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1.
Proc Natl Acad Sci U S A ; 119(15): e2116973119, 2022 04 12.
Article in English | MEDLINE | ID: mdl-35380897

ABSTRACT

Sensory hair cells (HCs) in the utricle are mechanoreceptors required to detect linear acceleration. After damage, the mammalian utricle partially restores the HC population and organ function, although regenerated HCs are primarily type II and immature. Whether native, surviving HCs can repair and contribute to this recovery is unclear. Here, we generated the Pou4f3DTR/+; Atoh1CreERTM/+; Rosa26RtdTomato/+ mouse to fate map HCs prior to ablation. After HC ablation, vestibular evoked potentials were abolished in all animals, with ∼57% later recovering responses. Relative to nonrecovery mice, recovery animals harbored more Atoh1-tdTomato+ surviving HCs. In both groups, surviving HCs displayed markers of both type I and type II subtypes and afferent synapses, despite distorted lamination and morphology. Surviving type II HCs remained innervated in both groups, whereas surviving type I HCs first lacked and later regained calyces in the recovery, but not the nonrecovery, group. Finally, surviving HCs initially displayed immature and subsequently mature-appearing bundles in the recovery group. These results demonstrate that surviving HCs are capable of self-repair and may contribute to the recovery of vestibular function.


Subject(s)
Hair Cells, Vestibular , Regeneration , Saccule and Utricle , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Survival/genetics , Hair Cells, Vestibular/physiology , Homeodomain Proteins/genetics , Mice , Mice, Mutant Strains , RNA, Untranslated/genetics , Regeneration/genetics , Saccule and Utricle/cytology , Saccule and Utricle/injuries , Saccule and Utricle/physiology , Transcription Factor Brn-3C/genetics
2.
Audiol Neurootol ; 29(5): 357-366, 2024.
Article in English | MEDLINE | ID: mdl-38493767

ABSTRACT

INTRODUCTION: Spatial navigation, the ability to move through one's environment, is a complex skill utilized in everyday life. The effects of specific vestibular end-organ deficits and hearing impairments on spatial navigation have received little to no attention. We hypothesized that hearing impairment adversely affects spatial navigation and that bimodal impairments (vestibular and hearing) further impair navigation ability. METHODS: Data from 182 participants in the Baltimore Longitudinal Study of Aging who had interpretable results for the video head impulse test (vHIT), cervical vestibular evoked myogenic potentials (cVEMP) and ocular vestibular evoked myogenic potentials (oVEMP), audiometric testing, and the triangle completion test (TCT) were retrospectively analyzed. Multiple linear regression, controlling for age, sex, and cognition, was employed to identify predictors of TCT performance in terms of end-point error, angle deviation, and distance walked. RESULTS: oVEMP abnormalities were associated with larger end-point error (p = 0.008) and larger angle deviation (p = 0.002) but were not associated with distance walked (p = 0.392). Abnormalities on cVEMP testing and vHIT were not associated with distance walked (p = 0.835, p = 0.300), end-point error (p = 0.256, p = 0.808), or angle deviation (p = 0.192, p = 0.966). Compared with normal-hearing adults, hearing-impaired adults walked a shorter distance during the TCT (p = 0.049) but had a similar end-point error (p = 0.302) and angle deviation (p = 0.466). There was no interaction between vestibular and hearing function for predicting spatial navigation ability. CONCLUSION: In this cohort analysis, utricular dysfunction and hearing impairment were associated with poorer spatial navigation performance. We postulate that hearing impairment negatively affects one's ability to use real-time, intrinsic auditory cues and/or prior experience to guide navigation.


Subject(s)
Hearing Loss , Spatial Navigation , Vestibular Evoked Myogenic Potentials , Humans , Male , Female , Aged , Longitudinal Studies , Spatial Navigation/physiology , Middle Aged , Hearing Loss/physiopathology , Vestibular Evoked Myogenic Potentials/physiology , Saccule and Utricle/physiopathology , Baltimore , Aging/physiology , Retrospective Studies , Aged, 80 and over , Independent Living , Adult , Vestibular Function Tests
3.
Article in English | MEDLINE | ID: mdl-39103504

ABSTRACT

PURPOSE: While some OVEMP recordings are morphologically straightforward, some are poor in appearance, which can create a challenge, as they often require a "second look" by another experienced assessor. Even OVEMPs in normal subjects are sometimes poorly formed, but we wondered if the morphological assessment of the OVEMP response might provide some additional diagnostic information. METHODS: A single experienced assessor evaluated the OVEMP recordings of 60 patients referred sequentially to a tertiary care centre, and categorized them as "easy to assess" (i.e. obvious to a minimally trained assessor) or "difficult to assess", often requiring a second look by another experienced assessor. RESULTS: In 48 patients, the results were easy to assess (regardless of the actual clinical results) while 12 were classified as "difficult". This figure reflected the rate of morphologically poor responses we found in our population of normative data. CONCLUSION: Our clinical concern is that many centres have given up relying on OVEMP assessment because the morphology of the wave may be challenging to interpret. OVEMP assessment often calls for a "second look", requiring a collaboration between two experienced assessors. It seems that this feature may not be diagnostically useful and poor OVEMP morphology may present a challenge in interpretation, but this should not be used as a reason to defer OVEMP testing.

4.
J Neurophysiol ; 129(5): 1157-1176, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37018758

ABSTRACT

The otolith end organs inform the brain about gravitational and linear accelerations, driving the otolith-ocular reflex (OOR) to stabilize the eyes during translational motion (e.g., moving forward without rotating) and head tilt with respect to gravity. We previously characterized OOR responses of normal chinchillas to whole body tilt and translation and to prosthetic electrical stimulation targeting the utricle and saccule via electrodes implanted in otherwise normal ears. Here we extend that work to examine OOR responses to tilt and translation stimuli after unilateral intratympanic gentamicin injection and to natural/mechanical and prosthetic/electrical stimulation delivered separately or in combination to animals with bilateral vestibular hypofunction after right ear intratympanic gentamicin injection followed by surgical disruption of the left labyrinth at the time of electrode implantation. Unilateral intratympanic gentamicin injection decreased natural OOR response magnitude to about half of normal, without markedly changing OOR response direction or symmetry. Subsequent surgical disruption of the contralateral labyrinth at the time of electrode implantation surgery further decreased OOR magnitude during natural stimulation, consistent with bimodal-bilateral otolith end organ hypofunction (ototoxic on the right ear, surgical on the left ear). Delivery of pulse frequency- or pulse amplitude-modulated prosthetic/electrical stimulation targeting the left utricle and saccule in phase with whole body tilt and translation motion stimuli yielded responses closer to normal than the deficient OOR responses of those same animals in response to head tilt and translation alone.NEW & NOTEWORTHY Previous studies to expand the scope of prosthetic stimulation of the otolith end organs showed that selective stimulation of the utricle and saccule is possible. This article further defines those possibilities by characterizing a diseased animal model and subsequently studying its responses to electrical stimulation alone and in combination with mechanical motion. We show that we can partially restore responses to tilt and translation in animals with unilateral gentamicin ototoxic injury and contralateral surgical disruption.


Subject(s)
Ototoxicity , Vestibule, Labyrinth , Animals , Reflex, Vestibulo-Ocular/physiology , Otolithic Membrane/physiology , Chinchilla , Gentamicins
5.
Am J Physiol Regul Integr Comp Physiol ; 325(2): R181-R192, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37306398

ABSTRACT

Static high magnetic fields (MFs) interact with the vestibular system of humans and rodents. In rats and mice, exposure to MFs causes perturbations such as head movements, circular locomotion, suppressed rearing, nystagmus, and conditioned taste aversion acquisition. To test the role of otoconia, two mutant mouse models were examined, head-tilt Nox3het (het) and tilted Otop1 (tlt), with mutations, respectively, in Nox3, encoding the NADPH oxidase 3 enzyme, and Otop1, encoding the otopetrin 1 proton channel, which are normally expressed in the otolith organs, and are critical for otoconia formation. Consequently, both mutants show a near complete loss of otoconia in the utricle and saccule, and are nonresponsive to linear acceleration. Mice were exposed to a 14.1 Tesla MF for 30 min. After exposure, locomotor activity, conditioned taste aversion and c-Fos (in het) were assessed. Wild-type mice exposed to the MF showed suppressed rearing, increased latency to rear, locomotor circling, and c-Fos in brainstem nuclei related to vestibular processing (prepositus, spinal vestibular, and supragenual nuclei). Mutant het mice showed no response to the magnet and were similar to sham animals in all assays. Unlike het, tlt mutants exposed to the MF showed significant locomotor circling and suppressed rearing compared with sham controls, although they failed to acquire a taste aversion. The residual responsiveness of tlt versus het mice might reflect a greater semicircular deficit in het mice. These results demonstrate the necessity of the otoconia for the full effect of exposure to high MFs, but also suggest a semicircular contribution.


Subject(s)
Otolithic Membrane , Vestibule, Labyrinth , Humans , Mice , Rats , Animals , Otolithic Membrane/physiology , Vestibule, Labyrinth/physiology , Magnetic Fields , Brain Stem , Locomotion , Membrane Proteins
6.
World J Urol ; 41(2): 595-600, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36592176

ABSTRACT

PURPOSE: To determine the prevalence, radiological characteristics, and clinical symptomatology of enlarged prostatic utricles and vagina masculinus in boys with disorders of sex development. METHODS: Over 10 years (from February 2012 to March 2022), 102 boys with severe hypospadias underwent voiding cystourethrography. All patients presented with disorders of sex development and Y material in the karyotype (46,XY karyotype, 46,XY/45,X mosaic, etc.). The age of the patients at the first examination ranged from 4 days to 27 months (mean age 2.7 months). RESULTS: Voiding cystourethrography revealed the presence of a cyst posterior to the urethra in 66 patients (64.7% of cases). There were 15 cases of "vagina masculinus" and 51 of enlarged prostatic utricles. These dilations were classified according to the Ikoma classification and cyst size. In more than 2/3 of cases, the cysts were small (less than 20 mm), and in less than 8% of cases, these cysts were large. In addition, retrograde opacification revealed the presence of vesicoureteral reflux in 20% of boys with a male vagina. The most severe hypospadias with a scrotal or perineal meatus are most at risk of developing an enlarged prostatic utricle, and 80% of patients with Ikoma Grade III had a scrotal or perineal meatus. CONCLUSION: This study shows that the prevalence of enlarged prostatic utricles and vagina masculinus is high in patients with severe hypospadias. Therefore, their search should be systematic, and for clinical and therapeutic interest, the enlarged prostatic utricles should be classified according to cyst size.


Subject(s)
Cysts , Disorders of Sex Development , Hypospadias , Female , Humans , Male , Infant , Infant, Newborn , Urethra , Vagina , Saccule and Utricle
7.
J Clin Ultrasound ; 51(6): 1067-1069, 2023.
Article in English | MEDLINE | ID: mdl-37130036

ABSTRACT

The giant prostatic utricle cyst, located behindthe bladder with removable irregular mixed echo, communicating with the urethraat the level of the seminal colliculus, was diagnosed by ultrasound andverified by pathology and surgery.


Subject(s)
Cysts , Prostatic Diseases , Male , Humans , Prostatic Diseases/diagnostic imaging , Prostatic Diseases/pathology , Prostate/diagnostic imaging , Pelvis/pathology , Urinary Bladder , Cysts/diagnostic imaging , Cysts/surgery
8.
Prog Urol ; 33(13): 681-696, 2023 Nov.
Article in French | MEDLINE | ID: mdl-38012911

ABSTRACT

BACKGROUND: At a time when increasing attention is being paid to the limitations and risks of in vitro fertilisation techniques, surgeries to improve male fertility are attracting growing interest. METHODS: Systematic review based on a Pubmed search of surgeries to improve male fertility. RESULTS: Vasovasostomy (VV) gives patency rates of 70-97% and pregnancy rates of 30-76%. Vasoepididymostomy (VE) gives patency rates of 80-84%, with pregnancy rates of 40-44%. The duration of obstruction and the age of the partner are 2 predictive parameters for the occurrence of a natural pregnancy. In cases of obstructive azoospermia due to pelvic obstruction (prostatic cyst, obstruction of the ejaculatory ducts), several surgical procedures may be proposed. Transurethral resection of the ejaculatory ducts leads to an improvement in sperm parameters in 63-83% of patients, with spontaneous pregnancy occurring in 12-31% of cases. Microsurgical cure of varicocele by the subinguinal route is a benchmark technique with recurrence rates of less than 4%. It improves live birth and pregnancy rates, both naturally and by in vitro fertilization, as well as sperm count, motility and DNA fragmentation rates. CONCLUSION: Whenever possible, the urologist should present the surgical options for improving male fertility to the ART team and to the couple, discussing the benefit/risk balance of the operation as part of a personalized approach.


Subject(s)
Semen , Vasovasostomy , Pregnancy , Female , Humans , Male , Vasovasostomy/methods , Pregnancy Rate , Spermatozoa , Fertility
9.
J Neurosci ; 41(37): 7779-7796, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34301830

ABSTRACT

Aging, disease, and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ∼95% of vestibular hair cells in adult mice, ∼20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for the recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations, and many regenerated hair cells had some properties of immature hair cells, including small transduction currents, voltage-gated sodium currents, and small or absent HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Furthermore, although mouse vestibular epithelia normally have slightly more type I hair cells than type II hair cells, regenerated hair cells acquired neither the low-voltage-activated potassium channels nor the afferent synaptic calyces that distinguish mature type I hair cells from type II hair cells and confer distinctive physiology. Thus, natural regeneration of vestibular hair cells in adult mice is limited in total cell number, cell type diversity, and extent of cellular differentiation, suggesting that manipulations are needed to promote full regeneration with the potential for recovery of vestibular function.SIGNIFICANCE STATEMENT Death of inner ear hair cells in adult mammals causes permanent loss of hearing and balance. In adult mice, the sudden death of most vestibular hair cells stimulates the production of new hair cells but does not restore balance. We investigated whether the lack of systems-level function reflects functional deficiencies in the regenerated hair cells. The regenerated population acquired mechanosensitivity, voltage-gated channels, and afferent synapses, but did not reproduce the full range of hair cell types. Notably, no regenerated cells acquired the distinctive properties of type I hair cells, a major functional class in amniote vestibular organs. To recover vestibular system function in adults, we may need to solve how to regenerate the normal variety of mature hair cells.


Subject(s)
Cell Differentiation/physiology , Hair Cells, Auditory, Inner/physiology , Regeneration/physiology , Synapses/physiology , Animals , Mice , Mice, Knockout , Synaptic Transmission/physiology
10.
J Neurophysiol ; 128(2): 364-377, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35830608

ABSTRACT

The inner ear of teleost fishes is composed of three paired multimodal otolithic end organs (saccule, utricle, and lagena), which encode auditory and vestibular inputs via the deflection of hair cells contained within the sensory epithelia of each organ. However, it remains unclear how the multimodal otolithic end organs of the teleost inner ear simultaneously integrate vestibular and auditory inputs. Therefore, microwire electrodes were chronically implanted using a 3-D printed micromanipulator into the utricular nerve of oyster toadfish (Opsanus tau) to determine how utricular afferents respond to conspecific mate vocalizations termed boatwhistles (180 Hz fundamental frequency) during movement. Utricular afferents were recorded while fish were passively moved using a sled system along an underwater track at variable speeds (velocity: 4.0-12.5 cm/s; acceleration: 0.2-2.6 cm/s2) and while fish freely swam (velocity: 3.5-18.6 cm/s; acceleration: 0.8-29.8 cm/s2). Afferent fiber activities (spikes/s) increased in response to the onset of passive and active movements; however, afferent fibers differentially adapted to sustained movements. In addition, utricular afferent fibers remained sensitive to playbacks of conspecific male boatwhistle vocalizations during both passive and active movements. Here, we demonstrate in alert toadfish that utricular afferents exhibit enhanced activity levels (spikes/s) in response to behaviorally relevant acoustic stimuli during swimming.NEW & NOTEWORTHY The inner ear of teleost fishes is composed of three paired multimodal otolithic end organs, which are sensitive to vestibular and auditory inputs. Previous studies investigating inner ear functions have primarily focused on the effects of unimodal stimuli; therefore, it remains unclear how otolithic end organs simultaneously encode multiple stimuli. Here, we show that utricular afferents remain sensitive to behaviorally relevant acoustic stimuli during swimming.


Subject(s)
Batrachoidiformes , Vestibule, Labyrinth , Acoustic Stimulation , Animals , Batrachoidiformes/physiology , Hair Cells, Auditory , Male , Saccule and Utricle
11.
J Neurophysiol ; 128(5): 1344-1354, 2022 11 01.
Article in English | MEDLINE | ID: mdl-36286323

ABSTRACT

The plainfin midshipman, Porichthys notatus, is a seasonally breeding vocal fish that relies on acoustic communication to mediate nocturnal reproductive behaviors. Reproductive females use their auditory senses to detect and localize "singing" males that produce multiharmonic advertisement (mate) calls during the breeding season. Previous work showed that the midshipman saccule, which is considered the primary end organ used for hearing in midshipman and most other fishes, exhibits reproductive state and hormone-dependent changes that enhance saccular auditory sensitivity. In contrast, the utricle was previously posited to serve primarily a vestibular function, but recent evidence in midshipman and related toadfish suggests that it may also serve an auditory function and aid in the detection of behaviorally relevant acoustic stimuli. Here, we characterized the auditory-evoked potentials recorded from utricular hair cells in reproductive and nonreproductive female midshipman in response to underwater sound to test the hypothesis that variation in reproductive state affects utricular auditory sensitivity. We show that utricular hair cells in reproductive females exhibit up to a sixfold increase in the utricular potential magnitude and have thresholds based on measures of particle acceleration (re: 1 ms-2) that are 7-10 dB lower than nonreproductive females across a broad range of frequencies, which include the dominant harmonics of male advertisement calls. This enhanced auditory sensitivity of the utricle likely plays an essential role in facilitating midshipman social and reproductive acoustic communication.NEW & NOTEWORTHY In many animals, vocal-acoustic communication is fundamental for facilitating social behaviors. For the vocal plainfin midshipman fish, the detection and localization of social acoustic signals are critical to the species' reproductive success. Here, we show that the utricle, an inner ear end organ often thought to primarily serve a vestibular function, serves an auditory function that is seasonally plastic and modulated by the animal's reproductive state effectively enhancing auditory sensitivity to courting male advertisement calls.


Subject(s)
Batrachoidiformes , Animals , Female , Male , Batrachoidiformes/physiology , Saccule and Utricle , Acoustic Stimulation , Hearing/physiology , Evoked Potentials, Auditory/physiology , Vocalization, Animal/physiology
12.
Purinergic Signal ; 18(2): 165-176, 2022 06.
Article in English | MEDLINE | ID: mdl-35344126

ABSTRACT

The inner ear comprises the cochlea and vestibular system, which detect sound and acceleration stimulation, respectively. The function of the inner ear is regulated by ion transport activity among sensory epithelial cells, neuronal cells, non-sensory epithelial cells, and luminal fluid with a unique ionic composition of high [K+] and low [Na+], which enables normal hearing and balance maintenance. One of the important mechanisms regulating ion transport in the inner ear is purinergic signaling. Various purinergic receptors are distributed throughout inner ear epithelial cells and neuronal cells. To date, most studies have focused on the role of purinergic receptors in the cochlea, and few studies have examined these receptors in the vestibular system. As purinergic receptors play an important role in the cochlea, they would likely do the same in the vestibular system, which is fairly similar to the cochlea in cellular structure and function. Based on available studies performed to date, purinergic signaling is postulated to be involved in the regulation of ion homeostasis, protection of hair cells, otoconia formation, and regulation of electrical signaling from the sensory epithelium to vestibular neurons. In this review, the distribution and roles of purinergic receptors in the peripheral vestibular system are summarized and discussed.


Subject(s)
Ear, Inner , Vestibular System , Cochlea/physiology , Ear, Inner/physiology , Receptors, Purinergic , Signal Transduction
13.
Exp Cell Res ; 398(1): 112395, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33279477

ABSTRACT

Loss of hair cells from vestibular epithelium results in balance dysfunction. The current therapeutic regimen for vestibular diseases is limited. Upon injury or Atoh1 overexpression, hair cell replacement occurs rapidly in the mammalian utricle, suggesting a promising approach to induce vestibular hair cell regeneration. In this study, we applied simultaneous gentamicin-mediated hair cell ablation and Atoh1 overexpression to induce neonatal utricular hair cell formation in vitro. We confirmed that type I hair cells were the primary targets of gentamicin. Furthermore, injury and Atoh1 overexpression promoted hair cell regeneration in a timely and efficient manner through robust viral transfection. Hair cells regenerated with type II characteristics in the striola and type I/II characteristics in non-sensory regions. Rare EdU+/myosin7a+ cells in sensory regions and robust EdU+/myosin7a+ signals in ectopic regions indicate that transdifferentiation of supporting cells in situ, and mitosis and differentiation of non-sensory epithelial cells in ectopic regions, are sources of regenerative hair cells. Distinct regeneration patterns in in situ and ectopic regions suggested robust plasticity of vestibular non-sensory epithelium, generating more developed hair cell subtypes and thus providing a promising stem cell-like source of hair cells. These findings suggest that simultaneously causing injury and overexpressing Atoh1 promotes hair cell regeneration efficacy and maturity, thus expanding the understanding of ectopic plasticity in neonatal vestibular organs.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Gentamicins/pharmacology , Hair Cells, Vestibular/drug effects , Saccule and Utricle/drug effects , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Hair Cells, Vestibular/metabolism , Hair Cells, Vestibular/pathology , Mice , Mice, Inbred C57BL , Saccule and Utricle/metabolism , Saccule and Utricle/pathology
14.
J Indian Assoc Pediatr Surg ; 27(4): 387-390, 2022.
Article in English | MEDLINE | ID: mdl-36238343

ABSTRACT

Introduction: Prostatic utricles (PUs) are the remnants of Mullerian ducts found in the male posterior urethra. Enlarged symptomatic utricles are known to be associated with hypospadias. There is a dearth of literature defining an enlarged utricle and also its clinical significance. Aims: The aim of this study was to describe anatomical difference of PUs of cases with severe hypospadias and also to find their clinical significance if any. Materials and Methods: A prospective study was carried out, and all patients with proximal hypospadias were enrolled. Cystoscopy was performed in all cases. Symptomatology, size, and location of PU were recorded. PU of >0.5 cm was considered enlarged. Results: In the present series, a total of 70 cases were included over a period of 2 years. Enlarged utricle was found in 47/70 (67.14%) on cystoscopy. They were wide-mouthed and negotiated 9 Fr/11 Fr cystoscope with ease. Recurrent epididymo-orchitis, recurrent urinary tract infection, and obstructive features were the most common complications requiring intervention. Conclusions: PUs in boys with hypospadias are enlarged as well as wide-mouthed. Most of these remain asymptomatic, but few of them carry the potential of complications. Cystoscopy helps in direct visualization of utricular anatomy, so it should be a preferred investigating modality for investigating a PU.

15.
J Neurosci ; 40(20): 3915-3932, 2020 05 13.
Article in English | MEDLINE | ID: mdl-32341094

ABSTRACT

Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed that in vivo expression of the YAP-S127A variant caused robust proliferation of neonatal mouse supporting cells, which produced progeny that expressed hair cell markers, but proliferative responses declined postnatally. Expression of YAP-5SA, which more effectively evades inhibitory phosphorylation, resulted in TEAD-dependent proliferation of striolar supporting cells, even in adult utricles. Conditional deletion of LATS1/2 kinases abolished the inhibitory phosphorylation of endogenous YAP and led to striolar proliferation in adult mouse utricles. The findings suggest that damage overcomes inhibitory Hippo signaling and facilitates regenerative proliferation in nonmammalian utricles, whereas constitutive LATS1/2 kinase activity suppresses YAP-TEAD signaling in mammalian utricles and contributes to maintaining the proliferative quiescence that appears to underlie the permanence of sensory deficits.SIGNIFICANCE STATEMENT Loud sounds, ototoxic drugs, infections, and aging kill sensory hair cells in the ear, causing irreversible hearing loss and balance deficits for millions. In nonmammals, damage evokes shape changes in supporting cells, which can divide and regenerate hair cells. Such shape changes are limited in mammalian ears, where supporting cells develop E-cadherin-rich apical junctions reinforced by robust F-actin bands, and the cells fail to divide. Here, we find that damage readily activates YAP in supporting cells within balance epithelia of chickens, but not mice. Deleting LATS kinases or expressing YAP variants that evade LATS-mediated inhibitory phosphorylation induces proliferation in supporting cells of adult mice. YAP signaling eventually may be harnessed to overcome proliferative quiescence that limits regeneration in mammalian ears.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Cell Cycle Proteins/physiology , Hair Cells, Auditory/physiology , Nerve Regeneration/genetics , Nerve Regeneration/physiology , Protein Serine-Threonine Kinases/physiology , Adaptor Proteins, Signal Transducing/genetics , Animals , Animals, Newborn , Cell Cycle Proteins/genetics , Cell Proliferation , Chick Embryo , Chickens , Gene Deletion , Genetic Variation , Hearing Loss/genetics , Hepatocyte Growth Factor/antagonists & inhibitors , Long-Acting Thyroid Stimulator , Mice , Mice, Knockout , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Saccule and Utricle/drug effects , Serine-Threonine Kinase 3 , Species Specificity , Tumor Suppressor Proteins/genetics , YAP-Signaling Proteins
16.
J Cell Physiol ; 236(7): 5235-5252, 2021 07.
Article in English | MEDLINE | ID: mdl-33368220

ABSTRACT

Intratympanic injection of gentamicin has proven to be an effective therapy for intractable vestibular dysfunction. However, most studies to date have focused on the cochlea, so little is known about the distribution and uptake of gentamicin by the counterpart of the auditory system, specifically vestibular hair cells (HCs). Here, with a combination of in vivo and in vitro approaches, we used a gentamicin-Texas Red (GTTR) conjugate to investigate the mechanisms of gentamicin vestibulotoxicity in the developing mammalian utricular HCs. In vivo, GTTR fluorescence was concentrated in the apical cytoplasm and the cellular membrane of neonatal utricular HCs, but scarce in the nucleus of HCs and supporting cells. Quantitative analysis showed the GTTR uptake by striolar HCs was significantly higher than that in the extrastriola. In addition, the GTTR fluorescence intensity in the striola was increased gradually from 1 to 8 days, peaking at 8-9 days postnatally. In vitro, utricle explants were incubated with GTTR and candidate uptake conduits, including mechanotransduction (MET) channels and endocytosis in the HC, were inhibited separately. GTTR uptake by HCs could be inhibited by quinine, a blocker of MET channels, under both normal and stressed conditions. Meanwhile, endocytic inhibition only reduced GTTR uptake in the CoCl2 hypoxia model. In sum, the maturation of MET channels mediated uptake of GTTR into vestibular HCs. Under stressed conditions, MET channels play a pronounced role, manifested by channel-dependent stress enhanced GTTR permeation, while endocytosis participates in GTTR entry in a more selective manner.


Subject(s)
Biological Transport/physiology , Gentamicins/pharmacology , Gentamicins/pharmacokinetics , Hair Cells, Auditory/metabolism , Saccule and Utricle/embryology , Animals , Endocytosis/drug effects , Female , Gentamicins/chemistry , Male , Membrane Transport Modulators/pharmacology , Mice , Mice, Inbred C57BL , Organ Culture Techniques , Quinine/pharmacology , Reactive Oxygen Species/metabolism , Saccule and Utricle/metabolism , Staining and Labeling , Vestibular Diseases/drug therapy , Vestibular Diseases/pathology , Xanthenes/chemistry
17.
J Anat ; 239(4): 801-828, 2021 10.
Article in English | MEDLINE | ID: mdl-34047378

ABSTRACT

The vertebrate inner ear is a labyrinthine sensory organ responsible for perceiving sound and body motion. While a great deal of research has been invested in understanding the auditory system, a growing body of work has begun to delineate the complex developmental program behind the apparatuses of the inner ear involved with vestibular function. These animal studies have helped identify genes involved in inner ear development and model syndromes known to include vestibular dysfunction, paving the way for generating treatments for people suffering from these disorders. This review will provide an overview of known inner ear anatomy and function and summarize the exciting discoveries behind inner ear development and the evolution of its vestibular apparatuses.


Subject(s)
Vestibule, Labyrinth , Animals , Humans , Vertebrates
18.
BMC Urol ; 21(1): 149, 2021 Nov 05.
Article in English | MEDLINE | ID: mdl-34736451

ABSTRACT

BACKGROUND: To explore whether opening the external urethral orifice in the coronal sulcus can reduce the incidence of epididymitis after operating on hypospadias with prostatic utricle cyst (PUC) connecting to the vas deferens. Group A consisted of 3 patients with severe hypospadias and PUC undergoing cystostomy, hypospadias correction and urethroplasty, along with the relocation of the external orifice of the urethra to the coronal sulcus. Group B consisted of 4 patients having initial hypospadias repaired with meatus in the orthotopic position in the glans, presenting with multiple epididymitis after hypospadias surgery and unsuccessful conservative treatment. MR confirmed that all the Group B patients had PUC connecting to the vas deferens. Group B patients underwent urethral dilatation along with urethral catheterization, cutting of the original corpus cavernosum that encapsulated the urethra, and extension of the position of the external urethral orifice to the coronal sulcus. RESULTS: In group A, 3 children underwent bladder fistula removal 2 weeks after the operation. The penis developed normally without any complications. Four children in group B underwent stent removal 12 weeks after operation, and one patient was still stenosed and dilated again. All patients in group B were followed without epididymitis recurrence. CONCLUSIONS: For patients with hypospadias complicating with a PUC, connecting to one side of the vas deferens, the positioning of the external urethral orifice in the coronary sulcus would be helpful to reduce the occurrence of epididymitis.


Subject(s)
Cysts/surgery , Hypospadias/surgery , Plastic Surgery Procedures/methods , Prostatic Diseases/surgery , Urologic Surgical Procedures, Male/methods , Catheterization , Child, Preschool , Cystostomy , Cysts/complications , Cysts/diagnostic imaging , Dilatation , Epididymitis/etiology , Epididymitis/prevention & control , Humans , Hypospadias/complications , Hypospadias/diagnostic imaging , Male , Postoperative Complications , Prostatic Diseases/complications , Prostatic Diseases/diagnostic imaging , Plastic Surgery Procedures/adverse effects , Stents , Urologic Surgical Procedures, Male/adverse effects
19.
Int J Urol ; 28(6): 689-694, 2021 06.
Article in English | MEDLINE | ID: mdl-33783036

ABSTRACT

OBJECTIVES: To report our single-center experience of the management of children with prostatic utricle cysts. METHODS: We retrospectively analyzed 15 children who were incidentally found to have a prostatic utricle cyst and were admitted to our department between October 2013 and August 2020. Clinical characteristics and management were collected and catalogued. RESULTS: Recurrent genitourinary tract infections were the most frequent complaint, and two-thirds of patients also had hypospadias. A connection between the posterior urethra and the prostatic utricle cyst was found in all cases. Two patients directly had their progressively enlarging prostatic utricle cyst resected laparoscopically. Endoscopic techniques were used in 13 patients, two of whom underwent laparoscopic excision for repeated symptoms. The mean (range) follow-up period was 34.9 (2-82) months. No recurrences were observed in four patients who underwent prostatic utricle cyst excision and eight patients who received endoscopic treatment. Three patients had recurrent symptoms after endoscopic treatment and were managed by nonsurgical treatment. CONCLUSIONS: Prostatic utricle cyst is a rare disease which can cause recurrent genitourinary tract infections. Extra attention should be paid to evaluation for prostatic utricle cyst in children with external genital anomalies. Retrograde urethrogram and magnetic resonance imaging are useful tools with which to distinguish prostatic utricle cyst from other cystic lesions that are located in the midline pelvis in male patients. Individualized treatment is appropriate when considering fertility preservation, recurrences and malignancy. Laparoscopic excision is feasible for symptomatic and large prostatic utricle cyst. Regular long-term monitoring is recommended for all patients with prostatic utricle cyst.


Subject(s)
Cysts , Prostatic Diseases , Child , Cysts/diagnostic imaging , Cysts/surgery , Humans , Male , Neoplasm Recurrence, Local , Prostatic Diseases/surgery , Retrospective Studies , Saccule and Utricle , Urethra
20.
Eur Arch Otorhinolaryngol ; 278(11): 4259-4268, 2021 Nov.
Article in English | MEDLINE | ID: mdl-33454811

ABSTRACT

PURPOSE: Ageing is process that brings about steady decline in most of the systems, and vestibular system is no different. Although the effects of advancing age on the functioning of the semicircular canals and saccule has been well explored, its impact on the utricle remains the least studied component. While some researchers have investigated the effect of advancing age on the utricular functioning by virtue of studying ocular-vestibular evoked myogenic potentials (oVEMP), the use of smaller sample sizes would hamper the generalization of their results. Therefore, the present study aimed at investigating the effect of advancing age on oVEMP using a substantially larger sample size than the predecessors. METHODS: A total of 480 individuals in the age range of 10-70 years were used as participants and were divided into six age groups, each one defined as a decade. Contralateral oVEMPs were elicited by 500-Hz tone-bursts and averaged over 200 sweeps to obtain the final waveform. RESULTS: There was a significant decline in the response rates, prolongation of latencies and reduction of peak-to-peak amplitude of oVEMP with increasing age after 50 years (p < 0.05). However, there was no significant difference among the age groups until 50 years of age on any of these parameters (p > 0.05). Further, there was no significant change in inter-aural amplitude difference ratio with increasing age (p > 0.05). CONCLUSION: The results of the study confirm significant impact of the ageing process on oVEMP after the age of 50 years and, therefore, age appropriate norms should be considered when using oVEMP for investigating utricular functioning in an individual, especially after the age of 50 years.


Subject(s)
Vestibular Evoked Myogenic Potentials , Adolescent , Adult , Aged , Aging , Child , Humans , Middle Aged , Saccule and Utricle , Semicircular Canals , Young Adult
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