Cochlear protection against noise exposure requires serotonin type 3A receptor via the medial olivocochlear system.

The cochlear efferent feedback system plays important roles in auditory processing, including regulation of the dynamic range of hearing, and provides protection against acoustic trauma. These functions are performed through medial olivocochlear (MOC) neurons. However, the underlying cellular and molecular mechanisms are not fully understood. The serotonin type 3A (5-HT3A) receptor is widely expressed throughout the nervous system, which suggests important roles in various neural functions. However, involvement of the 5-HT3A receptor in the MOC system remains unclear. We used mice in this study and found that the 5-HT3A receptor was expressed in MOC neurons that innervated outer hair cells in the cochlea and was involved in the activation of MOC neurons by noise exposure. 5-HT3A receptor knockout impaired MOC functions, potentiated noise-induced hearing loss, and increased loss of ribbon synapses following noise exposure. Furthermore, 5-HT3 receptor agonist treatment alleviated the noise-induced hearing loss and loss of ribbon synapses, which enhanced cochlear protection provided by the MOC system. Our findings demonstrate that the 5-HT3A receptor plays fundamental roles in the MOC system and critically contributes to protection from noise-induced hearing impairment.

Epiphycan is specifically expressed in cochlear supporting cells and is necessary for normal hearing.

The study of inner ear specific transcripts has revealed novel information about hereditary hearing loss and a mechanism of normal hearing. In this study, by analyzing a published cDNA library, we focused on Epiphycan (Epyc), a member of the small leucine-rich repeat proteoglycan family, whose transcript is enriched in the inner ear. Epyc mRNA was expressed abundantly and specifically in adult mice cochleae and was localized in supporting cells within the organ of Corti of both neonatal and adult mice. To examine the function of Epyc, we generated Epyc knockout (KO) mice using the CRISPR/Cas9 system. Epyc KO mice cochleae exhibited normal morphology. However, measurement of the auditory brain-stem response in Epyc KO mice revealed an elevated hearing threshold above 16 kHz frequency. This study suggests that Epyc is necessary for normal auditory function.

Evaluation of endolymphatic hydrops using 3-T MRI after intravenous gadolinium injection.

Aim of this work is to establish evaluation criteria for identifying endolymphatic hydrops in the vestibule and cochlea using a magnetic resonance imaging (MRI) scanner. This is a retrospective diagnostic study. We evaluated 70 ears of 35 unilateral Ménière's disease patients. We performed 3-T MRI 4 h after intravenous gadolinium injection. Otologists manually traced the outline of vestibule, cochlea, and endolymphatic space of the vestibule and cochlea on two-dimensional fluid-attenuated inversion-recovery (2D-FLAIR) images. The traced area was measured, and rates of endolymphatic space to the vestibule and cochlea were calculated. The same otologists judged whether the low signal intensity area of the cochlea was at the edge of the cochlea. For measuring the rate of endolymphatic space to the vestibule, when the cut-off value was 30%, the presence of endolymphatic hydrops was determined with sensitivity of 87.1% and specificity of 94.3%. In contrast, the rate of endolymphatic space to the cochlea produced low accuracy. Therefore, when the presence of endolymphatic hydrops in the cochlea was judged by whether the low signal intensity area in the cochlea was at the edge of cochlea, endolymphatic hydrops could be detected with sensitivity of 91.4% and specificity of 94.3%. We were able to identify endolymphatic hydrops in the vestibule when the rate of endolymphatic space to the vestibule was greater than 30%, and could detect endolymphatic hydrops in the cochlea when a low signal intensity area was located at the edge of the cochlea in 2D-FLAIR images. Level of evidence 4.

Functional Expression of an Osmosensitive Cation Channel, Transient Receptor Potential Vanilloid 4, in Rat Vestibular Ganglia.

Transient receptor potential vanilloid (TRPV) 4 is a nonselective cation channel expressed in sensory neurons such as those in the dorsal root and trigeminal ganglia, kidney, and inner ear. TRPV4 is activated by mechanical stress, heat, low osmotic pressure, low pH, and phorbol derivatives such as 4α-phorbol 12,13-didecanoate (4α-PDD). We investigated the expression of TRPV4 in rat vestibular ganglion (VG) neurons. The TRPV4 gene was successfully amplified from VG neuron mRNA using reverse-transcription polymerase chain reaction. Furthermore, immunoblotting showed positive expression of TRPV4 protein in VG neurons. Immunohistochemistry indicated that TRPV4 was localized predominantly on the plasma membrane of VG neurons. Calcium (Ca2+) imaging of VG neurons showed that 4α-PDD and/or hypotonic stimuli caused an increase in intracellular Ca2+ concentration ([Ca2+]i) that was almost completely inhibited by ruthenium red, a selective antagonist of TRPV channels. Interestingly, a [Ca2+]i increase was evoked by both hypotonic stimuli and 4α-PDD in approximately 38% of VG neurons. These data indicate that TRPV4 is functionally expressed in VG neurons as an ion channel and that TRPV4 likely participates in VG neurons for vestibular neurotransmission as an osmoreceptor and/or mechanoreceptor.

The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice.

Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.

[A unique Lemierre syndrome case in an elderly woman with deviation of the tongue].

We report herein on the case of a 71-year-old woman hospitalized for continued postauricular pain of unknown origin with tongue deviation. In view of the severe inflammatory reaction and multiple nodular shadows of the lungs, the existence of infectious disease was indicated. A contrast-enhanced CT scan of the neck revealed a thrombosis of the right internal jugular vein, osteomyelitis of right temporal-occipital bone and upper cervical spine, and cellulitis of the adjacent soft tissue. Multiple nodular shadows of the lungs were suspected to be the result of a metastatic septic embolism. Hence, she was diagnosed with Lemierre syndrome. Following treatment with long course of antimicrobial therapy including beta-lactams and clindamycin, complete recovery in this patient was achieved.

Stratification of patients with Menière's disease based on eye movement videos recorded from the beginning of vertigo attacks and contrast-enhanced MRI findings.

Purpose: Diagnosis of Menière's disease (MD) relies on subjective factors and the patients diagnosed with MD may have heterogeneous pathophysiologies. This study aims to stratify MD patients using two objective data, nystagmus videos and contrast-enhanced magnetic resonance imaging (CE-MRI). Methods: This is a retrospective cross-sectional study. According to the Japan Society for Equilibrium Research criteria (c-JSER), adults diagnosed with definite MD and who obtained videos recorded by portable nystagmus recorder immediately following vertigo attacks and underwent CE-MRI of the inner ear were included (ss = 91). Patients who obtained no nystagmus videos, who had undergone sac surgery, and those with long examination intervals were excluded (n = 40). Results: The gender of the subjects was 22 males and 29 females. The age range was 20-82 y, with a median of 54 y. Endolymphatic hydrops (EH) were observed on CE-MRI in 84% (43 patients). Thirty-one patients had unilateral EH. All of them demonstrated EH on the side of the presence of cochlear symptoms. The number of patients who had both nystagmus and EH was 38. Five patients only showed EH and 5 patients only exhibited nystagmus, while 3 patients did not have either. Of the 43 nystagmus records, 32 showed irritative nystagmus immediately after the vertigo episode. The direction of nystagmus later reversed in 44% of cases over 24 h. Conclusion: Patients were stratified into subgroups based on the presence or absence of EH and nystagmus. The side with cochlear symptoms was consistent with EH. The c-JSER allows for the diagnosis of early-stage MD patients, and it can be used to treat early MD and preserve hearing; however, this approach may also include patients with different pathologies.

Methamphetamine induces endoplasmic reticulum stress related gene CHOP/Gadd153/ddit3 in dopaminergic cells.

We examined the toxicity of methamphetamine and dopamine in CATH.a cells, which were derived from mouse dopamine-producing neural cells in the central nervous system. Use of the quantitative real-time polymerase chain reaction revealed that transcripts of the endoplasmic reticulum stress related gene (CHOP/Gadd153/ddit3) were considerably induced at 24-48 h after methamphetamine administration (but only under apoptotic conditions), whereas dopamine slightly induced CHOP/Gadd153/ddit3 transcripts at an early stage. We also found that dopamine and methamphetamine weakly induced transcripts for the glucose-regulated protein 78 gene (Grp78/Bip) at the early stage. Analysis by immunofluorescence microscopy demonstrated an increase of　CHOP/Gadd153/ddit3 and Grp78/Bip proteins at 24 h after methamphetamine administration. Treatment of CATH.a cells with methamphetamine caused a re-distribution of dopamine inside the cells, which mimicked the presynaptic activity of neurons with cell bodies located in the ventral tegmental area or the substantia nigra. Thus, we have demonstrated the existence of endoplasmic reticulum stress in a model of presynaptic dopaminergic neurons for the first time. Together with the recent evidence suggesting the importance of presynaptic toxicity, our findings provide new insights into the mechanisms of dopamine toxicity, which might represent one of the most important mechanisms of methamphetamine toxicity and addiction.

Daple deficiency causes hearing loss in adult mice by inducing defects in cochlear stereocilia and apical microtubules.

The V-shaped arrangement of hair bundles on cochlear hair cells is critical for auditory sensing. However, regulation of hair bundle arrangements has not been fully understood. Recently, defects in hair bundle arrangement were reported in postnatal Dishevelled-associating protein (ccdc88c, alias Daple)-deficient mice. In the present study, we found that adult Daple-/- mice exhibited hearing disturbances over a broad frequency range through auditory brainstem response testing. Consistently, distorted patterns of hair bundles were detected in almost all regions, more typically in the basal region of the cochlear duct. In adult Daple-/- mice, apical microtubules were irregularly aggregated, and the number of microtubules attached to plasma membranes was decreased. Similar phenotypes were manifested upon nocodazole treatment in a wild type cochlea culture without affecting the microtubule structure of the kinocilium. These results indicate critical role of Daple in hair bundle arrangement through the orchestration of apical microtubule distribution, and thereby in hearing, especially at high frequencies.

Effects of smoking cessation on gastric emptying in smokers.

BACKGROUND: Smoking cessation can lead to changes in appetite and weight gain in some patients; thus, smoking cessation may alter gastrointestinal motility. Effects of smoking cessation on gastric emptying in smokers have not been established. AIM: This study sought to determine how smoking cessation affects gastric emptying in smokers. METHODS: Participant group comprised 53 habitual smokers and 12 healthy nonsmokers. Habitual smokers were treated for 2 months with transdermal nicotine patches. Gastric emptying was studied using C acetate breath tests at the beginning of the study, and at 1 week and 9 weeks after cessation of patch use. Maximal CO2 excretion time (Tmax), CO2 excretion half-life (T1/2), and parameters beta and kappa, representing initial and subsequent gastric-emptying phases, respectively, were determined using conventional formulae. RESULTS: Before smoking cessation, Tmax was reached significantly later in smokers (0.94+/-0.3 h, P=0.014) than in controls (0.89+/-0.1 h). At 1 week after the end of treatment, Tmax was significantly decreased (from 1.05+/-0.32 h to 0.72+/-0.64 h, P=0.003). T1/2 also tended to decrease, but not significantly. Although beta was decreased significantly (from 2.46+/-0.40 to 2.17+/-0.58, P=0.022), kappa was unchanged. However, by 9 weeks after the end of treatment, Tmax (1.28+/-0.69 h) had increased to levels seen before treatment. CONCLUSIONS: Smoking cessation temporarily accelerates gastric emptying, and decreases in beta suggest that initial-phase gastric emptying accelerates after smoking cessation. The temporary acceleration of gastric emptying after smoking cessation may be involved in the temporary increase in appetite and weight gain seen after smoking cessation.

White blood cell count and cardiovascular biomarkers of atherosclerosis.

OBJECTIVE: To investigate the association with white blood cells (WBC) and atherosclerotic parameters including cardio-ankle vascular index (CAVI) and carotid intima-media thickness (CIMT) in the general population. METHODS: We investigated the relationship between WBC count and metabolic syndrome components, CAVI and CIMT in 3738 Japanese study participants. RESULTS: WBC count weakly correlated with CAVI in men (beta = 0.61, p = 0.043), but not in women (beta = 0.35, p = 0.17). On the other hand, WBC did not correlate with CIMT in either men or women (p = 0.41 and p = 0.71, respectively). CONCLUSION: WBC count was associated with lipids, blood pressure and body mass index, although the correlations with CAVI and CIMT were weak or absent.

Leptin to high-molecular-weight adiponectin ratio is independently correlated with carotid intima-media thickness in men, but not in women.

BACKGROUND: The leptin:adiponectin ratio (L:A ratio) is an independent predictor of carotid intima-media thickness (CIMT). OBJECTIVE: To evaluate whether the leptin:high-molecular-weight adiponectin ratio (L:HA ratio) is associated with CIMT in the general population. METHODS: We investigated the relationship between the L:HA ratio and CIMT in 233 Japanese study participants (106 men and 127 women). RESULTS: After adjustment for confounding factors, CIMT was significantly correlated with the log L:HA ratio (beta = 0.11, p = 0.014) in men, whereas no correlation was observed in women (beta = 0.01, p = 0.50). CONCLUSION: The L:HA ratio is closely correlated with CIMT in men, but not in women.

[Two cases of pleomorphic carcinoma with severe systemic inflammation].

We report two cases of pleomorphic carcinoma with fever and severe inflammatory reaction. In case 1, an abnormal mass shadow was found on the chest X-ray film of a 63-year-old man with bloody sputum. After right upper lobectomy, the tumor was diagnosed as pleomorphic carcinoma. About 7 months after surgical operation, he had fever and chest pain. Although his test results showed leukocytosis and his elevated serum CRP level indicated some infection, there were no signs of bacterial or fungal infection. Further examination revealed metases of lung cancer in the left adrenal gland, mediastinal and iliac lymph nodes. Serological study revealed elevated level of G-CSF, likely due to G-CSF producing metastatic tumors. In case 2, a 77-year-old man presented with continuous high fever. Examinations revealed elevated serum CRP level and multiple nodular shadows and enlarged supraclavicular and mediastinal lymph nodes on the chest CT, suggesting some infectious, connective tissue, or lymphoproliferative diseases. He was finally found to have pleomorphic carcinoma of the lung by histological examination of lymph nodes. The continuous high fever seemed to be a tumor-related fever, because it rapidly disappeared after administration of naproxen.

Rupture of Internal carotid artery pseudoaneurysm in the sphenoid sinus as a complication of deep neck space infection.

BACKGROUND: Pseudoaneurysm of the internal carotid artery (ICA) is a very rare but potentially fatal complication of deep neck space infection. METHODS: This paper describes a very rare case of an ICA pseudoaneurysm rupture in the sphenoid sinus caused by a deep neck abscess. RESULTS: A 62-year-old male with a deep neck space infection underwent surgical drainage. On the postoperative 21st day, however, he suddenly had massive epistaxis. A transnasal endoscopic examination found massive bleeding out of the sphenoid sinus. Immediate intra-arterial angiography revealed two pseudoaneurysms of the left ICA at the cavernous segment (C4) and the clinoid segment (C5), which were embolized with coils. The patient made an uneventful recovery after the embolization. CONCLUSION: We found no reports in the literature that pseudoaneurysms associated with a deep neck infection rupture in the sphenoid sinus. Prompt treatment along with accurate diagnosis is essential for successful management of such cases. J. Med. Invest. 66 : 188-189, February, 2019.

A Rare Case of Cryopyrin-associated Periodic Syndrome in an Elderly Woman with NLRP3 and MEFV Mutations.

We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory syndrome, a subtype of cryopyrin-associated periodic syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.

Change in endolymphatic hydrops 2 years after endolymphatic sac surgery evaluated by MRI.

OBJECTIVE: This study was performed to determine whether endolymphatic sac surgery improves vestibular and cochlear endolymphatic hydrops 2 years after sac surgery and to elucidate the relationship between the degree of improvement of endolymphatic hydrops and the changes in vertigo symptoms, the hearing level, and the summating potential/action potential ratio (-SP/AP ratio) by electrocochleography (ECochG) in patients with Ménière's disease (MD). METHODS: Twenty-one patients with unilateral MD who underwent sac surgery were included in this study. All patients underwent gadolinium-enhanced magnetic resonance imaging (Gd-MRI) before and 2 years after sac surgery. We evaluated the difference in vestibular and cochlear endolymphatic hydrops between before and after surgery in both ears and compared these findings with the frequency of vertigo attacks, hearing level, and ECochG findings. RESULTS: In affected ears, the presence of vestibular endolymphatic hydrops and the frequency of vertigo attacks significantly decreased after surgery. However, affected ears showed no significant improvement in the presence of cochlear endolymphatic hydrops or the -SP/AP ratio by ECochG; there was also no significant improvement or deterioration in the hearing level. CONCLUSION: The present findings suggest that sac surgery reduces vestibular endolymphatic hydrops and prevents aggravation of cochlear endolymphatic hydrops, and these changes lead to a reduction of vertigo attacks and suppress the progression of hearing impairment associated with vertigo attacks.

P2X2 Receptor Deficiency in Mouse Vestibular End Organs Attenuates Vestibular Function.

P2X2 receptors are ligand-gated cation channels activated by extracellular ATP that modulate neural transmission in various neuronal systems. Although the function and distribution of P2X2 receptors in the cochlea portion of the inner ear are well established, their physiological role in the vestibular portion is still not understood. Therefore, we investigated P2X2 receptor localization in the peripheral vestibular portion, and assessed their physiological function in vivo using P2X2 receptor knock out (P2X2-KO) mice. Histological analysis revealed that P2X2 receptors were localized on the epithelial surface of supporting and transitional cells of the vestibular end organs. To examine vestibular function in P2X2-KO mice, we conducted behavioral tests and tested the vestibulo-ocular reflex (VOR) during sinusoidal rotations. P2X2-KO mice exhibited significant motor balance impairment in the balance beam test. VOR gain in P2X2-KO mice was significantly reduced, with no decrease in the optokinetic response. In conclusion, we showed that P2X2 receptors are mainly localized in the supporting cells of the vestibular inner ear, and the loss of P2X2 receptors causes mild vestibular dysfunction. Taken together, our findings suggest that the P2X2 receptor plays a modulatory role in vestibular function.

Fibroblast growth factor 12 is expressed in spiral and vestibular ganglia and necessary for auditory and equilibrium function.

We investigated fibroblast growth factor 12 (FGF12) as a transcript enriched in the inner ear by searching published cDNA library databases. FGF12 is a fibroblast growth factor homologous factor, a subset of the FGF superfamily. To date, its localisation and function in the inner ear have not been determined. Here, we show that FGF12 mRNA is localised in spiral ganglion neurons (SGNs) and the vestibular ganglion. We also show that FGF12 protein is localised in SGNs, the vestibular ganglion, and nerve fibres extending beneath hair cells. Moreover, we investigated FGF12 function in auditory and vestibular systems using Fgf12-knockout (FGF12-KO) mice generated with CRISPR/Cas9 technology. Our results show that the inner ear morphology of FGF12-KO mice is not significantly different compared with wild-type mice. However, FGF12-KO mice exhibited an increased hearing threshold, as measured by the auditory brainstem response, as well as deficits in rotarod and balance beam performance tests. These results suggest that FGF12 is necessary for normal auditory and equilibrium function.

[A case of rheumatoid lung complicated by SELAPINA-induced pneumonia].

SELAPINA is generic product of PL granule which is one of the most common forms of combination remedies for the common cold in Japan, and includes acetaminophen. We report a case of SELAPINA-induced pneumonia successfully treated with glucocorticoid pulse therapy followed by orally administered prednisolone. A 68-year-old woman, who had been treated for rheumatoid arthiritis with pulmonary involvement, took SELAPINA with an antibiotic for 6 days because of her cold symptoms. She then suffered a high fever, cough, dyspnea, vomiting and diarrhea. Chest radiograph and high-resolution computed tomography (HRCT) scan revealed diffuse interstitial shadows. SELAPINA-induced pneumonia was diagnosed because the blastoid transformation test using her peripheral blood lymphocytes was positive on stimulation with SELAPINA, but negative for other medicines.

Paroxysmal vertigo with nystagmus in children.

INTRODUCTION: A pathological nystagmus is an objective sign that a patient feels vertigo. However, there have been few opportunities to observe and record pathological nystagmus during a paroxysmal vertigo attack. Furthermore, it can be difficult to obtain cooperation in pediatric patients. We present two cases of paroxysmal vertigo in children in whom we successfully recorded and analyzed their pathological nystagmus during a vertigo attack. METHODS: Of a total sample of 4349 patients seen at our hospital for dizziness in the last decade, a retrospective analysis revealed that 68 were children (<15 years old; 1.6%). Of these 68 children, we successfully identified pathological nystagmus during paroxysmal vertigo in only two (2.9%). RESULTS: Case 1 was a 4-year-old girl. She felt vertigo the strongest when her left ear was down in the supine position. We observed and recorded her nystagmus during a vertigo attack with her mother's permission. Her positional nystagmus in the supine position was horizontal persistent apogeotropic nystagmus. Rightward nystagmus in the left-ear-down supine position was stronger than leftward nystagmus in the right-ear-down supine position. Therefore, the diagnosis was right lateral canal type of benign paroxysmal positional vertigo, of which the pathophysiology was cupulolithiasis. The other patient was an 11-year-old boy. He had a family history of migraines. His vertigo attacks occurred after onset of a severe migraine and lasted between 2 and 48 h. During an attack that we observed, he showed nystagmus, which was direction-fixed right torsional and rightward in darkness. His mother had noticed that his eyes moved abnormally and that his left eye did not shift to the left side when he looked leftward. He was old enough to clearly express his own symptoms. Other neurological examinations were normal. The diagnosis was vestibular migraine. CONCLUSIONS: We analyzed a pathological nystagmus during paroxysmal vertigo in two children. We conclude that children can be diagnosed with a combination of careful history taking and accurate examinations of a pathological nystagmus.