Numerical Investigation of Layered Homogeneous Skull Model for Simulations of Transcranial Focused Ultrasound.

BACKGROUND AND OBJECTIVES: The influence of the intracranial pressure field must be discussed with the development of a single-element transducer for low-intensity transcranial focused ultrasound because the skull plays a significant role in blocking and dispersing ultrasound wave propagation. Ultrasound propagation is mainly affected by the structure and acoustic properties of the skull; thus, we aimed to investigate the impact of simplifying the acoustic properties of the skull on the simulation of the transcranial pressure field to present guidance for efficient skull modeling in full-wave simulations. MATERIALS AND METHODS: We constructed a three-dimensional computational model for ultrasound transmission with the same structure but varying acoustic properties of the skull. The structural information and heterogeneous acoustic properties of the skull were acquired from computed tomography images, and we segmented the skull into three layers (3 L), including spongy and compact bones. We then assigned homogeneous acoustic properties to a single layer (1 L) or 3 L of the skull. In addition, we investigated the influence of different types of transducers and different ultrasound frequencies (1.1 MHz, 0.5 MHz, and 0.25 MHz) on the intracranial pressure field to provide a comparison of the heterogenous and homogeneous models. RESULTS: We indicated the importance of numerical simulations in estimating the intracranial pressure field of the skull owing to beam distortions. When we simplified the skull model, both the 1 L and 3 L models showed contours of the acoustic focus comparable to those of the heterogeneous model. When we evaluated the peak pressure and volume of the acoustic focus, the 1 L model produced a better estimation of peak pressure with a difference <10%, and the 3 L model is suitable to obtain smaller errors in the volume of the acoustic focus. CONCLUSIONS: In conclusion, we examined the possibility of simplification of skull models using 1 L and 3 L homogeneous properties in the numerical simulation for focused ultrasound. The results show that the layered homogeneous model can provide characteristics comparable to those of the acoustic focus in heterogeneous models.

Improvement of morning headache in adults with obstructive sleep apnea after positive airway pressure therapy.

The aim of this study was to evaluate the association between obstructive sleep apnea and morning headache and to assess the improvement of morning headache following positive airway pressure therapy. One hundred and sixteen participants were enrolled in this study; all of them received positive airway pressure therapy for at least 3 months. We checked the differences in various sleep apnea-related parameters according to the presence of morning headache and evaluated the improvement of morning headache following positive airway pressure therapy. Among the 116 study participants, 103 were men, with a mean age and body mass index of 50.34 ± 10.23 years and 28.00 ± 4.21 kg/m2, respectively. The severity of morning headache was higher in the severe obstructive sleep apnea group than in the mild to moderate group (2.16 ± 1.70 vs. 1.50 ± 1.57, P = 0.027). However, the various polysomnographic parameters did not significantly differ according to the presence of headache. The Epworth sleepiness scale score was significantly higher in the morning headache presence group than in the absence group (10.90 ± 5.45 vs. 8.13 ± 4.27, P = 0.003). Furthermore, a notable correlation was observed between the reduction in daytime sleepiness and the improvement in morning headache following PAP treatment (r = 0.503, P < 0.001). Morning headache significantly improved following positive airway pressure therapy (prevalence: 53.4-16.4%; severity: 1.92 ± 1.67 vs. 0.86 ± 0.80, all P < 0.001), especially in the patients with morning headache before positive airway pressure therapy. Morning headache is significantly associated with daytime sleepiness and positive airway pressure therapy improves morning headache.

Hydrogen peroxide attenuates rhinovirus-induced anti-viral interferon secretion in sinonasal epithelial cells.

Background: Altered innate defense mechanisms, including an imbalance between oxidants and antioxidants release, have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). The aim of this study is to investigate whether oxidative stress may attenuate the secretion of anti-viral interferons in human sinonasal mucosa. Methods: The levels of H2O2 in nasal secretion were increased in patients with CRS with nasal polyps, compared with that of CRS patients without nasal polyps and control subjects. Normal sinonasal epithelial cells derived from healthy subjects were cultured under an air-liquid interface. The cultured cells were infected with rhinovirus 16 (RV 16) or treated with poly (I: C), TLR3 agonist, after being pretreated with an oxidative stressor, H2O2 or antioxidant, N-acetylcysteine (NAC). Thereafter, the expression levels of type I (IFN-ß) and type III (IFN-λ1 and λ2) interferons and interferon-stimulated genes (ISGs) were evaluated with RT-qPCR, ELISA, and western blot. Results: The data showed that the production of type I (IFN-ß) and type III (IFN-λ1 and λ2) interferons and ISGs was upregulated in cells infected with RV 16 or treated with poly (I: C). However, their up-regulated expression was attenuated in cells pretreated with H2O2, but not inhibited in cells pretreated with NAC. In line with these data, the up-regulated expression of TLR3, RIG-1, MDA5, and IRF3 was reduced in cells pretreated with H2O2, but not attenuated in cells treated with NAC. Furthermore, cells transfected with Nrf2 siRNA showed decreased secretion of anti-viral interferons whereas sulforaphane treatment enhanced the secretory capacity of antiviral interferons. Conclusions: These results suggest that the production of RV16-induced antiviral interferons may be attenuated by oxidative stress.

Methylene Blue Delivery Mediated by Focused Ultrasound-Induced Blood-Brain Barrier Disruption Reduces Neural Damage and Amyloid-Beta Plaques by AQP-4 Upregulation.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, causing progressive cognitive decline, memory impairment, and neurological deficits. Methylene blue (MB), an antioxidant, has emerged as a potential drug for the treatment of AD owing to its cognitive improvement and neuroprotective functions. Despite the small molecular size of MB, which can cross the BBB, the therapeutic effective dosage using a BBB-permeable delivery system in a specific brain localization remains unclear. In this study, we presented magnetic resonance-guided focused ultrasound (MRgFUS) as a delivery system to enhance BBB permeability for the effective treatment of AD. MRgFUS using two ultrasound intensities (0.25 and 0.32 MPa) was used to intravenously deliver MB to the hippocampal region. Compared with treatment with 0.25 MPa FUS, treatment with 0.32 MPa FUS significantly enhanced MB brain accumulation. Deposition of amyloid-ß (Aß) plaques and neural cell damage was significantly reduced in 0.32 MPa FUS/MB-treated APP/PS1 mice. Furthermore, aquaporin-4 expression increased significantly in the 0.32 MPa FUS and 0.32 MPa FUS/MB groups without glial fibrillary acidic protein activation. The results from this study demonstrate that FUS improved MB delivery to the brain, and FUS/MB combination treatment reduced the number of Aß plaques. This study revealed the potential of FUS-BBBD as an effective strategy to enhance the efficacy of therapeutic drugs for AD.

The new insight into the inflammatory response following focused ultrasound-mediated blood-brain barrier disruption.

BACKGROUND: Despite the great potential of FUS-BBB disruption (FUS-BBBD), it is still controversial whether FUS-BBBD acts as an inducing factor of neuro-inflammation or not, and the biological responses after FUS-BBBD triggers the inflammatory process are poorly understood. The aim of this study is to investigate the safety window for FUS levels based on a comprehensive safety assessment. METHODS: The mice were treated with two different ultrasound parameters (0.25 MPa and 0.42 MPa) in the thalamus region of brain. The efficacy of BBB opening was verified by dynamic contrast-enhanced MRI (DCE-MRI) and the cavitation monitoring. The transcriptome analysis was performed to investigate the molecular response for the two BBBD conditions after FUS-mediated BBB opening in time-dependent manners. Histological analysis was used for evaluation of the tissue damage, neuronal degeneration, and activation of glial cells induced by FUS-BBBD. RESULTS: The BBBD, as quantified by the Ktrans, was approximately threefold higher in 0.42 MPa-treated group than 0.25 MPa-treated group. While the minimal tissue/cellular damage was found in 0.25 MPa-treated group, visible damages containing microhemorrhages and degenerating neurons were detected in 0.42 MPa-treated group in accordance with the extent of BBBD. In transcriptome analysis, 0.42 MPa-treated group exhibited highly dynamic changes in the expression levels of an inflammatory response or NF-κB pathway-relative genes in a time-dependent manner whereas, 0.25 MPa was not altered. Interestingly, although it is clear that 0.42 MPa induces neuroinflammation through glial activation, neuroprotective properties were evident by the expression of A2-type astrocytes. CONCLUSIONS: Our findings propose that a well-defined BBBD parameter of 0.25 MPa could ensure the safety without cellular/tissue damage or sterile inflammatory response in the brain. Furthermore, the fact that the excessive sonication parameters at 0.42 MPa could induce a sterile inflammation response via glial activation suggested the possibility that could lead to tissue repair toward the homeostasis of the brain microenvironment through A2-type reactive astrocytes.

Rhinovirus-induced anti-viral interferon secretion is not deficient and not delayed in sinonasal epithelial cells of patients with chronic rhinosinusitis with nasal polyp.

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 stimulation with poly (I: C) in normal and inflammatory epithelial cells. Inflammatory epithelial cells were obtained from CRS patients with nasal polyps and normal epithelial cells were derived from ethmoid sinus mucosa during endoscopic reduction of blowout fracture or uncinate process mucosa of patients with septal deviation. Cultured cells were infected with RV 16 or treated with poly (I: C) for 24, 48, and 72 h. Cells and media were harvested at each time point and used to evaluate RV16 replication rates, the secretion of IFN-ß, -λ1, -λ2, viperin, Mx, and OAS, and the expression levels of TRL3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3. RV replication rates reached peak levels 48 h after inoculation in both normal and inflammatory epithelial cells and showed no difference between both groups of epithelial cells at any time point. The release of IFN-ß, -λ1, and -λ2 in normal and inflammatory epithelial cells was also strongly induced 48 h after RV16 inoculation but reached peak levels 24 h after poly (I: C) treatment. The expression levels of viperin, Mx, OAS, TLR3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3 showed similar patterns in both groups of epithelial cells. These results suggest that the production of RV16-induced antiviral interferons is not deficient or delayed in inflammatory epithelial cells from CRS patients with nasal polyps.

Novel Animal Model of Spontaneous Cerebral Petechial Hemorrhage Using Focused Ultrasound in Rats.

Background and Objectives: Petechial cerebral hemorrhages can be caused by various factors, such as traumas, cerebral infarctions, and aging, and is related to the disruption of the blood-brain barrier or the cellular damage of blood vessels. However, there is no animal model that recapitulates cerebral petechial hemorrhages. Materials and Methods: Here, we implemented a petechial hemorrhage using a novel technology, i.e., microbubble-assisted focused ultrasound (MB + FUS). Results: This method increases the permeability of the blood-brain barrier by directly applying mechanical force to the vascular endothelial cells through cavitation of the microbubbles. Microbubble-enhanced cavitation has the advantage of controlling the degree and location of petechial hemorrhages. Conclusions: We thus generated a preclinical rat model using noninvasive focal MB + FUS. This method is histologically similar to actual petechial hemorrhages of the brain and allows the achievement of a physiologically resembling petechial hemorrhage. In the future, this method shall be considered as a useful animal model for studying the pathophysiology and treatment of petechial cerebral hemorrhages.

Ultrasound stimulation improves inflammatory resolution, neuroprotection, and functional recovery after spinal cord injury.

Spinal cord injury (SCI) is associated with limited functional recovery. Despite advances in neuroscience, realistic therapeutic treatments for SCI remain unavailable. In this study, the effects of non-invasive ultrasound (US) treatment on behavior and inflammatory responses were evaluated in a rat model of SCI. Adult female Sprague-Dawley rats were subjected to spinal cord contusion injury. Two different US parameters (SCIU5: 5% and SCIU40: 40% duty cycle) were applied, and their effects on behavioral recovery after SCI were quantified. Tissue and neuronal responses were detected. Immunofluorescence was used to detect inflammatory markers. In the rat model of SCI, motor function was more effectively restored, and the lesion cavity area was smaller in the SCIU5 group. Furthermore, the SCIU5 protocol elicited an anti-inflammatory response at the injury site by reducing degenerative FJC-labeled neurons, macrophage/microglia activation, and infiltration. Thus, the lesion area decreased, and tissue density increased. Meanwhile, the SCIU40 protocol did not improve motor function or induce an anti-inflammatory response at the injury site. The SCIU5 protocol effectively accelerated the rate of improved exercise performance in the rat model while reducing inflammation. Accordingly, appropriate US stimulation may represent a promising treatment modality for SCI with beneficial anti-inflammatory effects.

Long-Term Outcomes of Nasoseptal Perforation Repair Using Anterior Maxillary Sinus Wall as an Interpositional Graft.

BACKGROUND: Various graft materials have been used to repair nasoseptal perforation, but there is no standardized treatment method. The anterior maxillary sinus wall is flattened in appearance and can be easily obtained in a sufficient amount for a large-sized nasoseptal perforation. OBJECTIVES: The aim of this study is to determine whether the anterior maxillary sinus wall is suitable as an interpositional graft in the surgical repair of septal or nasoseptal perforation. METHODS: This is a retrospective review of 21 patients who underwent repair of nasoseptal perforation using anterior maxillary sinus wall as an interpositional graft. The etiology, pre- and post-operative NOSE and GBI score, and perforation size were reviewed. The surgical outcome was considered successful if total closure was achieved after postoperative follow-up. RESULTS: 19 of the 21 perforations were successfully repaired with anterior maxillary sinus wall. Failure of the repair was found in 2 patients. Causal etiology of perforation was previous septoplasty in 10 patients, and electrocautery in 1 case, but not identified in 10 cases. The largest size was 2.7 × 2.2 cm. The most common symptoms were epistaxis, crusting, and nasal obstruction. Closure of septal perforation resulted in improved subjective symptoms and quality of life which were evaluated with NOSE and GBI score. CONCLUSION: Anterior maxillary sinus wall as interpositional graft between mucoperichondrial flaps can be used to reliably repair nasoseptal perforations.

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull.

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.

Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood-Brain Barrier Disruption in Rat Brain.

Interstitial solutes can be removed by various overlapping clearance systems, including blood-brain barrier (BBB) transport and glymphatic clearance. Recently, focused ultrasound (FUS)-induced BBB disruption (BBBD) has been applied to visualize glymphatic transport. Despite evidence that FUS-BBBD might facilitate glymphatic transport, the nature of fluid movement within the sonication region is yet to be determined. In this study, we sought to determine whether FUS-BBBD may facilitate the local movement of water molecules. Two different FUS conditions (0.60-0.65 MPa and 0.75-0.80 MPa) were used to induce BBBD in the caudate-putamen and thalamus regions of healthy Sprague-Dawley rats. The water diffusion caused by FUS-BBBD was analyzed using the apparent diffusion coefficient (ADC), axial diffusivity, radial diffusivity (RD), and fractional anisotropy, obtained at 5 min, 24 and 48 h, as well as the water channel expression of aquaporin-4 (AQP-4) immunostaining at 48 h after FUS-induced BBBD. In addition, hematoxylin and eosin histopathology and Fluoro-Jade C (FJC) immunostaining were performed to analyze brain damage. The signal changes in ADC and RD in the sonication groups showed significant and transient reduction at 5 min, with subsequent increases at 24 and 48 h after FUS-induced BBBD. When we applied higher sonication conditions, the ADC and RD showed enhancement until 48 h, and became comparable to contralateral values at 72 h. AQP-4 expression was upregulated after FUS-induced BBBD in both sonication conditions at 48 h. The results of this study provide preliminary evidence on how mechanical forces from FUS alter water dynamics through diffusion tensor imaging (DTI) measures and AQP4 expression.

Association Between Microbiota and Nasal Mucosal Diseases in terms of Immunity.

The pathogenesis of nasal inflammatory diseases is related to various factors such as anatomical structure, heredity, and environment. The nasal microbiota play a key role in coordinating immune system functions. Dysfunction of the microbiota has a significant impact on the occurrence and development of nasal inflammation. This review will introduce the positive and negative roles of microbiota involved in immunity surrounding nasal mucosal diseases such as chronic sinusitis and allergic rhinitis. In addition, we will also introduce recent developments in DNA sequencing, metabolomics, and proteomics combined with computation-based bioinformatics.

Auditory brainstem response test results in normal hearing adolescents with subjective tinnitus.

OBJECTIVES: The objective of the study was to analyze the auditory brainstem response (ABR) test results of adolescents with normal hearing threshold who have subjective tinnitus in an effort to determine the probable site of origin of tinnitus. METHODS: Among the patients who visited the outpatient clinic of the Department of Otolaryngology at our tertiary hospital from January 2016 to December 2019, adolescents aged 13-18 years with the chief complaint of unilateral subjective tinnitus and pure tone audiometry (PTA) within 25 dB HL were enrolled and retrospectively reviewed. The ABR test parameters (amplitudes and latencies of waves I, III, and V and interpeak latencies [IPLs] of waves I-III, III-V, and I-V) were analyzed and compared between tinnitus ears and contralateral ears without tinnitus. Study participants were divided into the chronic tinnitus (tinnitus duration ≥6 months) and non-chronic tinnitus (tinnitus duration <6 months) groups, and the difference between the two groups was analyzed. RESULTS: Ten adolescents were included in the study, and their ABR test results were reviewed. IPL III-V was significantly prolonged in tinnitus ears compared to non-tinnitus ears (p = 0.035). Although other parameters were found to be statistically non-significant, there was preponderance in ABR wave I amplitude; it was smaller in tinnitus ears of chronic tinnitus adolescents than in those of non-chronic tinnitus adolescents (p = 0.114). CONCLUSION: The probable site of origin of tinnitus in adolescents with normal hearing might be in the upper brainstem of the auditory pathway. Further analysis of ABR test results in adolescents with tinnitus and normal hearing can help clarify the pathophysiology of tinnitus in adolescents.

Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.

BACKGROUND: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. METHODS: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. RESULTS: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. CONCLUSIONS: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

Variation in Sleep Stability with Differences in Severity of Sleep-Disordered Breathing in Children.

OBJECTIVES: The aim of this study was to analyze the association between obstructive sleep apnea (OSA) severity and various cardiopulmonary coupling (CPC) parameters in children with OSA. STUDY DESIGN: Retrospective cross-sectional study. METHODS: A cross-sectional study was conducted among 117 children (aged 7.96 ± 3.54 years, 86 male) who underwent both full-night polysomnography (PSG) and CPC for suspicion of sleep-disordered breathing (SDB). We analyzed the association between various CPC and PSG findings. RESULTS: The apnea-hypopnea index (AHI) was negatively correlated with high frequency coupling (HFC, r = -0.374, P < .001) and very low frequency coupling (VLFC, r = -0.192, P = .038) and positively correlated with low frequency coupling (LFC, r = 0.503, P < .001), elevated low frequency coupling (e-LFC, r = 0.475, P < .001), and narrow and broad band e-LFC (e-LFCNB and e-LFCBB ; r = 0.221, P = .016 and r = 0.468, P < .001, respectively). The arousal index was negatively correlated with HFC (r = - 0.466, P < .001) and positively correlated with LFC, e-LFC, e-LFCNB , and e-LFCBB (r = 0.543, r = 0.460, r = 0.239, and r = 0.445, respectively; all P < .001). In addition, we also found a significant difference in various CPC values according to OSA severity. CONCLUSION: CPC parameters accurately reflect sleep fragmentation and OSA severity in children. Thus, we can verify objective sleep quality using CPC analysis, which is a simple method of analyzing sleep stability in children with SDB. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:435-439, 2021.

The Expression of ephrinA1/ephA2 Receptor Increases in Chronic Rhinosinusitis and ephrinA1/ephA2 Signaling Affects Rhinovirus-Induced Innate Immunity in Human Sinonasal Epithelial Cells.

EphA2 receptor and its ephrin ligands are involved in virus infection, epithelial permeability, and chemokine secretion. We hypothesized that ephrinA1/ephA2 signaling participates in rhinovirus (RV)-induced antiviral immune response in sinonasal mucosa of patients with chronic rhinosinusitis (CRS). Therefore, we investigated the expression of ephrinA1/ephA2 in normal and inflamed sinonasal mucosa and evaluated whether they regulate chemokine secretion and the production of antiviral immune mediators including interferons (IFNs) in RV-infected human primary sinonasal epithelial cells. For this purpose, the expression and distribution of ephrinA1/ephA2 in sinonasal mucosa were evaluated with RT-qPCR, immunofluorescence, and western blot. Their roles in chemokine secretion and the production of antiviral immune mediators such as type I and III IFNs, and interferon stimulated genes were evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to RV and poly(I:C). We found that ephrinA1/ephA2 were expressed in normal mucosa and their levels increased in inflamed sinonasal mucosa of CRS patients. RV infection or poly(I:C) treatment induced chemokine secretion which were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. The production of antiviral immune mediators enhanced by rhinovirus or poly (I:C) is increased by blocking ephA2 compared with that of cells stimulated by either rhinovirus or poly(I:C) alone. In addition, blocking ephA2 attenuated RV replication in cultured cells. Taken together, these results describe a novel role of ephrinA1/ephA2 signaling in antiviral innate immune response in sinonasal epithelium, suggesting their participation in RV-induced development and exacerbations of CRS.

A local difference in blood-brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound.

A blood-brain barrier (BBB) opening induced by focused ultrasound (FUS) has been widely studied as an effective way of treating brain diseases. We investigate the effect of ultrasound's incidence angle at caudate putamen (Cp) and thalamus (Th) of the rat brain by inducing the same power of focused ultrasound that corresponds to the acoustic pressure of 0.65 MPa in free field. The BBB permeability (Ktrans) was quantitatively evaluated with dynamic contrast-enhanced magnetic resonance imaging. The group averaged (n = 11) maximum Ktrans at Cp (0.021 ± 0.012 min-1) was 1.39 times smaller than the Ktrans of Th (0.029 ± 0.01 min-1) with p = 0.00343. The group averaged (n = 6) ultrasound's incidence angles measured using the computed tomography image of rat skulls were compared with the maximum Ktrans and showed a negatively linear relation R2 = 0.7972). The maximum acoustic pressure computed from the acoustic simulation showed higher average acoustic pressures at Th (0.37 ± 0.02 MPa) compared to pressures at Cp (0.32 ± 0.01 MPa) with p = 0.138 × 10-11. More red blood cell were observed at the Th region compared to the Cp region in the tissue staining. These results indicate that localized characteristics of the sonication target within the subject should be considered for safer and more efficient BBB disruption induced by FUS.

Analysis of Auditory Brainstem Response Change, according to Tinnitus Duration, in Patients with Tinnitus with Normal Hearing.

OBJECTIVES: The purpose of this study was to analyze auditory brainstem response (ABR) waveforms of patients with tinnitus with normal hearing, according to tinnitus duration, and demonstrate the possible pathophysiological mechanisms of tinnitus. MATERIALS AND METHODS: From January 2016 to December 2017, patients who presented to our hospital with tinnitus as their chief complaint were enrolled and reviewed retrospectively. Pure tone audiometry and ABR tests were performed. The patients were classified into three groups according to tinnitus duration: acute (<1 month), subacute (1-6 months), and chronic (>6 months). The amplitudes of waves I and V and the latencies of waves I, III, and V were evaluated. In this study, 177 ears of 128 patients with tinnitus with normal hearing were evaluated. RESULTS: Wave V amplitude was significantly lower during the subacute phase than during the acute phase. The absolute latency value of wave V was greater during the subacute phase than during the acute phase. The interpeak latency I-V was significantly prolonged during the subacute phase compared with the acute and chronic phases. Wave V amplitude, wave V absolute latency, and interpeak latency I-V varied significantly between cases with a 1-month and 6-month tinnitus history. CONCLUSION: The compensatory response to tinnitus decreased sharply after 1 month of symptoms. Early tinnitus identification and treatment initiation are recommended.

Comparisons among vestibular examinations and symptoms of vertigo in sudden sensorineural hearing loss patients.

OBJECTIVES: Vertigo in sudden sensorineural hearing loss (SSNHL) is hypothesized as an extension of the disease caused by the anatomical proximity of the cochlea and vestibule. The present study aimed to demonstrate the association of vestibular function test (VFT) results with SSNHL disease severity and prognosis. MATERIALS AND METHODS: This study assessed clinical records of 263 SSNHL patients admitted to our hospital, between January 2010 and October 2017. Steroid treatment comprised high-dose intravenous dexamethasone (16 mg/d) or oral methylprednisolone (64 mg/d) for 4 days and tapered oral methylprednisolone for 8 days after discharge. Caloric tests were performed in all patients, and cervical vestibular-evoked myogenic potential (c-VEMP) and ocular VEMP (o-VEMP) tests were performed in 209 and 144 patients, respectively. RESULTS: Ninety six patients had vertigo, and caloric abnormalities were observed in 119 patients. Initial PTA in patients with vertigo were worse than in those without vertigo (63.0 dB vs 72.7 dB, P = .002). Initial PTA in patients with abnormal o-VEMP was worse than in those with normal o-VEMP (61.4 dB vs 73.0 dB, P = .004). PTA improvement after steroid treatment in patients with vertigo was lower than in those without vertigo (25.0 dB vs 20.9 dB, P = .028). PTA improvement after treatment in patients with abnormal caloric results was lower than in those with normal caloric results (26.0 dB vs 18.4 dB, P = .013). CONCLUSION: The functions of vestibular organs, particularly the utricle and lateral semicircular canal, are associated with disease severity and hearing outcome in SSNHL patients.

Machine Learning Models for Predicting Hearing Prognosis in Unilateral Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVES: Prognosticating idiopathic sudden sensorineural hearing loss (ISSNHL) is an important challenge. In our study, a dataset was split into training and test sets and cross-validation was implemented on the training set, thereby determining the hyperparameters for machine learning models with high test accuracy and low bias. The effectiveness of the following five machine learning models for predicting the hearing prognosis in patients with ISSNHL after 1 month of treatment was assessed: adaptive boosting, K-nearest neighbor, multilayer perceptron, random forest (RF), and support vector machine (SVM). METHODS: The medical records of 523 patients with ISSNHL admitted to Korea University Ansan Hospital between January 2010 and October 2017 were retrospectively reviewed. In this study, we analyzed data from 227 patients (recovery, 106; no recovery, 121) after excluding those with missing data. To determine risk factors, statistical hypothesis tests (e.g., the two-sample t-test for continuous variables and the chi-square test for categorical variables) were conducted to compare patients who did or did not recover. Variables were selected using an RF model depending on two criteria (mean decreases in the Gini index and accuracy). RESULTS: The SVM model using selected predictors achieved both the highest accuracy (75.36%) and the highest F-score (0.74) on the test set. The RF model with selected variables demonstrated the second-highest accuracy (73.91%) and F-score (0.74). The RF model with the original variables showed the same accuracy (73.91%) as that of the RF model with selected variables, but a lower F-score (0.73). All the tested models, except RF, demonstrated better performance after variable selection based on RF. CONCLUSION: The SVM model with selected predictors was the best-performing of the tested prediction models. The RF model with selected predictors was the second-best model. Therefore, machine learning models can be used to predict hearing recovery in patients with ISSNHL.