Carboxypeptidase A6 suppresses the proliferation and invasion of colorectal cancer cells and is negatively regulated by miR-96-3p.

BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor, and this study aims to explore the role and the regulatory mechanism of carboxypeptidase A6 (CPA6) in CRC cells. METHODS: Specific shRNA targeting CPA6 mRNA was transfected into NCM460 and HT29 cells to down-regulate CPA expression, and expression plasmid was transfected into HCT116 cells to exogenously overexpress CPA6. The dual luciferase assay was used to detect the direct binding of miR-96-3p to CPA6 3'UTR. Phosphorylation and activation of Akt were detected using Western blot. Cells were treated with miR-96-3p mimics, Akt inhibitor (MK-2206) or agonist (SC79) for rescue experiments. The cell functions were evaluated using CCK-8, clone formation, transwell, and Western blot assays. Xenograft tumor assay was also used to analyze the effect of altered CPA6 expression on tumor growth. RESULTS: Knockdown of CPA6 promoted the proliferation, clone formation, migration, and invasion of NCM460 and HT29 cells in vitro, and the tumor growth of nude mouse xenograft tumor in vivo. Moreover, over-expression of CPA6 significantly inhibited the malignant proliferation and invasion of HCT116 cells in vitro, and the tumor growth of xenograft tumor in vivo. Furthermore, miR-96-3p could directly regulate CPA6 expression by targeting its 3'UTR, and miR-96-3p mimics rescued the inhibitory effects of CPA6 overexpression on the malignant proliferation and invasion of CRC cells. Finally, CPA6 knockdown enhanced Akt/mTOR phosphorylation and activation, while CPA6 overexpression inhibited Akt/mTOR activation. The regulatory effect of CPA6 on Akt/mTOR signaling was naturally regulated by miR-96-3p. Akt inhibitor or agonist rescued the effects of CPA6 knockdown or overexpression on proliferation and EMT of colon cancer cells. CONCLUSION: CPA6 has a significant tumor suppressive effect on CRC by inhibiting the activation of Akt/mTOR signaling, and miR-96-3p negatively regulates the expression of CPA6.

Traumatic-noise-induced hair cell death and hearing loss is mediated by activation of CaMKKß.

BACKGROUND: The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKß in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing. RESULTS: Treatment with short hairpin RNA of CaMKKß (shCaMKKß) via adeno-associated virus transduction significantly knocked down CaMKKß expression in the inner ear. Knockdown of CaMKKß significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKß small interfering RNA (siCaMKKß) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKß in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKß mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKß in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKß diminished noise-induced activation of AMPKα in OHCs. CONCLUSIONS: These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKß. Targeting CaMKKß is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKß pathway.

Assessing Agreement between Frequency-Specific Chirp Auditory Steady-State Response and Pure Tone Audiometry in Adults by Intraclass Correlation Coefficient.

INTRODUCTION: Chirp auditory steady-state response (ASSR) can be used to assess frequency-specific hearing thresholds. However, its reliability has not been confirmed yet. The purpose of this proposed study is to analyze the agreement of thresholds measured by chirp-ASSR and pure tone audiometry (PTA) to investigate the value of chirp-ASSR in hearing threshold evaluation. METHODS: Participants with normal hearing (age: 18-66, 108 ears) and patients with sensorineural hearing loss (age: 22-82, 75 ears) were tested using PTA and chirp-ASSR at 0.5, 1, 2, and 4 kHz, respectively. Intraclass correlation coefficient (ICC) and Bland-Altman plot were introduced to analyze the agreement between the 2 methods. RESULTS: One-hundred eight participants underwent both chirp-ASSR and PTA to estimate their thresholds. The ICCs yielded by these 2 methods are 0.757, 0.893, 0.883, and 0.921 (p < 0.001) at 0.5, 1, 2, and 4 kHz carrier frequency, respectively. However, there is a significant difference between the 2 methods at 2 kHz: the mean value of the ASSR thresholds is 5.27 dB HL higher than the value of PTA thresholds. Additionally, the 95% limits of agreement range from -27.48 to 26.66 dB HL at 0.5 kHz, from -18.19 to 17.87 dB HL at 1 kHz, from -12.01 to 22.55 dB HL at 2 kHz, and from -21.29 to 19.17 dB HL at 4 kHz, which are large enough to affect clinical decision-making. CONCLUSION: In this study, we have confirmed good to excellent correlation between chirp-ASSR and PTA in threshold estimation for adults with and without hearing loss. The degree of correlations is higher for participants with hearing loss and for measurements at high frequencies. However, significant systematic difference and large limits of agreement between the 2 methods have been found. These findings show that chirp-ASSR can be treated as a supplementary method to PTA when evaluating the hearing level, but the 2 methods are not interchangeable due to their systematic difference and large limits of agreement.

Chinese validation and clinical application of the tinnitus functional index.

OBJECTIVE: The Tinnitus Functional Index (TFI) is a new diagnostic measure of the functional impact of tinnitus that is also a sensitive measure of treatment-related changes. However, the TFI has not been translated into Chinese and fully validated in China. The aim of the present study was to evaluate the validity of a Chinese version of the TFI as a diagnostic measure of tinnitus severity in a sample of Chinese patients and to verify the value of its clinical application in China. DESIGN: A sample of 206 patients whose primary complaint was tinnitus was used to analyze the reliability and validity of the TFI. In addition, patients were asked to fill out the Tinnitus Handicap Inventory (THI) and the Center for Epidemiologic Studies-Depression Scale (CES-D), the Beck Anxiety Inventory (BAI), and the Satisfaction With Life Scale (SWLS) to compare TFI with their association. The internal consistency of the TFI was assessed with Cronbach's alpha coefficient. The factor structure of the TFI was assessed by Exploratory Factor Analysis (EFA). The extracted factors were compared to those of the original TFI scale. RESULTS: The reliability of the Chinese version of the TFI (Cronbach' s α = .969) showed high internal consistency. The exploratory factor analysis (EFA) of the TFI showed that six factors with one main factor could be extracted instead of eight factors as described in the original version. Nevertheless, relations to the original eight subscales could be demonstrated. A high correlation between the TFI and the THI (r = .865, p < 0.01) and lower correlations between the TFI and the CES-D (r = .334, p < 0.01), BAI (r = .559, p < 0.01), and SWLS (r = - 0.324, p < 0.01) confirmed the satisfactory convergent and discriminant validity of the TFI. CONCLUSION: After translated and validated a Chinese version of the TFI and found that the TFI had high reliability and validity, which means both instruments are reliable instruments to assess the severity of tinnitus in clinical applications in China.

Noise-Induced Loss of Hair Cells and Cochlear Synaptopathy Are Mediated by the Activation of AMPK.

UNLABELLED: Noise-induced hearing loss (NIHL) is a major unresolved public health problem. Here, we investigate pathomechanisms of sensory hair cell death and suggest a novel target for protective intervention. Cellular survival depends upon maintenance of energy homeostasis, largely by AMP-activated protein kinase (AMPK). In response to a noise exposure in CBA/J mice, the levels of phosphorylated AMPKα increased in hair cells in a noise intensity-dependent manner. Inhibition of AMPK via siRNA or the pharmacological inhibitor compound C attenuated noise-induced loss of outer hair cells (OHCs) and synaptic ribbons, and preserved auditory function. Additionally, noise exposure increased the activity of the upstream AMPK kinase liver kinase B1 (LKB1) in cochlear tissues. The inhibition of LKB1 by siRNA attenuated the noise-increased phosphorylation of AMPKα in OHCs, reduced the loss of inner hair cell synaptic ribbons and OHCs, and protected against NIHL. These results indicate that noise exposure induces hair cell death and synaptopathy by activating AMPK via LKB1-mediated pathways. Targeting these pathways may provide a novel route to prevent NIHL. SIGNIFICANCE STATEMENT: Our results demonstrate for the first time that the activation of AMP-activated protein kinase (AMPK) α in sensory hair cells is noise intensity dependent and contributes to noise-induced hearing loss by mediating the loss of inner hair cell synaptic ribbons and outer hair cells. Noise induces the phosphorylation of AMPKα1 by liver kinase B1 (LKB1), triggered by changes in intracellular ATP levels. The inhibition of AMPK activation by silencing AMPK or LKB1, or with the pharmacological inhibitor compound C, reduced outer hair cell and synaptic ribbon loss as well as noise-induced hearing loss. This study provides new insights into mechanisms of noise-induced hearing loss and suggests novel interventions for the prevention of the loss of sensory hair cells and cochlear synaptopathy.

Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling.

Our previous work has suggested that traumatic noise activates Rho-GTPase pathways in cochlear outer hair cells (OHCs), resulting in cell death and noise-induced hearing loss (NIHL). In this study, we investigated Rho effectors, Rho-associated kinases (ROCKs), and the targets of ROCKs, the ezrin-radixin-moesin (ERM) proteins, in the regulation of the cochlear actin cytoskeleton using adult CBA/J mice under conditions of noise-induced temporary threshold shift (TTS) and permanent threshold shift (PTS) hearing loss, which result in changes to the F/G-actin ratio. The levels of cochlear ROCK2 and p-ERM decreased 1 h after either TTS- or PTS-noise exposure. In contrast, ROCK2 and p-ERM in OHCs decreased only after PTS-, not after TTS-noise exposure. Treatment with lysophosphatidic acid, an activator of the Rho pathway, resulted in significant reversal of the F/G-actin ratio changes caused by noise exposure and attenuated OHC death and NIHL. Conversely, the down-regulation of ROCK2 by pretreatment with ROCK2 siRNA reduced the expression of ROCK2 and p-ERM in OHCs, exacerbated TTS to PTS, and worsened OHC loss. Additionally, pretreatment with siRNA against radixin, an ERM protein, aggravated TTS to PTS. Our results indicate that a ROCK2-mediated ERM-phosphorylation signaling cascade modulates noise-induced hair cell loss and NIHL by targeting the cytoskeleton. We propose the following cascade following noise trauma leading to alteration of the F-actin arrangement in the outer hair cell cytoskeleton: Noise exposure reduces the levels of GTP-RhoA and subsequently diminishes levels of RhoA effector ROCK2 (Rho-associated kinase 2). Phosphorylation of ezrin-radixin-moesin (ERM) by ROCK2 normally allows ERM to cross-link actin filaments with the plasma membrane. Noise-decreased levels of ROCK results in reduction of phosphorylation of ERM that leads to depolymerization of actin filaments. Lysophosphatidic acid (LPA), an agonist of RhoA, binds to the G-protein-coupled receptor (GPCR) leading to activation of RhoA through Gα12/13 and RhoGEF. Administration of LPA rescues the noise-diminished F/G-actin ratio.

Developing regional genetic counseling for southern Chinese with nonsyndromic hearing impairment: a unique mutational spectrum.

BACKGROUND: Racial and regional factors are important for the clinical diagnosis of non-syndromic hearing impairment. Comprehensive genetic analysis of deaf patients in different regions of China must be performed to provide effective genetic counseling. To evaluate the mutational spectrum of south Chinese families, we performed genetic analysis for non-syndromic hearing impairment in this population. METHODS: Complete clinical evaluations were performed on 701 unrelated patients with non-syndromic hearing impairment from six provinces in south China. Each subject was screened for common mutations, including SLC26A4 c.IVS7-2A > G, c.2168A > G; mitochondrial DNA m.1555A > G, m.1494C > T, m.7444G > A, m.7445A > G; GJB3 c.538C > T, c.547G > A; and WFS1 c.1901A > C, using pyrosequencing. GJB2 and SLC26A4 coding region mutation detection were performed using Sanger sequencing. RESULTS: Genetic analysis revealed that among the etiology of non-syndromic hearing impairment, GJB2, SLC26A4, and mitochondrial m.1555A > G mutations accounted for 18.0%, 13.1%, and 0.9%, respectively. Common mutations included GJB2 c.235delC, c.109G > A, SLC26A4 c.IVS7-2A > G, c.1229 T > C, and mitochondrial m.1555A > G. The total mutation rate was 45.1% in all patients examined in south China. Overall, the clear contribution of GJB2, SLC26A4, and mitochondrial m.1555A > G to the etiology of the non-syndromic deafness population in south China was 32.0%. CONCLUSIONS: Our study is the first genetic analysis of non-syndromic hearing impairment in south China, and revealed that a clear genetic etiology accounted for 32.0% of non-syndromic hearing cases in patients from these regions. The mutational spectrum of non-syndromic hearing impairment in the south Chinese population provides useful and targeted information to aid in genetic counseling.

Knockdown of LRCH4 Remodels Tumor Microenvironment Through Inhibiting YAP and TGF-ß/Smad Signaling Pathway in Colorectal Cancer.

BACKGROUND: Colorectal cancer is one of the most common gastrointestinal malignancies worldwide. LRCH4 is the top 1 gene associated with an unfavorable prognosis in colorectal cancer. METHODS: Here, we reported that the knockdown of LRCH4 inhibited the proliferation, migration and invasion in HT29 cells. RESULTS: The activity of Yes-Associated Protein (YAP), a transcription factor in the Hppo-YAP signaling pathway, was significantly inhibited by LRCH4-siRNA. LRCH4 knockdown also reversed the EMT and regulated the expression of extracellular matrix (ECM) protein, Fibronectin and Collagen IV in HT29 cells. In addition, the TGF-ß/Smad signaling pathway, as the downstream pathway of Yap, was also inhibited by LRCH4 knockdown. CONCLUSION: Knockdown of LRCH4 involved in the regulation of ECM and EMT and inhibited YAP and the TGF-ß/Smad signaling pathway in colorectal cancer cells. Our study provided a mechanism of LRCH4 on colorectal cancer cells, and a new potential target for clinical tumor treatment.

fNIRS Changes in the Middle Temporal and Occipital Cortices After a Cochlear Implant.

OBJECTIVES: The relationship between the middle temporal (MTG) and occipital cortices in post-lingually deaf (PLD) individuals is unclear. This study aimed to investigate changes in the MTG and occipital cortices excitability and their effects on the occipital cortex in individuals with PLD after receiving a cochlear implant (CI). METHODS: Twenty-six individuals with severe-to-profound binaural sensorineural PLD were assessed clinically. Nine individuals had received a unilateral cochlear implant over 6 months, while 17 had not. Brodmann area 19 (BA19, extra-striate occipital cortex) and MTG (auditory-related area of cortex) were selected as regions of interest. The excitability of the ROI was observed and compared in the surgery and no-surgery groups by functional near-infrared spectroscopy (fNIRS) in the resting state, and correlations between connectivity of the MTG and occipital cortex, and as well as the duration of time that had elapsed following CI surgery, were investigated. RESULTS: fNIRS revealed enhanced global cortical connectivity in the BA19 and MTG on the operative side (p < 0.05) and the connectivity between BA19 and the MTG also increased (p < 0.05). The connectivity between the MTG and BA19 was positively correlated with the duration of cochlear implantation, as was the case for BA18. CONCLUSION: There was evidence for remodeling of the cerebral cortex: increased excitability was observed in the MTG and BA19, and their connectivity was enhanced, indicating a synergistic effect. Moreover, the MTG may further stimulate the visual cortex by strengthening their connectivity after CI. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Characterization of the components in plasma EVs unveiling the link between EVs-derived complement C3 with the severity and initial treatment response of profound sudden sensorineural hearing loss.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is characterized by rapid, unexplained loss of hearing within a 72-hour period and exhibits a high incidence globally. Despite this, the outcomes of therapeutic interventions remain largely unpredictable, especially for those with profound hearing loss. Extracellular vesicles (EVs), nano-sized entities containing biological materials, are implicated in the development of numerous diseases. The specific relationship between EVs and both the severity and treatment effectiveness of SSNHL, however, is not well understood. METHODS: This study involved the analysis of medical records from the Department of Otolaryngology (September 1, 2020 - December 31, 2022) of patients diagnosed with SSNHL according to the 2015 Guidelines for Diagnosis and Treatment of Sudden Deafness in China. Peripheral blood samples from patients with various types of SSNHL before and after treatment were collected, alongside samples from healthy volunteers serving as controls. Plasma EVs were isolated using gel rejection chromatography and analyzed for concentration, marker presence, and morphology using Nanosight, Western blot, and transmission electron microscopy (TEM), respectively. Proteomics and miRNA assessments were conducted to identify differentially expressed proteins and miRNAs in the plasma EVs of SSNHL patients and healthy volunteers. Key proteins were further validated through Western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine the levels of complement C3 in plasma EVs, and correlation analyses were performed with audiological data pre- and post-treatment. RESULTS: Plasma from SSNHL patients of varying types was collected and their EVs were successfully isolated and characterized. Proteomic analysis revealed that complement C3 levels in the plasma EVs of patients with profound SSNHL were significantly higher compared to healthy controls. Differential expression of miRNAs in plasma EVs and their related functions were also identified. The study found that the level of complement C3 in plasma EVs, but not the total plasma complement C3, positively correlated with the severity of SSNHL in patients exhibiting positive therapeutic responses, particularly in those with initially lower levels of EV-associated complement C3. After treatment, complement C3 level was decreased in patients with initially higher levels of EV-associated complement C3. No significant correlation was observed between changes in plasma EV-derived complement C3 levels and the degree of hearing loss in either responders or non-responders among patients with profound SSNHL. CONCLUSION: Differential profiles of proteins and miRNAs were identified in patients with profound SSNHL. Notably, plasma EV-derived complement C3 was linked to both the severity and early treatment effectiveness of patients with profound SSNHL.

A Comprehensive Pan-Cancer Analysis of the Potential Biological Functions and Prognosis Values of RICTOR.

The importance of the network defined by phosphatidylinositol-3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) downstream of Receptor Tyrosine Kinase (RTK) has been recognized for many years. However, the central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently come to light. The function of RICTOR in pan-cancer still needs to be systematically elucidated. In this study, we examined RICTOR's molecular characteristics and clinical prognostic value by pan-cancer analysis. Our findings indicate that RICTOR was overexpressed in twelve cancer types, and a high RICTOR expression was linked to poor overall survival. Moreover, the CRISPR Achilles' knockout analysis revealed that RICTOR was a critical gene for the survival of many tumor cells. Function analysis revealed that RICTOR-related genes were mainly involved in TOR signaling and cell growth. We further demonstrated that the RICTOR expression was significantly influenced by genetic alteration and DNA-methylation in multiple cancer types. Additionally, we found a positive relationship between RICTOR expression and the immune infiltration of macrophages and cancer-associated fibroblasts in Colon adenocarcinoma and Head and Neck squamous cell carcinoma. Finally, we validated the ability of RICTOR in sustaining tumor growth and invasion in the Hela cell line using cell-cycle analysis, the cell proliferation assay, and wound-healing assay. Our pan-cancer analysis highlights the critical role of RICTOR in tumor progression and its potential as a prognostic marker for various cancer types.

Development of a Serum-Free Culture Method for Endothelial Cells of the Stria Vascularis and Their Pro-Inflammatory Secretome Changes Induced by Oxidative Stress.

OBJECTIVES: Reactive oxygen species in the stria vascularis (SV) of the cochlea may be involved in the pathogenesis of sensorineural hearing loss. However, the effects of oxidative stress on SV endothelial cells (SV-ECs) remain largely unknown, and no feasible in vitro cell culture model exists for the functional study of SV-ECs. METHODS: We isolated primary SV-ECs from the SV of neonatal mice. The apoptosis-reducing effects of fibronectin in SV-ECs cultured with serum-free medium were determined using ß-galactosidase staining and flow cytometry. SV-ECs incubated in serum-free medium were treated with various H2O2 concentrations to evaluate the effects of H2O2 on their viability. The secretome of SV-ECs treated with or without H2O2 (100 µM or 500 µM) was analyzed using high-resolution mass spectrometry. The function of the SV-EC secretome was evaluated by a macrophage assay. RESULTS: We successfully isolated and characterized the SV-ECs. Treatment with H2O2 at concentrations up to 500 µM for 2 hours and further incubation with serum-free medium in plates precoated with fibronectin showed no significant effect on apoptosis. Compared to the control SV-ECs, the amount of differential proteins in the secretome of SV-ECs stimulated with 500 µM H2O2 was much higher than in those treated with 100 µM H2O2. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses suggested that the proteins differentially expressed in SV-ECs treated with 500 µM H2O2 were involved in the regulation of multiple signaling pathways and cellular processes. The secretome of H2O2-stimulated SV-ECs exhibited significant pro-inflammatory effects on macrophages. CONCLUSION: We successfully established an in vitro serum-free culture method, identified the differential proteins released by oxidative stress-induced ECs and their functions, and revealed the pro-inflammatory effects of the secretome of H2O2-stimulated SV-ECs. Therefore, SV-ECs might elicit immunoregulatory effects on bystander cells in the microenvironment of oxidative stress-induced cochlea, especially cochlear macrophages.

Meta-Analysis Comparing Steroids and Diuretics in the Treatment of Acute Low-Tone Sensorineural Hearing Loss.

OBJECTIVE: Our objective was to perform a meta-analysis to compare the effectiveness of steroids and diuretics in the treatment of acute low-tone sensorineural hearing loss (ALHL). METHODS: PubMed, Google Scholar, and Sci databases were searched for randomized controlled trials (RCTs) examining the treatment of ALHL with steroids and diuretics. The Cochrane Reviewer's Handbook 5.0 evaluation criteria were used to evaluate the quality of the included RCTs. Meta-analysis was performed using Revman 5.3 software to compare the recovery rate of low-tone hearing levels between patients treated with steroids and diuretics. RESULTS: A total of 3 RCTs were included. There was no heterogeneity between the 3 studies (χ2 = 2.61, P = .27, I2 = 23%); thus, a fixed-effects model of analysis was used. Meta-analysis showed there was no significant difference in the recovery rate of patients treated with steroids and those treated with diuretics (odds ratio = 1.48, 95% confidence interval: 0.64-3.40, P = .36). CONCLUSION: Steroids and diuretics are equally effective for the treatment of ALHL.

Utilizing True Wireless Stereo Earbuds in Automated Pure-Tone Audiometry.

True wireless stereo (TWS) earbuds have become popular and widespread in recent years, and numerous automated pure-tone audiometer applications have been developed for portable devices. However, most of these applications require specifically designed earphones to which the public may not have access. Therefore, the present study investigates the accuracy of automated pure-tone audiometry based on TWS earbuds (Honor FlyPods). The procedure for developing an automated pure-tone audiometer is reported. Calibration of the TWS earbuds was accomplished by electroacoustic measurements and establishing corrected reference equivalent threshold sound pressure levels. The developed audiometer was then compared with a clinical audiometer using 20 hearing-impaired participants. The average signed and absolute deviations between hearing thresholds measured using the two audiometers were 3.1 dB and 6.7 dB, respectively. The overall accuracy rate in determining the presence/absence of hearing loss was 81%. The results show that the proposed procedure for an automated air-conduction audiometer based on TWS earbuds is feasible, and the system gives accurate hearing level estimation using the reported calibration framework.

Notched Sound Alleviates Tinnitus by Reorganization Emotional Center.

BACKGROUND: Tinnitus is a common disease, and sound therapy is an effective method to alleviate it. Previous studies have shown that notched sound not only changes levels of cortical blood oxygen, but affects blood oxygen in specific cerebral cortical areas, such as Brodmann area 46 (BA46), which is associated with emotion. Extensive evidence has confirmed that tinnitus is closely related to emotion. Whether notched sound plays a role in regulating the emotional center is still unclear. METHODS: This study included 29 patients with newly diagnosed chronic tinnitus who were treated with notched sound. Functional near-infrared spectroscopy (fNIRS) was conducted before and after treatment to observe bilateral changes in cortical blood oxygen in the cerebral hemispheres. We compared the changes in connectivity between the two regions of interest (the superior temporal gyrus and BA46), as wells as other cortical regions before and after treatment. RESULTS: The results showed (1) That global connectivity between the bilateral auditory cortex of the superior temporal sulcus and the ipsilateral cortex did not change significantly between baseline and the completion of treatment, and (2) That the connectivity between channel 14 and the right superior temporal sulcus decreased after treatment. The overall connectivity between the right BA46 region and the right cortex decreased after treatment, and decreases in connectivity after treatment were specifically found for channels 10 and 14 in the right parietal lobe and channels 16, 20, 21, and 22 in the frontal lobe, while there was no significant change on the left side. There were no significant changes in the questionnaire measures of tinnitus, anxiety, or depression before and after treatment. CONCLUSION: The results of the study indicate that cerebral cortex reorganization occurs in tinnitus patients after submitted to treatment with notched sound for 1 month, and that notched sound decreases the connectivity between the auditory cortex and specific brain regions. SIGNIFICANCE: Notched sound not only regulates the auditory center through lateral inhibition, but also alleviates tinnitus by reorganizing the emotional control center.

Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies.

Cisplatin is a highly effective antitumor drug generally used in the treatment of solid malignant tumors. However, cisplatin causes severe side effects such as bone marrow depression, nephrotoxicity, and ototoxicity, thus limiting its clinical application. The incidence of ototoxicity induced by cisplatin ranges from 20% to 70%, and it usually manifests as a progressive, bilateral and irreversible hearing loss. Although the etiology of cisplatin-induced ototoxicity remains unclear, an increasing body of evidence suggests that the ototoxicity of cisplatin is mainly related to the production of reactive oxygen species and activation of apoptotic pathway in cochlear tissues. Many drugs have been well proved to protect cisplatin-induced hearing loss in vitro and in vivo. However, the anti-tumor effect of cisplatin is also weakened by systemic administration of those drugs for hearing protection, especially antioxidants. Therefore, establishing a local administration strategy contributes to the otoprotection without affecting the effect of cisplatin. This review introduces the pathology of ototoxicity caused by cisplatin, and focuses on recent developments in the mechanisms and protective strategies of cisplatin-induced ototoxicity.

[The feature and distribution of functional ingredients among health food in China during 1996 to 2007--nutrients and representing substance].

OBJECTIVE: To investigate systematically the application of functional ingredients among healthy food products during 1996 to 2007, which existed from the 10 years periods by government approved, to assess the character or condition of ingredients, and analyze the reasons of it's centralization and contribution. METHODS: Data of functional/bioactive ingredients in functional/healthy food approved by government during 1996 to 2007 were recorded, and selected qualified products to built nutritional and functional ingredients database. Then, The profile map and contribution of each classified of the data was analyzed by statistics method and computer software. RESULTS: Total 9021 products were approved by gov. during 1996 to 2007, according the condition of samples, qualified 8645 products was as studied samples. The research had showed that Chinese herbs was the main port in ingredients, total 223-378 herbs were used. Nutritional and functional ingredients were second main ingredients, it was high numbers (280 more) among 8645 products. Flavonoids, Saponins and Polysaccharide are applied most widely, which is often to apply as the representing or symbolic substance when the product used a herb material as ingredient. CONCLUSION: Functional ingredients have a variegated appearance along with existent 27 function claims within regulation system. A representing substance was used as a feature that was a universality labeled to declare the characteristics or qualities of herb products. This should be individually reviewed in further and increase the technique on herb and claim.

Cortical Activation Patterns of Different Masking Noises and Correlation With Their Masking Efficacy, Determined by Functional Near-Infrared Spectroscopy.

Acoustic therapy in tinnitus treatment is poorly characterized, and efficacy assessment depends on subjective descriptions. Narrow-band noise, notched sound, and white noise have positive therapeutic effects on monotonous tinnitus. Considering the tonotopic characteristics of the auditory system and the spectral characteristics of these three masking sounds, the activation pattern of the auditory cortex and the mechanism of inhibiting tinnitus may be different. This study aimed to compare the activation patterns of three spectrally different masking noises and study the correlation between the masking effects and variational amplitude of oxygenated hemoglobin (HbO) in the corresponding cortical regions. We also assessed near-infrared spectroscopy brain function imaging (NIRS) as an objective assessment tool in acoustic therapy. Patients with persistent non-pulsatile tinnitus and control volunteers without tinnitus were enrolled in this study. The subjects were seated in a sound-proof room, with two optode arrays covering the bilateral temporal lobe. Auditory stimuli were presented; stimulation sequences followed the block design: different noises appeared randomly and repeated in five cycles. Tinnitus match and residual inhibition were performed in the tinnitus group. The data analyses were conducted using the NIRS_SPM toolbox. The group analysis results showed that the narrow-band noise caused a marginally significant decrease in HbO signal in the Brodmann 21 region (BA21), while white noise caused a significant increase in HbO signal in BA21. Notched sound did not cause significant changes in the HbO signal in the temporal cortex. And none of the three masking noises caused significant changes in the HbR signal in the temporal cortex. The depth of residual inhibition induced by the narrow-band noise and white noise significantly correlated with ΔHbO in the region of interest (ROI). However, neither the depth nor duration of the residual inhibition induced by notched sound correlated with the ΔHbO. Thus, NIRS showed three cortical activation patterns induced by three different masking noises, and correlations between residual inhibition effects and change of HbO amplitude were found. NIRS could therefore be applied in objective assessment of acoustic therapy.

Combined application of single-energy metal artifact reduction and reconstruction techniques in patients with Cochlear implants.

BACKGROUND: The purpose of this study was to develop an effective method of reducing metal artifacts in cochlear implant (CI) electrodes. METHODS: The temporal bones of 30 patients (34 ears) after CI were examined with 320-detector row computed tomography, which was evaluated by two senior radiologists using a double-blind method. Noise, artifact index, signal-to-noise ratio, and the subjective image quality score were compared before versus after using single-energy metal artifact reduction (SEMAR). The electrode position, single electrode visibility, and electrode count were evaluated using SEMAR combined with either multi-planar reconstruction (MPR) or maximum intensity projection. RESULTS: The two radiologists' measurements had good consistency. SEMAR significantly reduced the image noise and artifacts index and significantly improved the signal-to-noise ratio and subjective image quality score (P < 0.01). The combination of SEMAR with MPR was conducive to accurate assessment of electrode position and single-electrode visibility. The combination of SEMAR with MIP facilitated accurate and intuitive matching of the assessed electrode count with the number of electrodes implanted during the operation (P = 0.062). CONCLUSION: SEMAR significantly reduces metal artifacts generated by CI electrodes and improves the quality of computed tomography images. The combination of SEMAR with MPR and maximum intensity projection is beneficial for evaluating the position and number of CI electrodes.

Electrophysiologic Characteristics of Various Degrees of Selective Outer Hair Cell Loss in Rats.

HYPOTHESIS: The characteristics of auditory brainstem response (ABR), electrocochleogram (ECochG), and distortion product otoacoustic emissions (DPOAE) of different degrees of selective outer hair cells (OHCs) loss may be helpful for clinicians to evaluate the pathogeny, diagnosis, and rehabilitation of individuals' hearing loss. BACKGROUND: How many OHCs are necessary to maintain cochlear amplifier function remains unknown. The electrophysiologic characteristics may indicate different degrees of OHCs loss. METHODS: Electrophysiological characteristics were tested using 8-kHz pure-tone stimulus and OHCs counted specifically in the region of the cochlea corresponding to 8-kHz. Rat models of selective OHCs loss were established by injecting kanamycin (KM) at various dosages, and the region of 8-kHz was obtained by 8-kHz pure-tone exposure. RESULTS: The ABR thresholds were affected slightly with OHCs loss < 30%, and were increased dramatically with OHCs loss ranging from 30 to 70%, but the thresholds did not increase further when OHCs loss exceeded 70%. As OHCs loss increased, the compound action potential (CAP) amplitude decreased. The CAP amplitude and OHCs loss were negatively correlated. Moreover, the summating potential (SP)/action potential (AP) increased as OHCs loss increased. DPOAE and cochlear microphonics (CM) exhibited reduced amplitudes when OHCs loss < 30%. CONCLUSIONS: Electrophysiologic characteristics may indicate different degrees of OHCs loss. While OHCs loss > 70%, the cochlear amplification may lose completely, but it is difficult to detect OHCs loss < 30%, because the ABR or DPOAE may reveal "normal" at this level. Moreover, the decreased CAP amplitude or increased SP/AP may be indicators for OHCs loss.