Inactivation of NADPH oxidase organizer 1 results in severe imbalance.
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Otoconia are biominerals of the vestibular system that are indispensable for the perception of gravity. Despite their importance, the process of otoconia genesis is largely unknown. Reactive oxygen species (ROS) have been recognized for their toxic effects in antimicrobial host defense as well as in aging and carcinogenesis. Enzymes evolved for ROS production belong to the recently discovered NADPH oxidase (Nox) enzyme family . Here we show that the inactivation of a regulatory subunit, NADPH oxidase organizer 1 (Noxo1), resulted in the severe balance deficit seen in the spontaneous mutant "head slant" (hslt) mice whose phenotype was rescued by Noxo1 transgenes. Wild-type Noxo1 was expressed in the vestibular and cochlear epithelia and was required for ROS production by an oxidase complex. In contrast, the hslt mutation of Noxo1 was biochemically inactive and led to an arrest of otoconia genesis, characterized by a complete lack of calcium carbonate mineralization and an accumulation of otoconial protein, otoconin-90/95 (OC-90/95). These results suggest that ROS generated by a Noxo1-dependent vestibular oxidase are critical for otoconia formation and may be required for interactions among otoconial components. Noxo1 mutants implicate a constructive developmental role for ROS, in contrast to their previously described toxic effects. (+info)
Mixing model systems: using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development.
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Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies. (+info)
Regeneration of vestibular otolith afferents after ototoxic damage.
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Regeneration of receptor cells and subsequent functional recovery after damage in the auditory and vestibular systems of many vertebrates is well known. Spontaneous regeneration of mammalian hair cells does not occur. However, recent approaches provide hope for similar restoration of hearing and balance in humans after loss. Newly regenerated hair cells receive afferent terminal contacts, yet nothing is known about how reinnervation progresses or whether regenerated afferents finally develop normal termination fields. We hypothesized that neural regeneration in the vestibular otolith system would recapitulate the topographic phenotype of afferent innervation so characteristic of normal development. We used an ototoxic agent to produce complete vestibular receptor cell loss and epithelial denervation, and then quantitatively examined afferent regeneration at discrete periods up to 1 year in otolith maculas. Here, we report that bouton, dimorph, and calyx afferents all regenerate slowly at different time epochs, through a progressive temporal sequence. Furthermore, our data suggest that both the hair cells and their innervating afferents transdifferentiate from an early form into more advanced forms during regeneration. Finally, we show that regeneration remarkably recapitulates the topographic organization of afferent macular innervation, comparable with that developed through normative morphogenesis. However, we also show that regenerated terminal morphologies were significantly less complex than normal fibers. Whether these structural fiber changes lead to alterations in afferent responsiveness is unknown. If true, adaptive plasticity in the central neural processing of motion information would be necessitated, because it is known that many vestibular-related behaviors fully recover during regeneration. (+info)
Short-term efficacy of Epley's manoeuvre: a double-blind randomised trial.
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BACKGROUND: Benign paroxysmal positional vertigo of the posterior canal (PC-BPPV) is a common vestibular disorder and can be easily treated with Epley's manoeuvre. Thus far, the short-term efficacy of Epley's manoeuvre for treatment of PC-BPPV is unknown. OBJECTIVES: To evaluate the efficacy of Epley's manoeuvre for treatment of PC-BPPV 24 h after applying the manoeuvre. METHODS: The short-term efficacy of Epley's manoeuvre was compared with a sham procedure in 66 patients with PC-BPPV by using a double-blind randomised study design. RESULTS: 24 h after treatment, 28 of 35 (80%) patients in the Epley's manoeuvre group had neither vertigo nor nystagmus on positional testing compared with 3 of 31 (10%) patients in the sham group (p<0.001). CONCLUSION: Epley's manoeuvre is shown to resolve PC-BPPV both effectively and rapidly. (+info)
Vestibulo-ocular reflex to transient surge translation: complex geometric response ablated by normal aging.
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The linear vestibulo-ocular reflex (LVOR) to surge (fore-aft) translation has complex kinematics varying with target eccentricity and distance. To determine normal responses and aging changes, 9 younger [age, 28 +/- 2 (SE) yr] and 11 older subjects (age, 69 +/- 2 yr) underwent 0.5 g whole body surge transients while wearing binocular scleral search coils. Linear chair position and head acceleration were measured with a potentiometer and accelerometer. Subjects viewed centered and 10 degrees horizontally and vertically eccentric targets 50, 25, or 15 cm distant before unpredictable onset of randomly directed surge in darkness (LVOR) and light (V-LVOR). Response directions were kinematically appropriate to eccentricity in all subjects, but there were significantly more measurable LVOR and V-LVOR responses (63-79%) in younger than older subjects (38-44%, P < 0.01). Minimal LVOR latency averaged 48 +/- 4 ms for younger and significantly longer at 70 +/- 6 ms for older subjects. In the interval 200-300 ms after surge onset, horizontal LVOR gain (relative to ideal velocity) of younger subjects averaged over all target distances was 0.55 +/- 0.04 and was significantly reduced in older subjects to 0.33 +/- 0.04. Horizontal V-LVOR gain was 0.58 +/- 0.04 in younger and significantly lower at 0.35 +/- 0.06 in older subjects. Vertical gains did not differ significantly between groups. Target visibility had no effect in either group during the initial 200 ms. The LVOR and V-LVOR were augmented by saccades in younger more than older subjects. Aging thus decreases LVOR velocity gain, response rate, and saccade augmentation, but prolongs latency. (+info)
Separate Na,K-ATPase genes are required for otolith formation and semicircular canal development in zebrafish.
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We have investigated the role of Na,K-ATPase genes in zebrafish ear development. Six Na,K-ATPase genes are differentially expressed in the developing zebrafish inner ear. Antisense morpholino knockdown of Na,K-ATPase alpha1a.1 expression blocked formation of otoliths. This effect was phenocopied by treatment of embryos with ouabain, an inhibitor of Na,K-ATPase activity. The otolith defect produced by morpholinos was rescued by microinjection of zebrafish alpha1a.1 or rat alpha1 mRNA, while the ouabain-induced defect was rescued by expression of ouabain-resistant zebrafish alpha1a.1 or rat alpha1 mRNA. Knockdown of a second zebrafish alpha subunit, alpha1a.2, disrupted development of the semicircular canals. Knockdown of Na,K-ATPase beta2b expression also caused an otolith defect, suggesting that the beta2b subunit partners with the alpha1a.1 subunit to form a Na,K-ATPase required for otolith formation. These results reveal novel roles for Na,K-ATPase genes in vestibular system development and indicate that different isoforms play distinct functional roles in formation of inner ear structures. Our results highlight zebrafish gene knockdown-mRNA rescue as an approach that can be used to dissect the functional properties of zebrafish and mammalian Na,K-ATPase genes. (+info)
Roll rotation cues influence roll tilt perception assayed using a somatosensory technique.
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We investigated how the nervous system processes ambiguous cues from the otolith organs by measuring roll tilt perception elicited by two motion paradigms. In one paradigm (tilt), eight subjects were sinusoidally tilted in roll with the axis of rotation near ear level. Stimulus frequencies ranged from 0.005 to 0.7 Hz, and the peak amplitude of tilt was 20 degrees . During this paradigm, subjects experienced a sinusoidal variation of interaural gravitational force with a peak of 0.34 g. The second motion paradigm (translation) was designed to yield the same sinusoidal variation in interaural force but did not include a roll canal cue. This was achieved by sinusoidally translating the subjects along their interaural axis. For the 0.7-Hz translation trial, the subjects were simply translated from side to side. A centrifuge was used for the 0.005- to 0.5-Hz translation trials; the subjects were rotated in yaw at 250 degrees /s for 5 min before initiating sinusoidal translations yielding an interaural otolith stimulus composed of both centrifugal and radial acceleration. Using a somatosensory task to measure roll tilt perception, we found substantial differences in tilt perception during the two motion paradigms. Because the primary difference between the two motion paradigms was the presence of roll canal cues during roll tilt trials, these perceptual differences suggest that canal cues influence tilt perception. Specifically, rotational cues provided by the semicircular canals help the CNS resolve ambiguous otolith cues during head tilt, yielding more accurate tilt perception. (+info)
Diagnostic and treatment strategy of lateral semicircular canal canalolithiasis.
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A new strategy for the diagnosis and treatment both of geotropic and apogeotropic Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo is proposed. To this end, a new strategy of approach to Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo is described in order to rapidly highlight both the side and the affected canal. Thus, in the first treatment session, using the so-called "strategy of the minimum stimulus", a large percentage of cases are successfully treated, with the lowest number of vertigos for the patient. Following a review of the literature, 269 case studies, personally observed over a 4-year period, are described. The diagnostic strategy is performed by a single manoeuvre to determine whether the posterior semicircular canal or the lateral canal is affected. In the latter case, it is possible to highlight the affected sides both of the geotropic and apogeotropic forms. The therapeutic strategy comprises several liberatory manoeuvres, barbecue rotation techniques (Vannucchi-Asprella, Lempert), and Gufoni manoeuvre by continuously monitoring the ampullofugal movement of the otoliths. Almost 98% of cases are successfully treated at the first treatment diagnostic-therapeutic session. This approach to Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo allows a two-fold goal to be achieved, i.e., to effect both diagnosis and treatment at the first examination. Furthermore, thanks to the philosophy of the approach to Benign Paroxysmal Positional Vertigo, called the "Strategy of the minimum stimulus", patient compliance is very good since a very small number of vertigos are produced, and few neuro-vegetative disorders. (+info)