Mature dendritic cells enriched in regulatory molecules may control regulatory T cells and the prognosis of head and neck cancer.

We previously reported that regulatory T (Treg) cells expressing CTLA-4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we reveal that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)-17-related molecules. Increased expression of IL17A, IL17F, or IL23A contributes to a favorable prognosis of HNSCC. In the tumor microenvironment of HNSCC, IL23A and IL12B are expressed in mature dendritic cells enriched in regulatory molecules (mregDCs). The mregDCs in HNSCC are a migratory and mature phenotype; their signature genes strongly correlate with Treg signature genes in HNSCC. We also observed that IL17A was highly expressed in Th17 cells and exhausted CD8+ T cells in HNSCC. These data suggest that mregDCs in HNSCC may contribute to the prognosis by balancing Treg cells and effector T cells that produce IL-17. Targeting mregDCs may be a novel strategy for developing new immune therapies against HNSCC.

Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia.

Several false-positive results in the human ether-à-gogo-related gene test suggest that blockers of the rapid component of delayed rectifier K+ current (IKr) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among IKr blockers, even if the prolonged action potential duration is in the same range. To predict EAD in drug-induced arrhythmias, we proposed a prediction method based on the mechanisms underlying the difference in frequency of EAD among nonselective IKr blockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca2+ current (ICaL) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent ICaL blockade resulted in the suppression of EAD. However, when voltage-dependent ICaL blockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into ICaL in the model, bepridil and terfenadine induced EAD more than the voltage-independent ICaL blockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in ICaL blockade at negatively polarized potential. EAD occurrence was found to be associated with ICaL blockade measured at -20 mV. These results suggest that voltage dependence of ICaL blockade may be useful in predicting the different risks of nonselective IKr blockers.

Facial and hearing outcomes in transmastoid nerve decompression for Bell's palsy, with preservation of the ossicular chain.

OBJECTIVES: Facial nerve decompression is a salvage treatment for Bell's palsy patients for whom a poor prognosis is anticipated with standard medical treatment. The transmastoid approach is a frequently performed approach, but it remains unknown if this surgery is effective when the ossicular chain is preserved. This study aimed to determine the efficacy of facial nerve decompression using the transmastoid approach in Bell's palsy. DESIGN, SETTING AND PARTICIPANTS: This retrospective study included patients who had undergone transmastoid facial nerve decompression with ossicular chain preservation and patients who met the criteria for surgery, but received only medical treatment between January 2007 and May 2019, at a single centre. MAIN OUTCOME MEASURES: Attainment of House-Brackmann grade I at 12 months after onset of facial palsy. RESULTS: The recovery rate to House-Brackmann grade I in the decompression group in the early phase (≤18 days after onset) was higher than that of the medical treatment group, although the difference was not significant (70% vs 47%, P = .160). However, within this early surgery group, a subgroup of cases with ≥95% facial nerve degeneration demonstrated a significant improvement in recovery rate (73% vs 30%, P = .018). Among surgeries performed in the late phase (≥19 days), only a subgroup with ≥95% facial nerve degeneration was available for analysis, and the difference in recovery rate was not significant compared with medical treatment alone (26% vs 30%, P = 1.00). Post-surgical hearing evaluation demonstrated that average hearing deterioration was 1.3 dB which was non-significant, suggesting this procedure does not cause hearing loss. CONCLUSIONS: Transmastoid facial nerve decompression with ossicular chain preservation in the early phase after symptom-onset is an effective salvage treatment for severe Bell's palsy with ≥95% facial nerve degeneration.

Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer.

FOXP3+ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4+ and surface-CTLA-4- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4+ Treg cells were PD-1+ , actively proliferated and associated with CD45RA- FOXP3high Treg cells with strong suppressive function. Thus, surface-CTLA-4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.

Proton Pump Inhibitor Ameliorates Taste Disturbance among Patients with Laryngopharyngeal Reflux: A Randomized Controlled Study.

Patients with laryngopharyngeal reflux (LPR) were reported to suffer from hypogeusia that affects quality of life. Proton pump inhibitor (PPI) is a useful drug in the treatment of LPR, but its effect on hypogeusia is not known. We therefore assessed the effects of PPI or a histamine H2 receptor antagonist (H2 blocker) on hypogeusia among patients with LPR. Both PPI and H2 blocker could inhibit acid reflux. LPR was diagnosed with reflux finding score and reflux symptom index. The visual analogue scale (VAS) of taste disturbance symptoms and the gustatory tests were assessed before and 8 weeks after treatment with esomeprazole, a PPI (20 patients, aged 50.0 ± 1.7 years) or famotidine, a H2 blocker (20 patients, aged 47.1 ± 1.8 years). There were no significant differences in VAS scores and recognition thresholds for four basic tastes between the two groups before treatment. Only PPI therapy significantly decreased the VAS scores, suggesting the improvement of taste perception. Moreover, PPI therapy significantly decreased recognition thresholds for bitter taste in the anterior tongue (chorda tympani nerve area) and the thresholds in the posterior tongue (glossopharyngeal nerve area) for salty, sour, and bitter tastes. By contrast, H2-blocker therapy caused no significant changes of thresholds in the anterior tongue, but improved the threshold only for bitter in the posterior tongue, the value of which was however significantly higher than that in PPI group. In conclusion, PPI could ameliorate hypogeusia by improving bitter, salty, and sour tastes among patients with LPR.

Preoperative transcatheter arterial embolization using a gelatin sponge for head and neck tumors.

Purpose: To evaluate the usefulness of preoperative transcatheter arterial embolization using a gelatin sponge for hypervascular head and neck tumors to reduce intraoperative blood loss (IBL).　　　　 Material and methods: Nineteen patients underwent preoperative transcatheter arterial embolization for hypervascular head and neck tumors using a gelatin sponge. The technical success rate, devascularization rate, IBL, and complications were evaluated. Angiography images obtained before and after preoperative embolization were compared in all patients, and the devascularization rate was assessed from the relative reduction rate of contrast agent volumes. Results: The technical success rate was 100%. The median devascularization rate was 95% (range, 75-100%). The median period between embolization and surgical resection was one day (range, 1-12 days). The median IBL was 122 ml (range, 0-3780 ml). Blood transfusions were required in three cases, and their IBL and devascularization rates were 850, 1959, and 3780 ml, and 75%, 90%, and 80%, respectively. There was a complication of cerebral embolism in one out of 19 cases (5%). Conclusions: Preoperative transcatheter arterial embolization using a gelatin sponge was feasible and may contribute to decreasing IBL.

Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case-control study.

BACKGROUND: Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M-SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features. METHODS: The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first-visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders. RESULTS: Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58-7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose-response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052). CONCLUSIONS: The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2018;124:118-24. © 2017 American Cancer Society.

Ramsay Hunt syndrome associated with solitary nucleus, spinal trigeminal nucleus and tract, and vestibular nucleus involvement on sequential magnetic resonance imaging.

Ramsay Hunt syndrome (RHS) is an acute peripheral facial nerve paralysis typically accompanied by erythematous vesicular lesions of the auricular skin. The etiology is considered to be geniculate ganglionitis due to reactivation of varicella-zoster virus (VZV). Encephalitis is a rare but serious complication of VZV reactivation. Clarifying the regional and temporal evolution of the lesions on magnetic resonance imaging (MRI) would help with understanding the pathology of the lesion, but this information is lacking in encephalitis with RHS. Therefore, here, we reviewed sequential MR images in three RHS cases complicated by brainstem lesions. All the regions of the lesions represent specific neuronal structures-the ipsilateral solitary nucleus (SN) and spinal trigeminal nucleus and tract (STNT) in case 1; bilateral SN, ipsilateral STNT, and vestibular nucleus in case 2; ipsilateral SN and vestibular nucleus in case 3-and this seems to account for the persistent robust symptoms. Case 1 initially showed no abnormalities on MRI and cases 2 and 3 showed weak signals on the first MRI which subsequently plateaued. These observations suggest the timeframe within which it becomes possible to detect regional and temporal evolution, namely, that the distribution of the affected regions expands between weeks 2 and 5 after onset of facial paralysis. These observations and the findings of a literature review indicate that the SN, STNT, and vestibular nucleus are relatively prone to developing encephalitis after RHS.

Sleep Disturbance and Hyperactivity Detected by Actigraphy in Rats with Allergic Rhinitis or Attention-Deficit Hyperactivity Disorder.

Actigraphy is an easy and noninvasive method used to monitor human ultradian cycles. However, to our knowledge, it has been not applied to experiments with rodents. Therefore, using actigraphy, we assessed the ultradian cycles and behavior of rats. Rats with or without allergic rhinitis wore an actigraphy device, and triaxial acceleration was recorded. The counts that represent physical activity were lower from 8:00 to 20:00 than those from 20:00 to 8:00 in control rats, suggesting that their sleep phase was from 8:00 to 20:00 and their awake phase from 20:00 to 8:00. The counts from 8:00 to 10:00 were significantly higher in allergic rhinitis rats than in control rats (p < 0.01), suggesting the presence of difficulty with sleep induction in rats with allergic rhinitis. The counts from 18:00 to 20:00 were also significantly higher in allergic rhinitis rats than in control rats (p < 0.05), suggesting the presence of early awakening in rats with allergic rhinitis. Moreover, the counts were significantly higher in allergic rhinitis rats than in control rats from 20:00 to 8:00. These results suggest that rats with allergic rhinitis experienced hyperactivity disorder during the daytime. Additionally, hyperreactivity and difficulty with sleep induction were observed in 6-hydroxydopamine-lesioned rats, an animal model of attention-deficit hyperactivity disorder. This study shows for the first time that actigraphy can be successfully used for behavioral analysis in rodents. These rat models could be useful for analyzing the mechanisms involved in sleep disturbances and hyperactivity disorder.

Inwardly rectifying potassium channels: their structure, function, and physiological roles.

Inwardly rectifying K(+) (Kir) channels allow K(+) to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are seven Kir channel subfamilies that can be classified into four functional groups: classical Kir channels (Kir2.x) are constitutively active, G protein-gated Kir channels (Kir3.x) are regulated by G protein-coupled receptors, ATP-sensitive K(+) channels (Kir6.x) are tightly linked to cellular metabolism, and K(+) transport channels (Kir1.x, Kir4.x, Kir5.x, and Kir7.x). Inward rectification results from pore block by intracellular substances such as Mg(2+) and polyamines. Kir channel activity can be modulated by ions, phospholipids, and binding proteins. The basic building block of a Kir channel is made up of two transmembrane helices with cytoplasmic NH(2) and COOH termini and an extracellular loop which folds back to form the pore-lining ion selectivity filter. In vivo, functional Kir channels are composed of four such subunits which are either homo- or heterotetramers. Gene targeting and genetic analysis have linked Kir channel dysfunction to diverse pathologies. The crystal structure of different Kir channels is opening the way to understanding the structure-function relationships of this simple but diverse ion channel family.

Broadened population-level frequency tuning in the auditory cortex of tinnitus patients.

Tinnitus is a phantom auditory perception without an external sound source and is one of the most common public health concerns that impair the quality of life of many individuals. However, its neural mechanisms remain unclear. We herein examined population-level frequency tuning in the auditory cortex of unilateral tinnitus patients with similar hearing levels in both ears using magnetoencephalography. We compared auditory-evoked neural activities elicited by a stimulation to the tinnitus and nontinnitus ears. Objective magnetoencephalographic data suggested that population-level frequency tuning corresponding to the tinnitus ear was significantly broader than that corresponding to the nontinnitus ear in the human auditory cortex. The results obtained support the hypothesis that pathological alterations in inhibitory neural networks play an important role in the perception of subjective tinnitus.NEW & NOTEWORTHY Although subjective tinnitus is one of the most common public health concerns that impair the quality of life of many individuals, no standard treatment or objective diagnostic method currently exists. We herein revealed that population-level frequency tuning was significantly broader in the tinnitus ear than in the nontinnitus ear. The results of the present study provide an insight into the development of an objective diagnostic method for subjective tinnitus.

Heterogeneous impact of alcohol consumption according to treatment method on survival in head and neck cancer: A prospective study.

Alcohol consumption is an established risk factor, and also a potential prognostic factor, for squamous cell carcinoma of the head and neck (HNSCC). However, little is known about whether the prognostic impact of alcohol consumption differs by treatment method. We evaluated the association between alcohol drinking and survival by treatment method to the primary site in 427 patients with HNSCC treated between 2005 and 2013 at Aichi Cancer Center Central Hospital (Nagoya, Japan). The impact of alcohol on prognosis was measured by multivariable Cox regression analysis adjusted for established prognostic factors. Among all HNSCC patients, the overall survival rate was significantly poorer with increased levels of alcohol consumption in multivariable analysis (trend P = 0.038). Stratification by treatment method and primary site revealed that the impact of drinking was heterogeneous. Among laryngopharyngeal cancer (laryngeal, oropharyngeal, and hypopharyngeal cancer) patients receiving radiotherapy (n = 141), a significant dose-response relationship was observed (trend P = 0.034). In contrast, among laryngopharyngeal cancer patients treated with surgery (n = 80), no obvious impact of alcohol was observed. This heterogeneity in the impact of alcohol between surgery and radiotherapy was significant (for interaction, P = 0.048). Furthermore, among patients with oral cavity cancer treated by surgery, a significant impact of drinking on survival was seen with tongue cancer, but not with non-tongue oral cancer. We observed a significant inverse association between alcohol drinking and prognosis among HNSCC patients, and its impact was heterogeneous by treatment method and primary site.

Expression of cancer/testis antigens in salivary gland carcinomas with reference to MAGE-A and NY-ESO-1 expression in adenoid cystic carcinoma.

AIMS: Cancer/testis antigens (CTAs) are detected in cancer cells but not in healthy normal tissues, with the exception of gametogenic tissues. CTAs are highly immunogenic proteins, and thus represent ideal targets for cytotoxic T-lymphocyte-mediated specific immune therapy. The aim of this study was to screen CTA expression in various types of salivary gland carcinoma and to clarify clinicopathological significance of MAGE-A and NY-ESO-1 expression in adenoid cystic carcinomas (AdCCs) of the salivary gland, which is one of the most common salivary gland carcinomas, and usually has a fatal outcome. METHODS AND RESULTS: We used immunohistochemistry to examine the expression of four CTAs (MAGE-A, NY-ESO-1, CT7, and GAGE7) in various types of salivary gland carcinoma (n = 95). When carcinoma cases were divided into low-grade and intermediate/high-grade types, NY-ESO-1 and CT7 were expressed more frequently in intermediate/high-grade carcinomas. We then focused on MAGE-A and NY-ESO-1 expression in a large cohort of adenoid cystic carcinomas (AdCCs) (n = 46). MAGE-A and NY-ESO-1 were frequently expressed in AdCC; specifically, MAGE-A was expressed in >60% of the AdCC cases. MAGE-A expression and tumour site (minor salivary gland) were identified as independent risk factors for locoregional tumour recurrence. CONCLUSIONS: These findings suggest that CTAs may be expressed in a variety of salivary gland carcinomas, especially in those with higher histological grades. In addition, MAGE-A, which is frequently expressed in AdCC cases, may be a useful prognostic factor for poorer locoregional recurrence-free survival.

Chemo-selection with docetaxel, cisplatin and 5-fluorouracil (TPF) regimen followed by radiation therapy or surgery for pharyngeal and laryngeal carcinoma.

BACKGROUND: Induction chemotherapy for patients with head and neck cancer is widely performed, and several advantages of induction chemotherapy have been reported. However, there is currently insufficient evidence to strongly recommend induction chemotherapy. In this study, we analyzed the outcomes for patients treated with induction chemotherapy and subsequent definitive treatments. METHODS: Operable patients with untreated oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma treated with induction chemotherapy were included in this retrospective study. We conducted induction chemotherapy using docetaxel, cisplatin and 5-fluorouracil and performed subsequent surgical treatment or radiotherapy according to the response to induction chemotherapy. RESULTS: A total of 65 patients were included in this study, and 50 patients (76.9%) had Stage IV tumors. The response to induction chemotherapy was CR in two patients, PR in 55 patients, and SD in eight patients. The subsequent definitive treatment was radiotherapy in 60 patients, and surgery in five patients. The 3-year overall survival rates for patients who received radiotherapy and surgery were 88.4% and 75.0%, respectively (P = 0.30). The 3-year disease-free survival rates for patients who received radiotherapy and surgery were 68.0% and 0%, respectively (P = 0.01). The 3-year laryngeal dysfunction free survival rates for patients who received RT and surgery were 77.8% and 0%, respectively (P < 0.01). CONCLUSIONS: We achieved favorable survival outcomes and high larynx preservation rates. Our results suggest that induction chemotherapy using TPF regimen is one of the optimal treatment strategies when treating head and neck cancers. Further prospective studies with a larger cohort are required to confirm our findings.

Repair of Orbital Floor Fracture With Modified Transnasal Endoscopic Approach Through Anterior Space to Nasolacrimal Duct.

OBJECTIVES: Endoscopic approach provides excellent magnification and visualization, and a purely transnasal approach is minimally invasive method. However, it is very difficult to repair anterior and lateral fractures with the previous transnasal endoscopic approaches, since repair of orbital fractures is managed through the middle meatus and ostium from the posterior side of the nasolacrimal duct with side-viewing endoscope and curved instruments. Therefore, the authors used modified transnasal endoscopic approach as an alternative for repair of orbital floor fractures in order to effectively reach the lateral or anterior fracture of the orbital floor with straight endoscope and instruments endoscopically. METHODS: Modified transnasal endoscopic approach through anterior space to nasolacrimal duct was performed in patients with orbital floor fracture, when patients rejected extranasal approach and reconstruction could not be performed by the previous purely transnasal endoscopic approach. After removal of the medial maxillary bone, the lateral wall of nose was shifted in the medial direction to allow wider access to the maxillary sinus. The bone fragments entrapping the orbital content are removed carefully, and correction of periorbita is performed. After surgery, patients were asked whether they have symptoms and/or complications. RESULTS: This modified approach was performed in 15 patients (10 males and 5 females). Mean age at surgery was 37.6 years with a range between 17 and 67. Double vision disappeared in all patients. CONCLUSIONS: This novel approach appears to be a safe and effective technique for the repair of orbital floor fractures.

Intranasal administration of IL-35 inhibits allergic responses and symptoms in mice with allergic rhinitis.

BACKGROUND: IL-35 was recently identified as an anti-inflammatory cytokine. We previously reported that recombinant fusion protein of murine IL-35 and human IgG1 Fc fragment (rIL-35) reduced Th2 cytokines (IL-4 and IL-5) in vitro. However, it is unclear whether IL-35 can attenuate nasal allergic responses and symptoms of allergic rhinitis in vivo. METHODS: To investigate the in vivo effect of IL-35 on allergic rhinitis in mice, mice were sensitized with ovalbumin (OVA). Intranasal administration of rIL-35 and intranasal challenge of OVA were then performed. Nasal symptoms were estimated after the last nasal challenge. Nasal tissue and cervical lymph nodes (CLN) were collected. OVA-specific IgE in sera, OVA-specific T cell response, and the production of cytokines (IL-4, IL-5, and IL-10) stimulated by the OVA antigen were measured. The transcription level of Foxp3 and the frequency of CD4+CD25+ regulatory T cells were also measured. RESULTS: rIL-35 significantly inhibited the number of sneezes and nasal rubbing movements. It also reduced the number of eosinophils in the nasal mucosa and significantly decreased the level of OVA-specific IgE, the OVA-specific T cell proliferation, and the production of IL-4 and IL-5. Furthermore, rIL-35 significantly increased the production of IL-10, the transcription level of Foxp3, and the frequency of CD4+CD25+ regulatory T cells. CONCLUSIONS: This study showed for the first time that rIL-35 inhibits nasal allergic responses and symptoms in mice, and that rIL-35 increases IL-10, Foxp3, and CD4+CD25+ regulatory T cells in CLN. This study also suggests that intranasal administration of IL-35 can attenuate allergic rhinitis.

Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): A retrospective analysis of 235 patients from a nationwide survey in Japan.

OBJECTIVE: We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV). METHODS: This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text. RESULTS: Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p < 0.05), both ANCAs-negative phenotype (p < 0.001), and headache (p < 0.001). The administration of corticosteroid together with an immunosuppressant was an independent predicting factor for lack of disease relapse (odds ratio [OR] = 1.90, p = 0.03) and an improvement in hearing loss (OR =2.58, p = 0.0002). CONCLUSION: Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.

The unique electrical properties in an extracellular fluid of the mammalian cochlea; their functional roles, homeostatic processes, and pathological significance.

The cochlea of the mammalian inner ear contains an endolymph that exhibits an endocochlear potential (EP) of +80 mV with a [K(+)] of 150 mM. This unusual extracellular solution is maintained by the cochlear lateral wall, a double-layered epithelial-like tissue. Acoustic stimuli allow endolymphatic K(+) to enter sensory hair cells and excite them. The positive EP accelerates this K(+) influx, thereby sensitizing hearing. K(+) exits from hair cells and circulates back to the lateral wall, which unidirectionally transports K(+) to the endolymph. In vivo electrophysiological assays demonstrated that the EP stems primarily from two K(+) diffusion potentials yielded by [K(+)] gradients between intracellular and extracellular compartments in the lateral wall. Such gradients seem to be controlled by ion channels and transporters expressed in particular membrane domains of the two layers. Analyses of human deafness genes and genetically modified mice suggested the contribution of these channels and transporters to EP and hearing. A computational model, which reconstitutes unidirectional K(+) transport by incorporating channels and transporters in the lateral wall and connects this transport to hair cell transcellular K(+) fluxes, simulates the circulation current flowing between the endolymph and the perilymph. In this model, modulation of the circulation current profile accounts for the processes leading to EP loss under pathological conditions. This article not only summarizes the unique physiological and molecular mechanisms underlying homeostasis of the EP and their pathological relevance but also describes the interplay between EP and circulation current.

The unique ion permeability profile of cochlear fibrocytes and its contribution to establishing their positive resting membrane potential.

Eukaryotic cells exhibit negative resting membrane potential (RMP) owing to the high K(+) permeability of the plasma membrane and the asymmetric [K(+)] between the extracellular and intracellular compartments. However, cochlear fibrocytes, which comprise the basolateral surface of a multilayer epithelial-like tissue, exhibit a RMP of +5 to +12 mV in vivo. This positive RMP is critical for the formation of an endocochlear potential (EP) of +80 mV in a K(+)-rich extracellular fluid, endolymph. The epithelial-like tissue bathes fibrocytes in a regular extracellular fluid, perilymph, and apically faces the endolymph. The EP, which is essential for hearing, represents the potential difference across the tissue. Using in vivo electrophysiological approaches, we describe a potential mechanism underlying the unusual RMP of guinea pig fibrocytes. The RMP was +9.0 ± 3.7 mV when fibrocytes were exposed to an artificial control perilymph (n = 28 cochleae). Perilymphatic perfusion of a solution containing low [Na(+)] (1 mM) markedly hyperpolarized the RMP to -31.1 ± 11.2 mV (n = 10; p < 0.0001 versus the control, Tukey-Kramer test after one-way ANOVA). Accordingly, the EP decreased. Little change in RMP was observed when the cells were treated with a high [K(+)] of 30 mM (+10.4 ± 2.3 mV; n = 7; p = 0.942 versus the control). During the infusion of a low [Cl(-)] solution (2.4 mM), the RMP moderately hyperpolarized to -0.9 ± 3.4 mV (n = 5; p < 0.01 versus the control), although the membranes, if governed by Cl(-) permeability, should be depolarized. These observations imply that the fibrocyte membranes are more permeable to Na(+) than K(+) and Cl(-), and this unique profile and [Na(+)] gradient across the membranes contribute to the positive RMP.

Prognostic Value of Drinking Status and Aldehyde Dehydrogenase 2 Polymorphism in Patients With Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The association between alcohol drinking, aldehyde dehydrogenase 2 (ALDH2) polymorphism, and survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unclear. METHODS: We performed a retrospective cohort study of 267 HNSCC patients at Aichi Cancer Center. Of these, 65 patients (24%) were non-drinkers, 104 (39%) were light drinkers (ethanol <46 g or <5 days/week), 46 (17%) were moderate drinkers (ethanol intake 46-68 g/day and ≥5 days/week), and 52 (20%) were heavy drinkers (ethanol intake ≥69 g and ≥5 days/week). The prognostic value of pre-treatment drinking status and ALDH2 polymorphism was investigated using multivariate proportional hazard models. RESULTS: Drinking status was associated with disease-free survival (DFS) in HNSCC patients, with marginal statistical significance (5-year DFS: 67.9% [95% confidence interval {CI}, 53.8-78.4%] for non-drinkers, 57.6% [95% CI, 47.4-66.6%] for light drinkers, 46.1% [95% CI, 30.8-60.1%] for moderate drinkers, and 43.5% [95% CI, 29.3-56.9%] for heavy drinkers; P = 0.088). However, this association lost significance when multivariate analyses were adjusted for established prognostic factors. ALDH2 genotype was not significantly associated with DFS in HNSCC patients (5-year DFS: 85.7% [95% CI, 53.9-96.2%] for Lys/Lys, 56.2% [95% CI, 47.4-64.1%] for Glu/Lys, and 50.5% [95% CI, 40.3-59.7%] for Glu/Glu; P = 0.154). After stratification by ALDH2 genotype, we observed a significant positive dose-response relationship between drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu (Ptrend = 0.029). CONCLUSIONS: In this study, we identified a significant positive dose-response relationship between pre-treatment drinking status and DFS in HNSCC patients with ALDH2 Glu/Glu. To confirm this association, further study is warranted.