Mining and evaluation of adverse event signals for capmatinib based on the FAERS database.

Objective: To conduct a comprehensive data analysis based on the FDA's Adverse Event Reporting System (FAERS) to mine possible adverse event (AE) signals of Capmatinib, providing valuable references for its clinical application. Methods: Capmatinib was the primary suspected drug in the search of FAERS database from the second quarter of 2020 to the fourth quarter of 2023. Data processing, screening, and classification were performed using methods such as the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Results: A total of 1,991 AE reports directly related to Capmatinib were screened, identifying 269 Preferred Terms (PTs) involving 26 System Organ Classes (SOCs). Besides the AEs recorded in the drug label (such as edema, nausea, fatigue, and dyspnea), the study unearthed other high-risk AEs not listed in the label, including Renal and urinary disorders, Vocal cord paralysis, and Ear and labyrinth disorders. Among these, renal and urinary disorders, and ear and labyrinth disorders had a higher frequency and intensity of signals, suggesting that their mechanisms of occurrence could be a future research direction. Conclusion: This study uncovered new potential AEs of Capmatinib based on the FAERS database, providing reference for its safe clinical use. Special attention should be given to the occurrence of ear and labyrinth disorders and renal and urinary disorders, primarily presenting as pseudo-acute kidney injury, during treatment.

Our Experience with Labyrinthine Fistula: Prospective Hearing Outcomes.

Introduction: Chronic otitis media with cholesteatoma is a locally destructive middle ear infection with bone erosive properties which can lead to fistula if erodes labyrinth. Materials and Methods: A prospective observational study was conducted at tertiary health care centre with a total of 12 patients who presented with complaints of otorrhoea, hearing loss and vertigo. Such patients were evaluated clinic audiologically and radiologically as a pre op assessment. Post-surgery audiological assessment was done. Results: Hearing preservation was seen in 91.7% patients and none of the patients had iatrogenic sensorineural hearing loss. Conclusion: Complete removal of the cholesteatoma is beneficial and does not lead to any iatrogenic SNHL when performed meticulously. A newer way of diagnosing membranous labyrinthine breach utilizing Magnetic Resonance Imaging T2 Diffusion Weighted (MRI- T2 DW) sequence can be implemented.

The whole is lesser than the sum of its parts? Dissecting layer-enriched samples of rodent placenta is worth the effort.

Gene expression in the placenta, assessed by bulk RNA-seq, is a common method to explore placental function. Many rodent studies homogenize the entire placenta, and yet doing so may obscure differences within specific functional regions such as the labyrinth, junctional zone and decidua. Conversely, analysis of the whole placenta could generate apparent differences due to changes in composition (e.g., relative amounts of labyrinth vs junctional zone) rather than differential gene expression. We assess the value of dissecting and separately analysing the labyrinth and junctional zone/decidua by comparing RNA-seq results from the labyrinth, junctional zone/decidua combined, and whole placenta from an experiment examining effects of maternal food restriction and fetal sex in C57BL6/J mice at gestational day 17.5. The number of genes identified as differentially expressed in response to maternal food restriction was substantially higher in the labyrinth (910 genes), than in the junctional zone/decidua (50 genes), which in turn was slightly higher than in the whole placenta (3 genes). Only one gene was differentially expressed in all 3 tissue types, and 20 genes were differentially expressed in both the labyrinth and junctional zone/decidua. The larger number of differentially expressed genes in the labyrinth was due to both larger effect sizes and estimates of effect sizes having smaller standard errors. While dissection to obtain layer-enriched samples is slightly more time-consuming than collection of whole placenta and requires some practice, our results show that layer-enrichment is clearly worth the effort.

Gravitational change-induced alteration of the vestibular function and gene expression in the vestibular ganglion of mice.

Gravity has profoundly influenced life on Earth, yet how organisms adapt to changes in gravity remains largely unknown. This study examines vestibular plasticity, specifically how the vestibular system responds to altered gravity. We subjected male C57BL/6J mice to hypergravity (2 G) followed by normal gravity (1 G) to analyze changes in vestibular function and gene expression. Mice showed significant vestibular dysfunction, assessed by righting reflex tests, which persisted for days but reversed at 1 G after exposure to 2 G. Gene expression analysis in the vestibular ganglion identified significant changes in 212 genes out of 49,585 due to gravitational changes. Specifically, 25 genes were upregulated under 2 G and recovered at 1 G after 2 G exposure, while one gene showed the opposite trend. Key neural function genes like Shisa3, Slc25a37, Ntn4, and Snca were involved. Our results reveal that hypergravity-induced vestibular dysfunction is reversible and highlight genes critical for adaptation.

Low-Frequency Sound-Insulation Performance of Labyrinth-Type Helmholtz and Thin-Film Compound Acoustic Metamaterial.

This paper presents a type of acoustic metamaterial that combines a labyrinth channel with a Helmholtz cavity and a thin film. The labyrinth-opening design and thin-film combination contribute to the metamaterial's exceptional sound-insulation performance. After comprehensive research, it is observed that in the frequency range of 20-1200 Hz, this acoustic metamaterial exhibits multiple sound-insulation peaks, showing a high overall sound-insulation quality. Specifically, the first sound-insulation peak is 26.3 Hz, with a bandwidth of 13 Hz and giving a transmission loss of 56.5 dB, showing excellent low-frequency sound-insulation performance. To further understand the low-frequency sound-insulation mechanism, this paper uses the equivalent model method to conduct an acoustic-electrical analogy, construct an equivalent model of the acoustic metamaterial, and delve into the sound-insulation mechanism at the first sound-insulation peak. To confirm the validity of the theoretical calculations, physical experiments are carried out by 3D printing experimental samples. The analysis of the experimental data has yielded results that are consistent with the simulation data, providing empirical evidence for the accuracy of the theoretical model. The material has significant practical application value. Finally, various factors are studied in depth based on the established equivalent model, which can provide valuable insights for the design and practical engineering application of acoustic metamaterials.

Neutrophil Extracellular Traps Affect Human Inner Ear Vascular Permeability.

The integrity of the blood-labyrinth barrier (BLB) is essential for inner ear homeostasis, regulating the ionic composition of endolymph and perilymph and preventing harmful substance entry. Endothelial hyperpermeability, central in inflammatory and immune responses, is managed through complex intercellular communication and molecular signaling pathways. Recent studies link BLB permeability dysregulation to auditory pathologies like acoustic trauma, autoimmune inner ear diseases, and presbycusis. Polymorphonuclear granulocytes (PMNs), or neutrophils, significantly modulate vascular permeability, impacting endothelial barrier properties. Neutrophil extracellular traps (NETs) are involved in diseases with autoimmune and autoinflammatory bases. The present study evaluated the impact of NETs on a BLB cellular model using a Transwell® setup. Our findings revealed a concentration-dependent impact of NETs on human inner ear-derived endothelial cells. In particular, endothelial permeability markers increased, as indicated by reduced transepithelial electrical resistance, enhanced dextran permeability, and downregulated junctional gene expression (ZO1, OCL, and CDH5). Changes in cytoskeletal architecture were also observed. These preliminary results pave the way for further research into the potential involvement of NETs in BLB impairment and implications for auditory disorders.

Hyperglycemia-induced oxidative stress exacerbates mitochondrial apoptosis damage to cochlear stria vascularis pericytes via the ROS-mediated Bcl-2/CytC/AIF pathway.

OBJECTIVES: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss. METHODS: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes. RESULTS: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis. DISCUSSION: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.

Insular dwarfism in horses from the Aegean Sea and the Japanese archipelago.

The horse (Equus caballus) varieties from Skyros and Rhodes islands (Greece) in the Aegean archipelago are extremely small, reaching shoulder heights of only about 1 m. Furthermore, the Japanese archipelago is home to eight small, native horse breeds. We investigated the evolutionary morphology and provided a review of historical documentations of these horses of cultural interest in Greece and Japan, thus providing a comparison of the independent evolution of small size in islands. We integrate cranial data from historical literature with data from newly gathered and curated skulls and analyse a measurement dataset featuring various domestic and mainland horse breeds and varieties. We use non-invasive imaging to study and measure 3D models of the bony labyrinth, housing the inner ear, and the braincase endocast. When considering the effects of allometry by regressing each PC1 scores (for each set of measurements) with the cranial geometric mean from linear measurements as a body size proxy, we show that size explains a large amount of the shape variation in horse crania, the bony labyrinths and brain endocasts. We found high intrabreed variation in all the analysed datasets. Globally, there are at least 30 distinct horse populations on islands, offering the chance to further study processes of convergence in morphological divergence and evaluate the effect of drift and the environment. Supplementary Information: The online version contains supplementary material available at 10.1007/s42991-024-00408-4.

Gray-tone appearances on 4-hour delayed gadolinium-enhanced magnetic resonance imaging indicate severe inner ear pathology and symptoms in sudden sensorineural hearing loss.

Objective: Hybrid of reversed image of positive endolymph signal and negative image of perilymph signal (HYDROPS) in delayed gadolinium-enhanced magnetic resonance imaging (MRI) typically depicts normal inner ear as "white-tone" and endolymphatic hydrops as "black-transparent" appearances, whereas ears with auditory and vestibular disorders are occasionally depicted as "gray-tone." This study aimed to investigate the pathological basis of sudden sensorineural hearing loss (SSNHL) patients with "gray-tone" appearances on HYDROPS. Methods: Delayed gadolinium-enhanced MRI examinations were conducted on 29 subjects with unilateral SSNHL. We mainly analyzed positive perilymph image (PPI) and positive endolymph image (PEI), which were components HYDROPS. Results: On PPI, signal intensity (SI) values extracted from the cochlear and vestibular region of interest (ROI) were higher in the SSNHL ears with dizziness/vertigo symptom at the first visit compared to the healthy ear. Additionally, the PPI/PEI enhancement pattern in the vestibule was associated with a high prevalence of hearing and vestibular deteriorations at the first visit and poor hearing improvement after treatment. Conclusion: Enhancement on PPI/PEI may result from leakage of gadolinium into the inner ear following breakdown of the blood-labyrinth barrier, with high SI being correlated with the amount of leakage. Particularly, a significant leakage into the endolymphatic space, defined as PPI+/PEI+, indicates severe inner ear pathology. Ultimately, we emphasize that the "gray-tone" appearance in the inner ear on HYDROPS comprises enhancements on both PPI and PEI and propose a new classification for evaluating SSNHL Peri- and Endolymphatic image Enhancement pattern in Delayed gadolinium-enhanced MRI (SPEED). Level of Evidence: 4.

Mfsd2a regulates the blood-labyrinth-barrier formation and function through tight junctions and transcytosis.

The Blood-Labyrinth Barrier (BLB) is pivotal for the maintenance of lymphatic homeostasis within the inner ear, yet the intricacies of its development and function are inadequately understood. The present investigation delves into the contribution of the Mfsd2a molecule, integral to the structural and functional integrity of the Blood-Brain Barrier (BBB), to the ontogeny and sustenance of the BLB. Our empirical findings delineate that the maturation of the BLB in murine models is not realized until approximately two weeks post-birth, with preceding stages characterized by notable permeability. Transcriptomic analysis elucidates a marked augmentation in Mfsd2a expression within the lateral wall of the cochlea in specimens exhibiting an intact BLB. Moreover, both in vitro and in vivo assays substantiate that a diminution in Mfsd2a expression detrimentally impacts BLB permeability and structural integrity, principally via the attenuation of tight junction protein expression and the enhancement of endothelial cell transcytosis. These insights underscore the indispensable role of Mfsd2a in ensuring BLB integrity and propose it as a viable target for therapeutic interventions aimed at the amelioration of hearing loss.

Reversible opening of the blood-labyrinth barrier by low-pressure pulsed ultrasound and microbubbles for the treatment of inner ear diseases.

Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases. However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig's inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin. Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe3O4@CUR NPs) could be efficiently delivered into the inner ear. We observed better drug accumulation in the perilymph of the inner ear, resulting in less drug (cisplatin)-induced ototoxicity. Furthermore, physiological, hematological, and histological studies showed that the modulation of the BLB by low-pressure USMB was a safe process without significant adverse effects. We conclude that USMB could become a promising strategy for the systematic delivery of therapeutics in the treatment of inner ear diseases.

Activation of Src Kinase Mediates the Disruption of Adherens Junction in the Blood-labyrinth Barrier after Acoustic Trauma.

BACKGROUND: Adherens junction in the blood-labyrinth barrier is largely unexplored because it is traditionally thought to be less important than the tight junction. Since increasing evidence indicates that it actually functions upstream of tight junction adherens junction may potentially be a better target for ameliorating the leakage of the blood-labyrinth barrier under pathological conditions such as acoustic trauma. AIMS: This study was conducted to investigate the pathogenesis of the disruption of adherens junction after acoustic trauma and explore potential therapeutic targets. METHODS: Critical targets that regulated the disruption of adherens junction were investigated by techniques such as immunofluorescence and Western blottingin C57BL/6J mice. RESULTS: Upregulation of Vascular Endothelial Growth Factor (VEGF) and downregulation of Pigment Epithelium-derived Factor (PEDF) coactivated VEGF-PEDF/VEGF receptor 2 (VEGFR2) signaling pathway in the stria vascularis after noise exposure. Downstream effector Src kinase was then activated to degrade VE-cadherin and dissociate adherens junction which led to the leakage of the blood-labyrinth barrier. By inhibiting VEGFR2 or Src kinase VE-cadherin degradation and blood-labyrinth barrier leakage could be attenuated but Src kinase represented a better target to ameliorate blood-labyrinth barrier leakage as inhibiting it would not interfere with vascular endothelium repair neurotrophy and pericytes proliferation mediated by upstream VEGFR2. CONCLUSION: Src kinase may represent a promising target to relieve noise-induced disruption of adherens junction and hyperpermeability of the blood-labyrinth barrier.

The role of SLC26A4 in bony labyrinth development and otoconial mineralization in mouse models.

Inner ear malformations are predominantly attributed to developmental arrest during the embryonic stage of membranous labyrinth development. Due to the inherent difficulty in clinically assessing the status of the membranous labyrinth, these malformations are diagnosed with radiographic imaging, based on the morphological characteristics of the bony labyrinth. While extensive research has elucidated the intricacies of membranous labyrinth development in mouse models, comprehensive investigations into the developmental trajectory of the bony labyrinth, especially about its calcification process, have been notably lacking. One of the most prominent types of inner ear malformations is known as incomplete partition (IP), characterized by nearly normal external cochlear appearance but pronounced irregularities in the morphology of the modiolus and inter-scalar septa. IP type II (IP-II), also known as Mondini dysplasia, is generally accompanied by an enlargement of the vestibular aqueduct and is primarily attributed to mutations in the SLC26A4 gene. In the case of IP-II, the modiolus and inter-scalar septa of the cochlear apex are underdeveloped or missing, resulting in the manifestation of a cystic structure on radiographic imaging. In this overview, we not only explore the normal development of the bony labyrinth in mice but also present our observations on otolith mineralization. Furthermore, we investigated the specifics of bony labyrinth and otolith mineralization in Slc26a4-deficient mice, which served as an animal model for IP-II. We ensured that these findings promise to provide valuable insights for the establishment of therapeutic interventions, optimal timing, targeted sites, and preventive measures when considering the management of this condition.

Pneumo-Membranous Labyrinth After Hyperbaric Oxygen Therapy for Sudden Sensorineural Hearing Loss.

Pneumo-membranous labyrinth is an almost unique condition, in which air extends into the membranous labyrinth, filling the endolymphatic sac through the vestibular aqueduct. In this manuscript, we describe and discuss a case of pneumo-membranous labyrinth, with air bubbles extending also to the endolymphatic sac, resulting in anacusis, following hyperbaric oxygen therapy for sudden sensorineural hearing loss. The patient was successfully rehabilitated with a cochlear implant, obtaining a pure-tone average of 30 dB, with a speech discrimination score of 100% at 70 dB. Laryngoscope, 134:3773-3777, 2024.

Unveiling the Intricacies of the Inner Ear Anatomy: Novel 3D-Printed Model for Detailed Visualization and Functional Demonstrations.

OBJECTIVES: This research aimed to print realistically detailed and magnified three-dimensional models of the inner ear, specifically focusing on visualising its complex labyrinth structure and functioning simulation. METHODS: Temporal bone computed-tomography data were imported into Mimics software to construct an initial three-dimensional inner-ear model. Subsequently, the model was amplified and printed with precision using a three-dimensional printer. Five senior attending physicians evaluated the printed model using a Likert scale to gauge its morphological accuracy, clinical applicability and anatomical teaching value. RESULTS: The printed inner-ear model effectively demonstrated the intricate internal structure. All five physicians agreed that the model closely resembled the real inner ear in shape and structure, and simulated certain inner-ear functions. The model was considered highly valuable for understanding anatomical structure and disorders. CONCLUSION: The three-dimensionally printed inner-ear model is highly simulated and provides a valuable visual tool for studying inner-ear anatomy and clinical teaching, benefiting otologists.

Quercetin attenuates cisplatin-induced mitochondrial apoptosis via PI3K/Akt mediated inhibition of oxidative stress in pericytes and improves the blood labyrinth barrier permeability.

Cisplatin (CDDP) is broadly employed to treat different cancers, whereas there are no drugs approved by the Food and Drug Administration (FDA) for preventing its side effects, including ototoxicity. Quercetin (QU) is a widely available natural flavonoid compound with anti-tumor and antioxidant properties. The research was designed to explore the protective effects of QU on CDDP-induced ototoxicity and its underlying mechanisms in male C57BL/6 J mice and primary cultured pericytes (PCs). Hearing changes, morphological changes of stria vascularis, blood labyrinth barrier (BLB) permeability and expression of apoptotic proteins were observed in vivo by using the auditory brainstem response (ABR) test, HE staining, Evans blue staining, immunohistochemistry, western blotting, etc. Oxidative stress levels, mitochondrial function and endothelial barrier changes were observed in vitro by using DCFH-DA probe detection, flow cytometry, JC-1 probe, immunofluorescence and the establishment in vitro BLB models, etc. QU pretreatment activates the PI3K/AKT signaling pathway, inhibits CDDP-induced oxidative stress, protects mitochondrial function, and reduces mitochondrial apoptosis in PCs. However, PI3K/AKT specific inhibitor (LY294002) partially reverses the protective effects of QU. In addition, in vitro BLB models were established by coculturing PCs and endothelial cells (ECs), which suggests that QU both reduces the CDDP-induced apoptosis in PCs and improves the endothelial barrier permeability. On the whole, the research findings suggest that QU can be used as a novel treatment to reduce CDDP-induced ototoxicity.

A critical evaluation of "leakage" at the cochlear blood-stria-barrier and its functional significance.

The blood-labyrinth-barrier (BLB) is a semipermeable boundary between the vasculature and three separate fluid spaces of the inner ear, the perilymph, the endolymph and the intrastrial space. An important component of the BLB is the blood-stria-barrier, which shepherds the passage of ions and metabolites from strial capillaries into the intrastrial space. Some investigators have reported increased "leakage" from these capillaries following certain experimental interventions, or in the presence of inflammation or genetic variants. This leakage is generally thought to be harmful to cochlear function, principally by lowering the endocochlear potential (EP). Here, we examine evidence for this dogma. We find that strial capillaries are not exclusive, and that the asserted detrimental influence of strial capillary leakage is often confounded by hair cell damage or intrinsic dysfunction of the stria. The vast majority of previous reports speculate about the influence of strial vascular barrier function on the EP without directly measuring the EP. We argue that strial capillary leakage is common across conditions and species, and does not significantly impact the EP or hearing thresholds, either on evidentiary or theoretical grounds. Instead, strial capillary endothelial cells and pericytes are dynamic and allow permeability of varying degrees in response to specific conditions. We present observations from mice and demonstrate that the mechanisms of strial capillary transport are heterogeneous and inconsistent among inbred strains.

Balancing Act: A Comprehensive Review of Vestibular Evaluation in Cochlear Implants.

Cochlear implantation, a transformative intervention for individuals with profound hearing loss, has evolved significantly over the years. However, its impact on the vestibular system, responsible for balance and spatial orientation, remains a subject of ongoing research and clinical consideration. This narrative review highlights key aspects of vestibular evaluation in patients undergoing cochlear implantation. Preoperative vestibular assessment is crucial to establish baseline vestibular function and identify any pre-existing balance issues. Various tests, including caloric, rotational chair, vestibular-evoked myogenic potential, and video head impulse tests, play a vital role in evaluating vestibular function. The goal is to assess the risk of vestibular disturbances arising from the surgery, guide surgical planning, and detect pre-existing alterations that could be totally or partially compensated. While some patients experience minimal vestibular disruptions, others may encounter transient or persistent balance issues following cochlear implant surgery. Postoperative vestibular testing allows for the early detection of such disturbances, enabling timely interventions like vestibular rehabilitation and evaluating changes produced due to surgical complications or changes in the patient's prior conditions. Challenges in vestibular evaluation include individual variability in patient responses, the proximity of the cochlea to the vestibular system, and the need to tailor testing protocols to individual needs. Further research is essential to refine testing protocols, minimize vestibular disturbances, and improve outcomes for cochlear implant candidates. A multidisciplinary approach involving otolaryngologists, audiologists, and physical therapists is integral to comprehensive patient care in this context. In conclusion, vestibular evaluation in patients undergoing cochlear implantation is critical for optimizing surgical planning, managing postoperative issues, and enhancing the overall quality of life for individuals embarking on the journey of restored hearing.