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PloS One 2019The vast majority of hearing loss, the most common sensory impairment, and vertigo, which commonly causes falls, both reflect underlying dysfunction of inner ear cells.... (Clinical Trial)
Clinical Trial
The vast majority of hearing loss, the most common sensory impairment, and vertigo, which commonly causes falls, both reflect underlying dysfunction of inner ear cells. Perilymph sampling can thus provide molecular cues to hearing and balance disorders. While such "liquid biopsy" of the inner ear is not yet in routine clinical practice, previous studies have uncovered alterations in perilymph in patients with certain types of hearing loss. However, the proteome of perilymph from patients with intact hearing has been unknown. Furthermore, no complete characterization of perilymph from patients with vestibular dysfunction has been reported. Here, using liquid-chromatography with tandem mass spectrometry, we analyzed samples of normal perilymph collected from three patients with skull base meningiomas and intact hearing. We identified 228 proteins that were common across the samples, establishing a greatly expanded proteome of the previously inferred normal human perilymph. Further comparison to perilymph obtained from three patients with vestibular dysfunction with drop attacks due to Meniere's disease showed 38 proteins with significantly differential abundance. The abundance of four protein candidates with previously unknown roles in inner ear biology was validated in murine cochleae by immunohistochemistry and in situ hybridization: AACT, HGFAC, EFEMP1, and TGFBI. Together, these results motivate future work in characterizing the normal human perilymph and identifying biomarkers of inner ear disease.
Topics: Animals; Biomarkers; Chromatography, Liquid; Cochlea; Female; Humans; Male; Meniere Disease; Mice; Middle Aged; Perilymph; Proteome; Tandem Mass Spectrometry; Vertigo
PubMed: 31185063
DOI: 10.1371/journal.pone.0218292 -
International Archives of... Jul 2017Recent advances in surgical techniques and electrode design have made residual hearing preservation during cochlear implantation (CI) possible, achievable, and... (Review)
Review
Recent advances in surgical techniques and electrode design have made residual hearing preservation during cochlear implantation (CI) possible, achievable, and desirable. The objective of this study was to review the literature regarding methods used for hearing preservation during CI surgery. We performed a search in the LILACS, MEDLINE, SciELO, PubMed databases, and Cochrane Library, using the keywords CI, hearing preservation, CI electrode design, and CI soft surgery. We fully read about 15 studies that met the criteria described in "study selection". The studies showed that several factors could contribute to possible cochlear damage during or after CI surgery and must be kept in mind; mechanical damage during electrode insertion, shock waves in the perilymph fluid due to implantation, acoustic trauma due to drilling, loss of perilymph and disruption of inner ear fluid homeostasis, potential bacterial infection, and secondary intracochlear fibrous tissue formation. The desire to preserve residual hearing has led to the development of the soft-surgery protocols with its various components; avoiding entry of blood into the cochlea and the use of hyaluronate seem to be reasonably supported, whereas the use of topical steroids is questionable. The site of entry into the cochlea, electrode design, and the depth of insertion are also important contributing factors. Hearing preservation would be useful for CI patients to benefit from the residual low frequency, as well as for the children who could be candidate for future regenerative hair cell therapy.
PubMed: 28680501
DOI: 10.1055/s-0036-1585094 -
Frontiers in Neurology 2019Vestibular schwannomas (VSs) are benign tumors composed of differentiated neoplastic Schwann cells. They can be classified into two groups: sporadic VS and those... (Review)
Review
Vestibular schwannomas (VSs) are benign tumors composed of differentiated neoplastic Schwann cells. They can be classified into two groups: sporadic VS and those associated with neurofibromatosis type 2 (NF2). VSs usually grow slowly, initially causing unilateral sensorineural hearing loss (HL) and tinnitus. These tumors cause HL both due to compression of the auditory nerve or the labyrinthine artery and due to the secretion of different substances potentially toxic to the inner ear or the cochlear nerve. As more and more patients are diagnosed and need to be managed, we are more than ever in need of searching for biomarkers associated with these tumors. Owing to an unknown toxic substance generated by the tumor, HL in VS may be linked to a high protein amount of perilymph. Previous studies have identified perilymph proteins correlated with tumor-associated HL, including μ-Crystallin (CRYM), low density lipoprotein receptor-related protein 2 (LRP2), immunoglobulin (Ig) γ-4 chain C region, Ig κ-chain C region, complement C3, and immunoglobulin heavy constant γ 3. Besides, the presence of specific subtypes of heat shock protein 70 has been suggested to be associated with preservation of residual hearing. It has been recently demonstrated that chemokine receptor-4 (CXCR4) is overexpressed in sporadic VS as well as in NF2 tumors and that hearing disability and CXCR4 expression may be correlated. Further, the genetic profile of VS and its relationship with poor hearing has also been studied, including DNA methylation, deregulated genes, growth factors, and gene mutations. The knowledge of biomarkers associated with VS would be of significant value to maximize outcomes of hearing preservation in these patients.
PubMed: 31620068
DOI: 10.3389/fneur.2019.00978 -
Journal of Otolaryngology - Head & Neck... Dec 2017Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to... (Comparative Study)
Comparative Study
BACKGROUND
Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol.
STUDY DESIGN
Controlled animal research project.
METHODS
Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point.
RESULTS
Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood.
CONCLUSIONS
Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph.
Topics: Animals; Blood-Brain Barrier; Cerebrospinal Fluid; Drug Therapy, Combination; Ear, Inner; Enzyme-Linked Immunosorbent Assay; Gentamicins; Guinea Pigs; Mannitol; Models, Animal; Perilymph; Reference Values
PubMed: 29228990
DOI: 10.1186/s40463-017-0245-8 -
Otology & Neurotology : Official... Jul 2020: Local glucocorticosteroid ("steroid") therapy is widely used to treat the inner ears of patients with Menière's disease, idiopathic sudden sensorineural hearing loss...
: Local glucocorticosteroid ("steroid") therapy is widely used to treat the inner ears of patients with Menière's disease, idiopathic sudden sensorineural hearing loss and in combination with cochlear implants. Applied steroids have included dexamethasone, methylprednisolone, and triamcinolone. In reality, however, this is often not true and the steroid forms commonly applied are dexamethasone-phosphate, methylprednisolone-hemisuccinate, or triamcinolone-acetonide. In each case, the additional component is not a counter-ion but is covalently bound to the molecule to increase aqueous solubility or potency. These drug forms are approved for intravenous or intramuscular delivery and are used "off-label" in the ear. When given systemically, the molecular form of the drug is of minor importance as the drugs are rapidly metabolized. In contrast, when administered intratympanically, the exact form of the drug has a major influence on entry into perilymph and elimination from perilymph, which in turn influences distribution along the cochlear scalae. Dexamethasone-phosphate has completely different molecular properties to dexamethasone and has different pharmacokinetic properties entering and leaving perilymph. Molecular properties and perilymph pharmacokinetics also differ markedly for triamcinolone and triamcinolone-acetonide. Methylprednisolone-hemisuccinate has completely different molecular properties to methylprednisolone. In the ear, different steroid forms cannot therefore be regarded as equivalent in terms of pharmacokinetics or efficacy. This presents a terminology problem, where in many cases the drug stated in publications may not be the form actually administered. The lack of precision in nomenclature is a serious problem for the inner ear drug delivery field and needs to be recognized.
Topics: Dexamethasone; Ear, Inner; Hearing Loss, Sudden; Humans; Perilymph; Steroids
PubMed: 32195918
DOI: 10.1097/MAO.0000000000002624 -
Journal of Clinical Medicine Sep 2022Precision medicine for inner ear disorders has seen significant advances in recent years. However, unreliable access to the inner ear has impeded diagnostics and... (Review)
Review
OBJECTIVES
Precision medicine for inner ear disorders has seen significant advances in recent years. However, unreliable access to the inner ear has impeded diagnostics and therapeutic delivery. The purpose of this review is to describe the development, production, and utility of novel microneedles for intracochlear access.
METHODS
We summarize the current work on microneedles developed using two-photon polymerization (2PP) lithography for perforation of the round window membrane (RWM). We contextualize our findings with the existing literature in intracochlear diagnostics and delivery.
RESULTS
Two-photon polymerization lithography produces microneedles capable of perforating human and guinea pig RWMs without structural or functional damage. Solid microneedles may be used to perforate guinea pig RWMs in vivo with full reconstitution of the membrane in 48-72 h, and hollow microneedles may be used to aspirate perilymph or inject therapeutics into the inner ear. Microneedles produced with two-photon templated electrodeposition (2PTE) have greater strength and biocompatibility and may be used to perforate human RWMs.
CONCLUSIONS
Microneedles produced with 2PP lithography and 2PTE can safely and reliably perforate the RWM for intracochlear access. This technology is groundbreaking and enabling in the field of inner ear precision medicine.
PubMed: 36143121
DOI: 10.3390/jcm11185474 -
Frontiers in Neuroscience 2017The clinical uses of electrocochleography are reviewed with some technical notes on the apparatus needed to get clear recordings under different conditions.... (Review)
Review
The clinical uses of electrocochleography are reviewed with some technical notes on the apparatus needed to get clear recordings under different conditions. Electrocochleography can be used to estimate auditory thresholds in difficult to test children and a golf club electrode is described. The same electrode can be used to obtain electrical auditory brainstem responses (EABR). Diagnostic testing in the clinic can be performed with a transtympanic needle electrode, and a suitable disposable monopolar electrode is described. The use of tone bursts rather than click stimuli gives a better means of diagnosis of the presence of endolymphatic hydrops. Electrocochleography can be used to monitor the cochlear function during surgery and a long coaxial cable, which can be sterilized, is needed to avoid electrical artifacts. Recently electrocochleography has been used to monitor cochlear implant insertion and to record residual hearing using an electrode on the cochlear implant array as the non-inverting (active) electrode.
PubMed: 28634435
DOI: 10.3389/fnins.2017.00274 -
Frontiers in Neurology 2021Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's...
Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's disease are needed. miRNAs are small RNA sequences that downregulate mRNA translation and play a significant role in a variety of disease states, ultimately making them a promising biomarker. miRNAs can be readily isolated from human inner ear perilymph and serum, and may exhibit disease-specific profiles. Perilymph sampling was performed in 10 patients undergoing surgery; 5 patients with Meniere's disease and 5 patients with otosclerosis serving as controls. miRNAs were isolated from the serum of 5 patients with bilateral Menière's disease and compared to 5 healthy age-matched controls. For evaluation of miRNAs an Agilent miRNA gene chip was used. Analysis of miRNA expression was carried out using Qlucore and Ingenuitey Pathway Analysis software. Promising miRNAs biomarkers were validated using qPCR. In the perilymph of patients with Menière's disease, we identified 16 differentially expressed miRNAs that are predicted to regulate over 220 different cochlear genes. Six miRNAs are postulated to regulate aquaporin expression and twelve miRNAs are postulated to regulate a variety of inflammatory and autoimmune pathways. When comparing perilymph with serum samples, miRNA-1299 and-1270 were differentially expressed in both the perilymph and serum of Ménière's patients compared to controls. Further analysis using qPCR confirmed miRNA-1299 is downregulated over 3-fold in Meniere's disease serum samples compared to controls. Patients with Ménière's disease exhibit distinct miRNA expression profiles within both the perilymph and serum. The altered perilymph miRNAs identified can be linked to postulated Ménière's disease pathways and may serve as biomarkers. miRNA-1299 was validated to be downregulated in both the serum and perilymph of Menière's patients.
PubMed: 34220670
DOI: 10.3389/fneur.2021.646928 -
Hearing Research Oct 2018Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we... (Review)
Review
Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.
Topics: Animals; Drug Delivery Systems; Ear, Inner; Hearing; Hearing Loss; Humans; Labyrinth Diseases; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 29551306
DOI: 10.1016/j.heares.2018.03.002