Audiologic Status of Children with Confirmed Cytomegalovirus Infection: a Case Series.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of sensorineural hearing loss (SHNL) in children. Only about 10% to 15% of children with congenital CMV are symptomatic, and most are not diagnosed at birth. About 7% to 15% of clinically asymptomatic patients may develop later complications, including SNHL, which is the most common sequela in clinically asymptomatic patients. In this study, hearing status was investigated in children with confirmed CMV infection and neonatal hearing screening (NHS) histories were reviewed to explore hearing loss caused by CMV. METHODS: The medical records of 58 children who were diagnosed with confirmed CMV infection were reviewed for clinical symptoms and signs of CMV infection. Hearing status was evaluated with age-appropriate audiological test batteries. RESULTS: A total of 58 children (M:F = 32:26 patients; age at study: mean, 5.62 years, range, 1-10 years) were diagnosed serologically with CMV infection (14 patients, 21.1%), or diagnosed via PCR of serum (5, 7.9%) and/or PCR from urine (19, 26.8%). Hearing loss was confirmed in 11 children (19.0%), being bilateral in 6 (54.5%), and unilateral in 5 (45.5%). Note that 7 of 17 ears with hearing loss passed NHS and were diagnosed only after re-evaluation when CMV infection was identified. CONCLUSION: Hearing loss is a serious complication of CMV infection in children. Our results highlight the importance of timely audiological evaluation in children with clinically symptomatic CMV infection even if they pass NHS.

Association Between Hearing Impairment and Incident Depression: A Nationwide Follow-up Study.

BACKGROUND: Accumulating evidence suggests that hearing impairment is associated with the onset of depression. However, large-scale epidemiological studies are required to define this association more clearly. We aimed to investigate the risk of new-onset depression in Korean older adults with and without hearing impairment. METHODS: From the National Health Insurance Service-Senior Cohort, which is a retrospective-prospective hybrid database, we analyzed data for 254,466 older adults enrolled in the Korea National Health Insurance Service-Senior Cohort who underwent at least one health screening between 2003 and 2019. A Cox proportional hazards regression model was used to evaluate the association between hearing impairment and the risk of incident depression, which was presented as adjusted hazard ratios (aHR) with 95% confidence intervals (CIs). All participants were followed up until the date of incident depression, death, or December 31, 2019. RESULTS: During 3,417,682 person-years of follow-up investigation, hearing impairment was associated with a higher risk of incident depression (vs. no hearing impairment) in the final adjusted model (aHR, 1.11; 95% CI, 1.01-1.21; p = 0.033). Stratified analyses revealed a significant interaction among age, hearing impairment, and the risk of depression. Participants aged <65 years had a higher risk of depression (aHR, 1.29; 95% CI, 1.12-1.50; p < 0.001) than those aged 65 or above (aHR, 1.15; 95% CI, 1.01-1.30; p = 0.032). CONCLUSIONS: Hearing impairment is independently associated with a higher risk of depression among older adults. The prevention and treatment of hearing impairment may aid in mitigating the risk of incident depression. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:3144-3151, 2023.

Dysadherin expression promotes the motility and survival of human breast cancer cells by AKT activation.

High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho-AKT. The introduction of dysadherin cDNA into BT-474, MCF-7 and T-47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA-MB-231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin-mediated pro-metastatic effects, including epithelial-mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation.

Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is associated with a high potential for metastasis and disease recurrence, even after surgical resection. The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for chemo-resistance, recurrence, and metastasis. Dysadherin is a prognostic indicator of metastasis and poor survival in many different cancer types. In this study, we investigated the possible link between dysadherin and CSC in HCC. METHODS: We analyzed the functional implications of dysadherin on cancer stemness by modification of the dysadherin gene in HCC cell lines. RESULTS: The transfection of dysadherin cDNA into the liver cancer cell line PLC/PRF/5 enhanced the properties of CSCs, including anti-apoptosis, their sphere-forming ability, side population phenotype, and tumor initiation ability in vivo. Furthermore, knockdown of dysadherin in the liver cancer cell line SK-Hep1 suppressed its stem cell-like properties. CONCLUSIONS: These results show that dysadherin give rise to properties of CSC in HCC. Therefore, these findings suggest that dysadherin may be a potential molecular prognostic marker of HCC and may aid in the development of more effective therapies.

Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma.

UNLABELLED: Although hepatitis B virus X protein (HBx) has been implicated in abnormal lipid metabolism in hepatitis B virus (HBV)-associated hepatic steatosis, its underlying molecular mechanism remains unclear. Liver X receptor (LXR) plays an important role in regulating the expression of genes involved in hepatic lipogenesis. Here we demonstrate that LXRalpha and LXRbeta mediate HBV-associated hepatic steatosis. We have found that HBx induces the expression of LXR and its lipogenic target genes, such as sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and peroxisome proliferator-activated receptor, and this is accompanied by the accumulation of lipid droplets. RNA interference with LXR expression decreases the amount of lipid droplets as well as the expression of the lipogenic genes, and this indicates that HBx-induced lipogenesis is LXR-dependent. LXRalpha and HBx colocalize in the nucleus and are physically associated. HBx induces the transactivation function of LXRalpha by recruiting CREB binding protein to the promoter of the target gene. Furthermore, we have observed that expression of LXR is increased in the livers of HBx-transgenic mice. Finally, there is a significant increase in the expression of LXRbeta (P = 0.036), SREBP-1c (P = 0.008), FAS, and stearoyl-coenyzme A desaturase-1 (P = 0.001) in hepatocellular carcinoma (HCC) in comparison with adjacent nontumorous nodules in human HBV-associated HCC specimens. CONCLUSION: Our results suggest a novel association between HBx and LXR that may represent an important mechanism explaining HBx-induced hepatic lipogenesis during HBV-associated hepatic carcinogenesis.

Clusterin is highly expressed in tubular complexes during spontaneous pancreatitis of spontaneous hypertensive rats.

Pancreatitis is an inflammatory disorder of pancreas which leads to varying degrees of pancreatic endocrine and exocrine dysfunction and manifests in either acute or chronic forms. Spontaneous pancreatitis in experimental animals has rarely been reported. Here, we found acute to chronic courses of spontaneous pancreatitis in spontaneously hypertensive rats (SHRs), showing the formation of tubular complexes (TCs) and enhanced islet regeneration. We investigated the expression pattern of clusterin in the pancreas of SHRs based on immunohistochemistry (IHC). IHC analysis revealed the strong expression of clusterin in dedifferentiated duct-like cells and regenerative islets of TCs. These results imply that clusterin might be involved in the formation of TCs and parenchymal regeneration during rat pancreatitis.

Role of Emotional Distress in Prolongation of Dizziness: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Dizziness is a common condition in outpatient clinics. Comorbid conditions such as anxiety and/or depression often complicate a patient's ability to cope with dizziness. The purpose of the present study was to explore the extent of psychiatric distress using the Hospital Anxiety and Depression Scale (HADS) and to compare the results with the subjective severity of dizziness. SUBJECTS AND METHODS: The cross-sectional study included a total of 456 consecutive patients presenting with acute (n=327) and chronic (n=127) dizziness symptoms. The HADS was used to estimate emotional distress and compare between patients with acute and chronic dizziness symptoms. Also, we calculated correlations between subjective dizziness handicap scores and emotional distress using the total and subscale scores of the Dizziness Handicap Inventory (DHI), Disability Scale (DS), and HADS. RESULTS: The HADS total and subscale scores were significantly increased in patients with chronic dizziness (p<0.01) compared with those with acute symptoms. In patients with symptoms of both acute and chronic dizziness, moderate correlations were evident between the DHI and HADS total scores. When we compared DHI subscale scores with the HADS scores, the emotional DHI subscale scores correlated more highly with the HADS total scores and the scores on the anxiety and depression subscales, than did the functional or physical DHI subscale scores. CONCLUSIONS: Increased levels of distress measured using the HADS in patients with chronic symptoms suggest that emotional status of the patients may contribute to prolongation of dizziness symptoms from the acute phase.

Hearing Preservation During Cochlear Implantation and Electroacoustic Stimulation in Patients With SLC26A4 Mutations.

BACKGROUND AND OBJECTIVES: Patients with SCL26A4 mutations presenting with Mondini deformity and enlarged vestibular aqueduct (EVA) tend to have comparable residual hearing. Although cochlear implantation (CI) produces good results in this group, deterioration of residual hearing can be an adverse event after surgery due to accompanying cochlear malformation and perilymph leakage during cochleostomy. The purpose of this study was to investigate if CI in patients with SCL26A4 mutations via the round window (RW) approach could achieve preservation of residual hearing, and to evaluate their speech reception with electroacoustic stimulation (EAS). SUBJECTS AND METHODS: This is a retrospective chart review of eight patients with bilateral EVA, who were bi-allelic patients with SCL26A4 mutations. CI was performed in all patients by a single surgeon using the RW approach. Audiological results were compared before and after implantation. RESULTS: Additional hearing loss after CI was less than 10 dBHL in five out of eight patients. Average hearing deterioration after CI was 8.75 dB (range, 0-26). Six out of eight patients used EAS mode after CI. The acoustic stimulation frequency ranged from 271 to 438 Hz. Patients showed better speech recognition in quiet and in noise using EAS mode compared with electrical stimulation alone. CONCLUSIONS: Preservation of residual hearing could be achieved after CI in patients with the SLC26A4 mutation via the RW approach. For successful preservation of residual hearing, application of newly-developed soft electrode and meticulous surgical is necessary. Our study showed that patients with the SLC26A4 mutation can be good candidates for EAS surgery.

Improvement of sudden bilateral hearing loss after vertebral artery stenting.

Bilateral deafness is a rare but possible symptom of vertebrobasilar ischemia. We report a case of sudden bilateral sensorineural hearing loss caused by bilateral vertebral artery (VA) occlusion which dramatically improved after stenting. A 54-year-old man was admitted with sudden onset of bilateral deafness, vertigo, and drowsy mental status. Brain diffusion-weighted MRI showed acute infarction involving both the posterior inferior cerebellar artery and left posterior cerebral artery territory. Cerebral angiography showed bilateral distal VA occlusion, and emergency intracranial stenting was performed in the left VA. After reperfusion therapy his symptoms gradually improved, including hearing impairment. Endovascular stenting may be helpful in a patient with sudden deafness caused by bilateral VA occlusion.

Audiologic limitations of Vibrant Soundbridge device: Is the contralateral hearing aid fitting indispensable?

OBJECTIVES/HYPOTHESIS: The purpose of this study was to evaluate the audiologic limitations of the Vibrant Soundbridge (VSB) implant and the benefits of contralateral hearing aid (HA) fitting in VSB recipients. STUDY DESIGN: Retrospective study. METHODS: Twenty-three patients with symmetrical sensorineural or mixed hearing loss were enrolled in this study. The patients underwent VSB implantation in one ear and HA fitting in the other. Aided pure-tone audiometry was performed to measure the functional gains of each device. The Korean version of the Hearing in Noise Test (K-HINT) was used to determine the sentence speech perception in a quiet environment and the signal-to-noise ratio (SNR) in a noisy environment. RESULTS: VSB implantation resulted in hearing gains comparable to that of conventional HAs at high frequencies, whereas the functional gains at low frequencies were not satisfactory in the mixed hearing loss group. In these patients, the contralateral HA sufficiently amplified the low frequencies. The results of the K-HINT of the SNR in the VSB-aided ear were not significantly improved when compared to HA-aided contralateral ear. However, binaural fitting of a VSB and HA resulted in substantially improved SNR when compared to the unaided condition. This improvement of the SNR strongly correlated with functional gains at low frequencies in the contralateral HA-aided ear. CONCLUSIONS: Although unilateral VSB implantation is limited in terms of low-tone enhancement and speech perception in noisy environments, contralateral HA fitting can overcome these limitations and increase the efficacy of hearing rehabilitation. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2116-2123, 2016.

Early deterioration of residual hearing in patients with SLC26A4 mutations.

OBJECTIVES/HYPOTHESIS: To compare changes in hearing in patients with SLC26A4 during early and late childhood. STUDY DESIGN: Retrospective chart review. METHODS: A total of 102 patients with biallelic SLC26A4 mutations visited the tertiary referral otolaryngology department between March 2005 and February 2015. Newborn hearing screening tests had been performed on 22 of these patients. We analyzed 26 patients who underwent hearing tests more than twice using the same method (auditory brainstem response/auditory steady state response/play audiometry) before and after 3 years of age. We analyzed changes in hearing levels according to age. RESULTS: Among 22 patients with SLC26A4 mutations who underwent newborn hearing screening tests, seven (31.8%) passed the newborn hearing screening test in both ears, and six (27.3%) passed in one ear. Among 16 patients with SLC26A4 mutations who underwent hearing tests more than twice before age 3 years, the hearing levels of 14 (87.5%) deteriorated rapidly during this time. Among 16 patients with SLC26A4 mutations who underwent hearing tests more than twice after the age of 3 years, two (12.5%) patients' hearing levels deteriorated; the hearing levels of most of the patients were relatively stable. CONCLUSIONS: These data suggest that many patients with SLC26A4 mutations have significant residual hearing at birth, and that the hearing deterioration in these patients occurs before 3 years of age. After age 3 years, the residual hearing was relatively stable and did not tend to deteriorate. Therefore, in patients with a pendrin mutation, early intervention to preserve residual hearing should be a clinical focus. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E286-E291, 2016.

Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells.

Thiazolidinediones, synthetic ligands of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), improve peripheral insulin sensitivity and glucose-stimulated insulin secretion in pancreatic beta-cells. To explore the role of PPAR-gamma in glucose sensing of beta-cells, we have dissected the beta-cell-specific glucokinase (betaGK) promoter, which constitutes glucose-sensing apparatus in pancreatic beta-cells, and identified a peroxisomal proliferator response element (PPRE) in the promoter. The betaGK-PPRE is located in the region between +47 and +68 bp. PPAR-gamma/retinoid X receptor-alpha heterodimer binds to the element and activates the betaGK promoter. The betaGK promoter lacking or having mutations in PPRE cannot be activated by PPAR-gamma. PPAR-gamma activates the betaGK promoter in beta-cells as well as non-beta-cells. Furthermore, troglitazone increases endogenous GK expression and its enzyme activity in beta-cell lines. These results indicate that PPAR-gamma can regulate GK expression in beta-cells. Taking these results together with our previous work, we conclude that PPAR-gamma regulates gene expression of glucose-sensing apparatus and thereby improves glucose-sensing ability of beta-cells, contributing to the restoration of beta-cell function in type 2 diabetic subjects by troglitazone.

Improvement of sudden bilateral hearing loss after vertebral artery stenting.

Bilateral deafness is a rare but possible symptom of vertebrobasilar ischemia. We report a case of sudden bilateral sensorineural hearing loss caused by bilateral vertebral artery (VA) occlusion which dramatically improved after stenting. A 54-year-old man was admitted with sudden onset of bilateral deafness, vertigo, and drowsy mental status. Brain diffusion-weighted MRI showed acute infarction involving both the posterior inferior cerebellar artery and left posterior cerebral artery territory. Cerebral angiography showed bilateral distal VA occlusion, and emergency intracranial stenting was performed in the left VA. After reperfusion therapy his symptoms gradually improved, including hearing impairment. Endovascular stenting may be helpful in a patient with sudden deafness caused by bilateral VA occlusion.

Long-Term Outcomes of Acute Low-Tone Hearing Loss.

BACKGROUND AND OBJECTIVES: Although acute low-tone hearing loss has been associated with cochlear hydrops or early stage Meniere's disease, its prognosis in the short-term has been reported to be better than sudden hearing loss. However, recurrence of hearing loss and possible progression to Meniere's disease remain important concerns in the clinical setting. This study aims to investigate the long-term audiological outcomes of acute low-tone hearing loss. SUBJECTS AND METHODS: A retrospective review of patients presenting with a first attack of acute low-tone hearing loss was performed. Of the 77 patients, 33 were followed up for more than 3 months. Progression, recovery of hearing loss and recurrence of hearing loss were examined. Also, correlation between long-term outcomes and associated clinical factors were analyzed. RESULTS: Twenty-five patients (75.7%) had complete hearing recovery, five patients (15.1%) had partial recovery, two patients (6.0%) had no recovery, and one patient (3.0%) had progression of hearing loss 1 month after initial treatment. Thirty-three patients were followed up for more than 3 months (mean 22 months, range 3-79 months). Recurrences of acute low-tone hearing loss were observed in five patients (15.2%). All of the recurrences occurred during the first 12 months of follow-up. Long-term prognosis correlated with the initial therapy results (R(2)=0.693). CONCLUSIONS: Recurrences of hearing loss were documented in five patients (15.2%), and all of these cases occurred within one year of the first attack. Audiological outcomes after initial therapy may predict the recurrence of acute low-tone hearing loss.

A Case of Incus Vibroplasty: Postoperative Changes in Residual Hearing.

In patients with mild to severe hearing loss, conventional hearing aids offer limited benefits and several problems with feedback and cosmesis. Middle ear implants are a feasible option for patients with moderate to severe hearing loss who are unable to achieve adequate benefit from or cannot tolerate hearing aids for various reasons. Here we present a case of middle ear implant surgery using Vibrant Soundbridge with incus vibroplasty technique, and describe the hearing changes during postoperative follow-up.

Electrogenic transport and K(+) ion channel expression by the human endolymphatic sac epithelium.

The endolymphatic sac (ES) is a cystic organ that is a part of the inner ear and is connected to the cochlea and vestibule. The ES is thought to be involved in inner ear ion homeostasis and fluid volume regulation for the maintenance of hearing and balance function. Many ion channels, transporters, and exchangers have been identified in the ES luminal epithelium, mainly in animal studies, but there has been no functional study investigating ion transport using human ES tissue. We designed the first functional experiments on electrogenic transport in human ES and investigated the contribution of K(+) channels in the electrogenic transport, which has been rarely identified, even in animal studies, using electrophysiological/pharmacological and molecular biological methods. As a result, we identified functional and molecular evidence for the essential participation of K(+) channels in the electrogenic transport of human ES epithelium. The identified K(+) channels involved in the electrogenic transport were KCNN2, KCNJ14, KCNK2, and KCNK6, and the K(+) transports via those channels are thought to play an important role in the maintenance of the unique ionic milieu of the inner ear fluid.

Obesity Resistance and Enhanced Insulin Sensitivity in Ahnak-/- Mice Fed a High Fat Diet Are Related to Impaired Adipogenesis and Increased Energy Expenditure.

OBJECTIVE: Recent evidence has suggested that AHNAK expression is altered in obesity, although its role in adipose tissue development remains unclear. The objective of this study was to determine the molecular mechanism by which Ahnak influences adipogenesis and glucose homeostasis. DESIGN: We investigated the in vitro role of AHNAK in adipogenesis using adipose-derived mesenchymal stem cells (ADSCs) and C3H10T1/2 cells. AHNAK-KO male mice were fed a high-fat diet (HFD; 60% calories from fat) and examined for glucose and insulin tolerances, for body fat compositions, and by hyperinsulinemic-euglycemic clamping. Energy expenditures were assessed using metabolic cages and by measuring the expression levels of genes involved in thermogenesis in white or brown adipose tissues. RESULTS: Adipogenesis in ADSCs was impaired in AHNAK-KO mice. The loss of AHNAK led to decreased BMP4/SMAD1 signaling, resulting in the downregulation of key regulators of adipocyte differentiation (P<0.05). AHNAK directly interacted with SMAD1 on the Pparγ2 promoter. Concomitantly, HFD-fed AHNAK-KO mice displayed reduced hepatosteatosis and improved metabolic profiles, including improved glucose tolerance (P<0.001), enhanced insulin sensitivity (P<0.001), and increased energy expenditure (P<0.05), without undergoing alterations in food intake and physical activity. CONCLUSION: AHNAK plays a crucial role in body fat accumulation by regulating adipose tissue development via interaction with the SMAD1 protein and can be involved in metabolic homeostasis.

Induction of telomerase activity during an early burst of proliferation in pancreatic regeneration.

Telomerase activity (TA) and telomerase reverse transcriptase (rTERT) were investigated in Sprague-Dawley rats, killed at 6 and 12 h, and 1, 2, 3, 7, and 14 days after 90% pancreatectomy (px), by TRAPeze enzyme-linked immunosorbent assay telomerase detection and reverse transcriptase-polymerase chain reaction. TA increased at 2 days and reached a maximum at 3 days after px, when the small ductules showed the highest proliferation activity. After 3 days, TA decreased to basal levels as the ductules differentiated into new endocrine and exocrine pancreas. The expression of rTERT showed a correlation with TA. These results suggest telomerase is actively regulated during pancreatic regeneration.

High aldehyde dehydrogenase activity enhances stem cell features in breast cancer cells by activating hypoxia-inducible factor-2α.

High aldehyde dehydrogenase (ALDH) activity has been recognized as a marker of cancer stem cells (CSCs) in breast cancer. In this study, we examined whether inhibition of ALDH activity suppresses stem-like cell properties in a 4T1 syngeneic mouse model of breast cancer. We found that ALDH-positive 4T1 cells showed stem cell-like properties in vitro and in vivo. Blockade of ALDH activity reduced the growth of CSCs in breast cancer cell lines. Treatment of mice with the ALDH inhibitor diethylaminobenzaldehyde (DEAB) significantly suppressed 4T1 cell metastasis to the lung. Recent evidence suggests that ALDH affects the response of stem cells to hypoxia; therefore, we examined a possible link between ALDH and hypoxia signaling in breast cancer. Hypoxia-inducible factor-2α (HIF-2α) was highly dysregulated in ALDH-positive 4T1 cells. We observed that ALDH was highly correlated with the HIF-2α expression in breast cancer cell lines and tissues. DEAB treatment of breast cancer cells reduced the expression of HIF-2α in vitro. In addition, reduction of HIF-2α expression suppressed in vitro self-renewal ability and in vivo tumor initiation in ALDH-positive 4T1 cells. Therefore, our findings may provide the evidence necessary for exploring a new strategy in the treatment of breast cancer.

Ras activation contributes to the maintenance and expansion of Sca-1pos cells in a mouse model of breast cancer.

The cancer stem cell (CSC) hypothesis proposes that CSCs are the root of cancer and cause cancer metastasis and recurrence. In this study, we examined whether Ras signaling is associated with stemness of the CSCs population characterized by the stem cell antigen (Sca-1) phenotype in a 4T1 syngeneic mouse model of breast cancer. The Sca-1(pos) putative CSCs had high levels of activated Ras and phosphorylated MEK (p-MEK), compared with counterparts. The Ras farnesylation inhibitor (FTI-277) suppressed the maintenance and expansion of CSCs. Therefore, selective inhibition of Ras activation may be useful for stem-specific cancer therapy.