Methodological Quality of Systematic Reviews and Meta-analyses Published in High-Impact Otolaryngology Journals.

OBJECTIVE: To assess the methodological quality of intervention-focused systematic reviews (SRs) and meta-analyses (MAs) published in high-impact otolaryngology journals. DATA SOURCES: Ovid Medline, Embase, and Cochrane Library. REVIEW METHODS: A comprehensive search was performed for SR and MA citations from 2012 to 2017 in the 10 highest impact factor otolaryngology journals. Abstracts were screened to identify published manuscripts in which the authors indicated clearly that they were performing an SR or MA. Applying a modified typology of reviews, 4 reviewers characterized the review type as SR, MA, or another review type. A simplified version of the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews 2) tool was used to assess the reporting and methodological quality of the SRs and MAs that were focused on interventions. RESULTS: Search and abstract screening generated 499 manuscripts that identified themselves as performing an SR or MA. A substantial number (85/499, 17%) were review types other than SRs or MAs, including 34 (7%) that were literature reviews. In total, 236 SRs and MAs focused on interventions. Over 50% of these SRs and MAs had weaknesses in at least 3 of the 16 items in the AMSTAR 2, and over 40% had weaknesses in at least 2 of the 7 critical domains. Ninety-nine percent of SRs and MAs provided critically low confidence in the results of the reviews. CONCLUSION: Intervention-focused SRs and MAs published in high-impact otolaryngology journals have important methodological limitations that diminish confidence in the results of these reviews.

GluA2-Containing AMPA Receptors Distinguish Ribbon-Associated from Ribbonless Afferent Contacts on Rat Cochlear Hair Cells.

Mechanosensory hair cells release glutamate at ribbon synapses to excite postsynaptic afferent neurons, via AMPA-type ionotropic glutamate receptors (AMPARs). However, type II afferent neurons contacting outer hair cells in the mammalian cochlea were thought to differ in this respect, failing to show GluA immunolabeling and with many "ribbonless" afferent contacts. Here it is shown that antibodies to the AMPAR subunit GluA2 labeled afferent contacts below inner and outer hair cells in the rat cochlea, and that synaptic currents in type II afferents had AMPAR-specific pharmacology. Only half the postsynaptic densities of type II afferents that labeled for PSD-95, Shank, or Homer were associated with GluA2 immunopuncta or presynaptic ribbons, the "empty slots" corresponding to ribbonless contacts described previously. These results extend the universality of AMPAergic transmission by hair cells, and support the existence of silent afferent contacts.

Cochlear implants: clinical and societal outcomes.

Over the past 30 years, hearing care clinicians have increasingly relied on cochlear implants to restore auditory sensitivity in selected patients with advanced sensorineural hearing loss. This article examines the impact of intervention with cochlear implantation in children and adults. The authors report a range of clinic-based results and patient-based outcomes reflected in the reported literature on cochlear implants. The authors describe the basic assessment of the physiologic response to auditory nerve stimulation; measures of receptive and productive benefit; and surveys of life effects as reflected measures of quality of life, educational attainment, and economic impact.

Cochlear coiling pattern and orientation differences in cochlear implant candidates.

BACKGROUND: Detailed studies of cochlear morphology can guide our approach to cochleostomy and electrode insertion to optimize neuronal and hair cell preservation and ultimate electrode location. METHODS: Normal developed cochleae from 124 cochlear implant candidates were studied. We performed morphometric analysis of the right cochleae in all subjects based on computed tomographic data. The length and width of the cochlear base, the angle between the first and second turn of the cochlea, and the cochlear orientation within the cranial base were measured and compared across age groups. In cochlear implant candidates with underdeveloped cochleae (n = 7), we performed similar measurements and assessed the modiolar inlet area on 3D volume rendered images. RESULTS: The birth to 1 year and 1- to 2-year age groups showed insignificant differences in the lengths and widths of the cochlear base, although variability was considerable, and a significantly wider angle (from the midsagittal line) than that of the older age groupings (p < 0.05). For underdeveloped cochleae, the length and width of the cochlear base were significantly smaller and angled between the first and second turn differed from the normal developed group. The modiolar inlet also was significantly smaller in the underdeveloped cochleae compared with normal cochleae. CONCLUSION: We observed that perspective 3D-volume rendering of the cochlea enables the determination of key features of cochlear morphology and orientation that may escape detection with routine computed tomographic scanning. Infants and young toddler candidates demonstrate greater variability in the dimensions of the cochlear base and in the orientation of the cochlea within the cranium. As evolving surgical techniques and device design enhance the ability of the surgeon to avoid cochlear damage and optimize electrode location, refined morphometric information may assist the surgeon in tailoring strategies of scala tympani implantation.

[Ultra-structural study of the lateral portion of the auditory sensorial organ using a decalcification-free method]. / Estudio ultraestructural de la porción lateral del órgano sensorial auditivo mediante un método sin descalcificación.

OBJECTIVE: To explain the development of a new personal technique to study the spiral ligament and stria vascularis in Guinea pig cochleae by obtaining sample tissue without decalcification and to assess its validity for electron microscopy analysis. MATERIAL AND METHOD: Samples were taken from five female Guinea pigs weighing 200-250 g and were fixed in glutaraldehyde and paraformaldehyde for analysis of the spiral ligament and stria vascularis ultrastructure by transmission electron microscopy. RESULTS: All of the ultrastructure components in the spiral ligament and stria vascularis could be examined without the need for decalcification. CONCLUSIONS: Our method to obtain and analyze samples of cochlea side wall is valid, easy and faster.

Estudio ultraestructural de la porción lateral del órgano sensorial auditivo mediante un método sin descalcificación / Ultra-structural study of the lateral portion of the auditory sensorial organ using a decalcification-free method

Objetivo: Explicar el desarrollo de una técnica personal de estudio de la estría vascular y ligamento espiral de la cóclea en cobaya mediante la obtención de la muestra sin necesidad de descalcificación y valorar su validez para su análisis con microscopio electrónico. Material y método: Se obtuvieron muestras de 5 hembras de cobaya de 200-250 g que se fijaron con glutaraldehído y paraformaldehído, y se analizó la ultra estructura del ligamento espiral y la estría vascular obtenidos mediante microscopio electrónico de transmisión. Resultados: Se pudo observar todos los componentes ultraestructurales del ligamento espiral y la estría vascular sin necesidad de descalcificar. Conclusiones: Nuestro método de obtención de las muestras es una forma válida, sencilla y más rápida que otros métodos para la obtención y el estudio de la porción lateral de la cóclea (AU)

Objective: To explain the development of a new personal technique to study the spiral ligament and stria vascularis in Guinea pig cochleae by obtaining sample tissue without decalcification and to assess its validity for electron microscopy analysis. Material and method: Samples were taken from five female Guinea pigs weighing 200-250 g and were fixed in glutaraldehyde and paraformaldehyde for analysis of the spiral ligament and stria vascularis ultra structure by transmission electron microscopy. Results: All of the ultra structure components in the spiral ligament and stria vascularis could be examined without the need for decalcification. Conclusions: Our method to obtain and analyze samples of cochlea side wall is valid, easy and faster (AU)

Differentiation of inner ear stem cells to functional sensory neurons.

Inner ear stem cells can be isolated by neurosphere formation from the vestibular organs and the cochlea. The cells are pluripotent, with the potential to become hair cells and neurons, the cochlear cell types whose loss causes deafness. Here we describe the control of cell fate decisions that determine the phenotype adopted by these progenitors, and we determine whether differentiation to sensory neurons is preferred over other types of neurons. Differentiation of progenitor cells recapitulated developmental pathways of embryonic sensory neurons. Based on marker expression, retinoic acid increased the yield of neurons and the percentage of sensory neurons obtained and caused a sharp increase in Pax2, a key transcription factor of cranial placodes. Markers of embryonic auditory and other sensory neurons, GATA3, Brn3a, and islet1, could be detected after 3 days of differentiation of the cells, and markers of the sensory phenotype, peripherin, calretinin, TrkC, and TrkB were expressed after 10 days. The differentiated cells had tetrodotoxin-sensitive sodium currents and fired action potentials, and recordings revealed functional AMPA type-glutamate receptors, further indicating that these cells had developed neuronal features. Neurons differentiated from these stem cells grew processes to hair cells in vitro. Development of functional activity in cells with the markers of sensory neurons suggested that the inner ear stem cells might have the capacity to replace cells lost due to neural degeneration.

Stem cells for the replacement of inner ear neurons and hair cells.

Stem cells in the nervous system have some capacity to restore damaged tissue. Proliferation of stem cells endows them with self-renewal ability and accounts for in vitro formation of neurospheres, clonally derived colonies of floating cells. However, damage to the nervous system is not readily repaired, suggesting that the stem cells do not provide an easily recruited source of cells for regeneration. The vestibular and auditory organs, despite their limited ability to replace damaged cells, appear to contain cells with stem cell properties. These inner ear stem cells, identified by neurosphere formation and by their expression of markers of inner ear progenitors, can differentiate to hair cells and neurons. Differentiated cells obtained from inner ear stem cells expressed sensory neuron markers and, after co-culture with the organ of Corti, grew processes that extended to hair cells. The neurons expressed synaptic vesicle markers at points of contact with hair cells. Exogenous stem cells have also been used for hair cell and neuron replacement. Embryonic stem cells are one potential source of both hair cells and sensory neurons. Neural progenitors made from embryonic stem cells, transplanted into the inner ear of gerbils that had been de-afferented by treatment with a toxin, differentiated into cells that expressed neuronal markers and grew processes both peripherally into the organ of Corti and centrally. The regrowth of these neurons suggests that it may be possible to replace auditory neurons that have degenerated with neurons that restore auditory function by regenerating connections to hair cells.

The potential role of endogenous stem cells in regeneration of the inner ear.

Stem cells in various mammalian organs retain the capacity to renew themselves and may be able to restore damaged tissue. Their existence has been proven by genetic tracer studies that demonstrate their differentiation into multiple tissue types and by their ability to self-renew through proliferation. Stem cells from the adult nervous system proliferate to form clonal floating colonies called spheres in vitro, and recent studies have demonstrated sphere formation by cells in the cochlea in addition to the vestibular system and the auditory ganglia, indicating that these tissues contain cells with stem cell properties. The presence of stem cells in the inner ear raises the hope of regeneration of mammalian inner ear cells but is difficult to correlate with the lack of spontaneous regeneration seen in the inner ear after tissue damage. Loss of stem cells postnatally in the cochlea may correlate with the loss of regenerative capacity and may limit our ability to stimulate regeneration. Retention of sphere forming ability in adult vestibular tissues suggests that the limited capacity for repair may be attributed to the continued presence of progenitor cells. Future strategies for regeneration must consider the distribution of endogenous stem cells in the inner ear and whether the tissue retains cells with the capacity for regeneration.

Differential distribution of stem cells in the auditory and vestibular organs of the inner ear.

The adult mammalian cochlea lacks regenerative capacity, which is the main reason for the permanence of hearing loss. Vestibular organs, in contrast, replace a small number of lost hair cells. The reason for this difference is unknown. In this work we show isolation of sphere-forming stem cells from the early postnatal organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise to cells that express multiple hair cell markers and express functional ion channels reminiscent of nascent hair cells. Spiral ganglion stem cells display features of neural stem cells and can give rise to neurons and glial cell types. We found that the ability for sphere formation in the mouse cochlea decreases about 100-fold during the second and third postnatal weeks; this decrease is substantially faster than the reduction of stem cells in vestibular organs, which maintain their stem cell population also at older ages. Coincidentally, the relative expression of developmental and progenitor cell markers in the cochlea decreases during the first 3 postnatal weeks, which is in sharp contrast to the vestibular system, where expression of progenitor cell markers remains constant or even increases during this period. Our findings indicate that the lack of regenerative capacity in the adult mammalian cochlea is either a result of an early postnatal loss of stem cells or diminishment of stem cell features of maturing cochlear cells.

Reinnervation of hair cells by auditory neurons after selective removal of spiral ganglion neurons.

Hearing loss can be caused by primary degeneration of spiral ganglion neurons or by secondary degeneration of these neurons after hair cell loss. The replacement of auditory neurons would be an important step in any attempt to restore auditory function in patients with damaged inner ear neurons or hair cells. Application of beta-bungarotoxin, a toxin derived from snake venom, to an explant of the cochlea eradicates spiral ganglion neurons while sparing the other cochlear cell types. The toxin was found to bind to the neurons and to cause apoptotic cell death without affecting hair cells or other inner ear cell types as indicated by TUNEL staining, and, thus, the toxin provides a highly specific means of deafferentation of hair cells. We therefore used the denervated organ of Corti for the study of neuronal regeneration and synaptogenesis with hair cells and found that spiral ganglion neurons obtained from the cochlea of an untreated newborn mouse reinnervated hair cells in the toxin-treated organ of Corti and expressed synaptic vesicle markers at points of contact with hair cells. These findings suggest that it may be possible to replace degenerated neurons by grafting new cells into the organ of Corti.