunn rat as a particular instance in this regard. PMID: 30921643 [PubMed - as supplied by publisher]
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