Role of the periotic mesenchyme in the development of sensory cells in early mouse cochlea

Objective:To investigate the role of the periotic mesenchyme(POM)in the development of sensory cells of developing auditory epithelium.Methods:Developing auditory epithelium with or without periotic mesenchyme was isolated from mice at embryonic days 11.5(E11.5),E12.5 and E13.5,respectively,and cultured in vitro to an equivalent of E18.5’s epithelium in vivo.Then,the explants were co-stained with antibodies targeting myosin VIIA,Sox2 and BrdU.Results:More hair cells in E11.5 t 7 DIV,E12.5 t 6 DIV and E13.5 t 5 DIV auditory epithelia were found upon culture with POM(225.90±62.44,476.94±100.81,and 1386.60±202.38,respectively)compared with the non-POM group(68.17±23.74,205.00±44.23,and 1266.80±38.84,respectively).Moreover,regardless of developmental stage,the mesenchymal tissue increased the amount of cochlear sensory cells as well as the ratio of differentiated hair cells to total sensory cells.Conclusions:The periotic mesenchyme promotes the development of cochlear sensory cells,and its effect depends on the developmental stage of the auditory epithelium.

Stability of computed tomography densitometry in patients with otosclerosis:a two-year follow-up

Objectives:To quantify the progression of otosclerosis in the unoperated ear between two stapedotomy procedures for patients with bilateral otosclerosis which can help to determine whether a HRCT scan should be re-performed before the second surgery for patients who already received HRCT imaging before the initial surgery.Methods:35 patients who underwent bilateral stapedotomy were included.Two rounds of HRCT examination and audiometry were performed at the time of the first surgery and second surgery on the ear that was not operated on during the initial surgery.The relationship between the changes in HRCT densitometry and audiometry over time was analyzed.Results:The second round of HRCT did not add significant information about the changes to the otosclerosis lesions in either the imaging diagnosis or the HRCT density values except for small changes in the HRCT densitometry readings at the area anterior to the inner auditory(P=0.01).While the changes in HRCT manifestation are small,changes near the fissula ante fenestram(FAF)were still positively correlated with the air bone gap(ABG)of patients(p=0.031,r=0.388).Conclusions:The progression of lesions in otosclerosis is slow resulting in small and insignificant changes to the HRCT features.Therefore,a repeat HRCT evaluations prior to surgery is not necessary for patients who have had a previous HRCT evaluation within 2 years of the operation.The small changes in HRCT manifestation near the FAF were still correlated with negative effects on the ABG which could cause worsened hearing thresholds over this timeframe。

Novel heterozygous USH1C mutation impacts hair cell mechanotransduction and causes progressive hearing loss

Hearing loss is one of the most common sensory disorders worldwide,affecting approximately 466 million people,including 34 million children[1].Genetic mutations accounts for approximately 60%of inherited hearing loss cases[2,3].These genetic changes result in a wide variety of clinical manifestations,ranging from nonsyndromic hearing loss(NSHL)to over 400 syndromes involving hearing loss and from mild adult-onset hearing loss to profound congenital deafness,covering the entire spectrum of Mendelian inheritance.

Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development

Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

Hidden hearing loss:current perspectives and potential therapies

Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The pathological mechanisms of HHL are complicated and are not yet fully understood.HHL can be resulted from disorders of the central nervous system such as auditory cortex,and/or pathological changes of inner ear.Thus far,2 pathological phenomena,synaptopathy and auditory nerve demyelination,have been reported as underlying causes of otogenic HHL.Here,we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.

Evaluation on Effectiveness of a New System as well as Analysis on Optimal Horizontal Eye Position for Vertical Video Head Impulse Test

Objective To compare the performances among three different systems for video head impulse test(vHIT),and to identify an optimal target angle for precisely evaluating the function of vertical semicircular canals in vHIT.Methods A two-center prospective study was done.Participants were sit 1.2 m away from the wall in a noise-proved room that dedicated for vHIT experiments.During the comparison experiments,similar settings were ensured in both hospitals,with the same distance to wall and angle of staring.For each equipment,the procedures followed the developers’recommendations.The same examiner performed the comparison between two systems in one location.For the eye-position projects,targets were placed on the wall sequentially at the pre-marked lines for different angles.For the comparison projects,9 and 13 participants were recruited,respectively.Any participant with otologic or vestibular disorders was excluded.A total of 26 healthy participants were recruited in the eye-position experiments,16 of which were further involved in inter-examiner tests.Results Our evaluations of three different systems showed that a new vHIT system,VertiGoggles®ZT-VNG-I(VG)performed as good as the long-tested Otometrics®ICS impulse(Oto)and EyeSeeCam®(ESC).During the comparison,we validated 25-degree,instead of right ahead at 0 degree,is a better place to set the targets when torsion was applied at vertical semicircular canal planes.Conclusion The new VG system is good for clinical practices.Furthermore,we proposed a new protocol to set the targets 25 degrees from right ahead after tilting head 45 degrees to evaluate vertical canals during vHIT.

Inhibiting DNA methylation alleviates cisplatininduced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)assessment.Reactive oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red probes.Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

Bioinspired structural color particles with multi-layer graphene oxide encapsulated nanoparticle components

Because of the unique features of spherical symmetry,angle-independency,good monodispersity,controllable components and morphologies,structural color particles(SCPs)have found great significances in various fields such as sensing,monitoring,biological assays,etc.Here,inspired by the melanosome-derived bright structural colors and the self-adhesivity of mussels,we present a kind of bioinspired SCPs assembled from polydopamine(PDA)-adhered multi-layer graphene oxide(GO)encapsulated silica nanoparticles(SNs).It is demonstrated that compared with traditional SCPs,the designed particles possess brighter and more vibrant structural colors,and no complicated modification is required during the functionalization process due to the abundant inherent functional groups of GO.The resultant SCPs are verified to be capable for direct hybridization chain reaction and multiplexed nucleic acid assays.These properties indicate the promising prospects of our designed SCPs.

The p.(Pro170Leu) variant in NOG impairs noggin secretion and causes autosomal dominant congenital conductive hearing loss due to stapes ankylosis

Conductive hearing loss is the impairment in the mechanical transduction of sound wave through the external ear and the middle ear.Although most cases are sporadic due to acquired causes such as infections(otitis media and otitis externa),cerumen obstruction,and injuries,congenital structural defects are uncommon for significant etiologies to recognize.Stapes ankylosis is characterized by conductive hearing loss.It may be difficult to differentiate from otosclerosis,the most common cause of progressive conductive hearing loss,by audiologic evaluation,when the diagnosis is delayed.Skeletal anomalies may be subtle,such that the syndrome may not be recognized(Brown et al.,2002).

Artificial Water Channel that Couples with Cell Protrusion Formation

In natural systems,water transport across the cellular plasma membranes is mainly mediated by naturally occurring channel protein aquaporins(AQPs),which lead to a series of important physiological functions including cell migration.The construction of artificial analogs of the natural AQPs would generate a new strategy for treating AQP-related diseases.In this report,an artificial water channel has been developed from a unimolecular tubular molecule,which featured structural encapsulation of a single-file water wire composed of oppositely orientated dipolar water molecules.This AQP-like structure endowed the artificial channel in living cells with AQP-like water permeability and selectivity.Interestingly,the artificial channel coupled with cell protrusion formation by mediating water transmembrane transport,leading to cell shape change and migration acceleration.The artificial channel-facilitated cell migration showed application in enhancing in vivo healing of traumatic injury.

18例先天性内耳发育不良继发脑脊液耳漏诊疗总结（英文）

目的:介绍先天性内耳发育不良继发耳源性脑脊液渗漏的临床表现、诊断、手术方法及预后。创新点:总结了先天性内耳发育不良所致的脑脊液耳漏儿童与成人的畸形特点,为先天性内耳畸形导致的脑脊液耳漏提供诊疗参考。方法:回顾性分析2007～2017年我组18例内耳发育不良继发耳源性脑脊液渗漏患者,随访至少4个月,平均随访时间为3年。介绍所有患者的临床表现特点,包括自述症状、影像学表现、手术方法及修复方法、术中渗漏位置、术后病程、手术成功率等。结论:在先天性内耳发育不良所致的脑脊液耳漏中,儿童的内耳畸形情况较成人更为严重。最常见的症状是脑膜炎、听力障碍和脑脊液耳漏或鼻漏。高分辨率CT(HRCT)对本病具有较高的诊断准确率。最常见的瘘口位于椭圆窗周围,包括镫骨足板和环形韧带。

Mechanism of aseptic inflammation upon the inner ear injury

Many factors can cause inner ear injury,such as noise exposure,chemicals,viral infection,and radiation.The main pathological manifestations of inner ear injury are local hypoxia-ischemia,micro-trauma,and an increased level of reactive oxygen species and inflammatory mediators.The contribution of the inflammatory response to the mediation of cochlear and vestibular pathologies has received increasing attention in recent years.Aseptic inflammation can devastate audition and balance,which can lead to many typical clinical inner ear diseases.In this review,we will discuss the most pertinent and recent research on inflammatory mechanisms in inner ear injury.We will also discuss the pathophysiology of some common and significant ear diseases,such as sudden sensorineural hearing loss,age-related hearing loss,noise-induced hearing loss,and Meniere’s disease.