Cerebellar Abscess Induced by Cochlear Fistula due to Chronic Suppurative Otitis Media.

Cochlear fistulas with cholesteatoma as the primary disease have been reported frequently in the relevant literature. However, there are no reports of cochlear fistula without cholesteatoma due to chronic suppurative otitis media with intracranial complications. We report a case of cochlear fistula due to chronic otitis media that was diagnosed after the onset of a cerebellar abscess. The patient was a 25-year-old man with severe autism. He was admitted to our hospital with otorrhea from his left ear, emesis, and impaired consciousness. Computed tomography (CT) of the head showed left suppurative otitis media, left cerebellar abscess, and brainstem compression due to hydrocephalus. Right extra-ventricular drainage and brain abscess drainage were urgently performed. The next day, foramen magnum decompression and abscess drainage with partial resection of the swollen cerebellum were performed for decompression purposes. He was subsequently treated with antimicrobial therapy, but magnetic resonance imaging of the head showed an increase in the size of the cerebellar abscess. Re-examination of the temporal bone CT scans revealed a bony defect in the left cochlear promontory angle. We assumed that the cochlear fistula was responsible for the otogenic brain abscess. Thus, the patient underwent surgical closure of the cochlear fistula. After the operation, the cerebellar abscess lesion gradually shrank, and his general condition stabilized. Cochlear fistula should be considered in the management of patients with inflammatory middle ear disease associated with otogenic intracranial complications in the middle ear.

Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear.

Light-gated ion channels and transporters have been applied to a broad array of excitable cells including neurons, cardiac myocytes, skeletal muscle cells and pancreatic ß-cells in an organism to clarify their physiological and pathological roles. Nonetheless, among nonexcitable cells, only glial cells have been studied in vivo by this approach. Here, by optogenetic stimulation of a different nonexcitable cell type in the cochlea of the inner ear, we induce and control hearing loss. To our knowledge, deafness animal models using optogenetics have not yet been established. Analysis of transgenic mice expressing channelrhodopsin-2 (ChR2) induced by an oligodendrocyte-specific promoter identified this channel in nonglial cells-melanocytes-of an epithelial-like tissue in the cochlea. The membrane potential of these cells underlies a highly positive potential in a K+-rich extracellular solution, endolymph; this electrical property is essential for hearing. Illumination of the cochlea to activate ChR2 and depolarize the melanocytes significantly impaired hearing within a few minutes, accompanied by a reduction in the endolymphatic potential. After cessation of the illumination, the hearing thresholds and potential returned to baseline during several minutes. These responses were replicable multiple times. ChR2 was also expressed in cochlear glial cells surrounding the neuronal components, but slight neural activation caused by the optical stimulation was unlikely to be involved in the hearing impairment. The acute-onset, reversible and repeatable phenotype, which is inaccessible to conventional gene-targeting and pharmacological approaches, seems to at least partially resemble the symptom in a population of patients with sensorineural hearing loss. Taken together, this mouse line may not only broaden applications of optogenetics but also contribute to the progress of translational research on deafness.

Computer modeling defines the system driving a constant current crucial for homeostasis in the mammalian cochlea by integrating unique ion transports.

The cochlear lateral wall-an epithelial-like tissue comprising inner and outer layers-maintains +80 mV in endolymph. This endocochlear potential supports hearing and represents the sum of all membrane potentials across apical and basolateral surfaces of both layers. The apical surfaces are governed by K+ equilibrium potentials. Underlying extracellular and intracellular [K+] is likely controlled by the "circulation current," which crosses the two layers and unidirectionally flows throughout the cochlea. This idea was conceptually reinforced by our computational model integrating ion channels and transporters; however, contribution of the outer layer's basolateral surface remains unclear. Recent experiments showed that this basolateral surface transports K+ using Na+, K+-ATPases and an unusual characteristic of greater permeability to Na+ than to other ions. To determine whether and how these machineries are involved in the circulation current, we used an in silico approach. In our updated model, the outer layer's basolateral surface was provided with only Na+, K+-ATPases, Na+ conductance, and leak conductance. Under normal conditions, the circulation current was assumed to consist of K+ and be driven predominantly by Na+, K+-ATPases. The model replicated the experimentally measured electrochemical properties in all compartments of the lateral wall, and endocochlear potential, under normal conditions and during blocking of Na+, K+-ATPases. Therefore, the circulation current across the outer layer's basolateral surface depends primarily on the three ion transport mechanisms. During the blockage, the reduced circulation current partially consisted of transiently evoked Na+ flow via the two conductances. This work defines the comprehensive system driving the circulation current.

Musashi-1 is the candidate of the regulator of hair cell progenitors during inner ear regeneration.

BACKGROUND: Hair cell loss in the cochlea is caused by ototoxic drugs, aging, and environmental stresses and could potentially lead to devastating pathophysiological effects. In adult mammals, hair cell loss is irreversible and may result in hearing and balance deficits. In contrast, nonmammalian vertebrates, including birds, can regenerate hair cells through differentiation of supporting cells and restore inner ear function, suggesting that hair cell progenitors are present in the population of supporting cells. RESULTS: In the present study, we aimed to identify novel genes related to regeneration in the chicken utricle by gene expression profiling of supporting cell and hair cell populations obtained by laser capture microdissection. The volcano plot identified 408 differentially expressed genes (twofold change, p = 0.05, Benjamini-Hochberg multiple testing correction), 175 of which were well annotated. Among these genes, we focused on Musashi-1 (MSI1), a marker of neural stem cells involved in Notch signaling, and the downstream genes in the Notch pathway. Higher expression of these genes in supporting cells compared with that in hair cells was confirmed by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry analysis demonstrated that MSI1 was mainly localized at the basal side of the supporting cell layer in normal chick utricles. During the regeneration period following aminoglycoside antibiotic-induced damage of chicken utricles, the expression levels of MSI1, hairy and enhancer of split-5, and cyclin D1 were increased, and BrdU labeling indicated that cell proliferation was enhanced. CONCLUSIONS: The findings of this study suggested that MSI1 played an important role in the proliferation of supporting cells in the inner ear during normal and damaged conditions and could be a potential therapeutic target in the treatment of vestibular defects.

Correction: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

[This corrects the article DOI: 10.1371/journal.pgen.1005778.].

Safety and efficacy of short-term oral immunotherapy with Cry j 1-galactomannan conjugate for Japanese cedar pollinosis: a randomized controlled trial.

Current allergen-specific immunotherapy (AIT) for pollinosis requires long-term treatment with potentially severe side effects. Therefore, development of an AIT that is safe and more convenient with a shorter regimen is needed. This prospective, double-blind, placebo-controlled trial randomized 55 participants with Japanese cedar pollinosis (JCP) to active or placebo groups to test the safety and efficacy of short-term oral immunotherapy (OIT) with Cry j 1-galactomannan conjugate for JCP. Mean symptom-medication score as the primary outcome in the active group improved 27.8% relative to the placebo group during the entire pollen season. As the secondary outcomes, mean medication score in active group improved significantly, by 56.2%, compared with placebo during the entire pollen season. Mean total symptom score was similar between active and placebo groups during the entire pollen season. There were no severe treatment-emergent adverse events in the active and placebo groups. Therefore short-term OIT with Cry j 1-galactomannan conjugate is safe, and effective for reducing the amount of medication use for JCP.

Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes.

CIC-DUX4 and BCOR-CCNB3 fusion-gene-associated small round cell sarcomas account for a proportion of pediatric small round cell sarcomas, but their pathological features have not been sufficiently clarified. We reviewed a large number of soft tissue tumors registered at our institution, retrieved the cases of unclassified tumors with a small round cell component, and subjected them to histopathological, immunohistochemical, and gene profile analysis. We reviewed 164 cases of unclassified tumors with a small round cell component and analyzed them by RT-PCR and FISH. Tumors positive for a specific fusion-gene were also subjected to histopathological and immunohistochemical examinations. We identified 16 cases of BCOR-CCNB3/CIC-associated (CIC-DUX4 or CIC gene rearrangement-positive) sarcomas. These included seven BCOR-CCNB3 sarcomas and nine CIC-associated sarcomas. Heterogeneous elements included a myxoid spindle cell component in three BCOR-CCNB3 sarcomas and an epithelioid cell component in two CIC-associated sarcomas (one CIC-DUX4-positive and one CIC-DUX4-negative sarcomas). Mitotic activity was low in both heterogeneous components. By immunohistochemistry, in seven BCOR-CCNB3 sarcomas expression of EMA was positive in two cases, of p63 in three, of CD56 in six, of TLE1 in seven, of NKX2.2 in two, of CCNB3 in seven, and of BCOR in six cases (one case could not be tested for BCOR). In nine cases of CIC-associated sarcoma, CD56 was expressed in five, alpha-smooth muscle actin in one, ERG in three, and CD99, WT1 and TLE1 each in eight cases. Both sarcoma types showed not only a small round cell component, but also a myxoid/epithelioid component with low mitotic activity.

A microsensing system for the in vivo real-time detection of local drug kinetics.

Real-time recording of the kinetics of systemically administered drugs in in vivo microenvironments may accelerate the development of effective medical therapies. However, conventional methods require considerable analyte quantities, have low sampling rates and do not address how drug kinetics correlate with target function over time. Here, we describe the development and application of a drug-sensing system consisting of a glass microelectrode and a microsensor composed of boron-doped diamond with a tip of around 40 µm in diameter. We show that, in the guinea pig cochlea, the system can measure-simultaneously and in real time-changes in the concentration of bumetanide (a diuretic that is ototoxic but applicable to epilepsy treatment) and the endocochlear potential underlying hearing. In the rat brain, we tracked the kinetics of the drug and the local field potentials representing neuronal activity. We also show that the actions of the antiepileptic drug lamotrigine and the anticancer reagent doxorubicin can be monitored in vivo. Our microsensing system offers the potential to detect pharmacological and physiological responses that might otherwise remain undetected.

[A Case of Pneumocystis Pneumonia after Cetuximab-based Bioradiotherapy].

Reports of drug-induced interstitial pneumonia caused by Cetuximab have been increasing. Pneumocystis pneumonia is important as a differential diagnosis of drug-induced interstitial pneumonia. We report herein on a 64-year-old man with pneumocystis pneumonia after cetuximab-based bioradiotherapy for laryngeal cancer. After radiotherapy, the patient developed multi-drug resistant pneumonia. Chest CT imaging revealed diffuse ground-glass opacities in the lung field. He was diagnosed as having pneumocystis pneumonia based on the bronchoalveolar lavage (BAL) findings, and then his symptoms improved after treatment with Trimethoprim/Sulfamethoxazole. It is important to assess the risk factor for pneumocystis pneumonia for early its detection and treatment.

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.

Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

Tracheobronchomegaly associated with laryngo-tracheal amyloidosis: First case report.

Tracheobronchomegaly (TBM) is a rare enlargement of the tracheal cartilage, also known as Mounier-Kuhn syndrome (MKS). Here, we describe an unusual case of acquired TBM in an adult, caused by amyloid regeneration and associated tracheal weakening, rather than by MKS. CT scan and fiberscopic examination of a 55-year-old woman suffering from severe dyspnea revealed TBM and subglottic stenosis, which was caused by deposition of amyloid tissue. We performed a tracheostomy and vaporized the subglottic stenosis with a CO2 laser, after which we installed a silicone T-tube. After the first operation, re-stenosis occurred, and the procedure was repeated; stenosis was subsequently cured and the dyspnea disappeared, after which the tracheostomy could be closed. This is the first report of adult TBM associated with amyloid deposition in the subglottis and trachea. This diagnosis is very difficult, as amyloid deposition in the trachea can have various clinical presentations.

Prognostic impact of salvage treatment on hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic corticosteroids: A retrospective observational study.

OBJECTIVE: To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment. METHODS: This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone). RESULTS: The linear regression model identified age (P=0.001), pretreatment hearing level (P<0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (<60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery. CONCLUSION: The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment.

Effect of short-term oral immunotherapy with Cry j1-galactomannan conjugate on quality of life in Japanese cedar pollinosis patients: A prospective, randomized, open-label study.

OBJECTIVE: We have recently reported that a new regimen of short-term oral immunotherapy (OIT) with the Cry j1-galactomannan conjugate for Japanese cedar pollinosis (JCP) is effective to the improvement in the symptoms and medication use during the pollen season and relatively safe. The effect of OIT on quality of life (QOL) of JCP patients has not been assessed. Therefore, we evaluated for the first time the effect of OIT on QOL during the Japanese cedar/cypress pollen season. METHODS: A prospective, randomized, open-label trial was conducted over a period of 4 months. Participants were randomly divided into two groups. The OIT and control groups comprised 23 and 24 subjects, respectively. The build-up phase was initiated 1 month before the expected pollen season. The maintenance phase was continued for 51 days during the peak of the cedar pollen season. The QOL score in the Japan Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) No. 1 and visual analog scale (VAS) throughout the pollen season were evaluated. RESULTS: Participants receiving OIT showed significant improvements in the total QOL score and VAS throughout the pollen season compared with the control group. In addition, the mean total QOL score and VAS correlated in both groups during the pollen season. CONCLUSION: The new regimen of short-term OIT using the Cry j1-galactomannan conjugate results in meaningful improvements in QOL of JCP patients. Our findings suggest that short-term OIT using allergen-galactomannan conjugates, as well as sublingual and subcutaneous immunotherapy, improves QOL of patients with pollinosis. The study was registered in UMIN-CTR (UMIN000013408) as the name of "a prospective, randomized, open study of oral Cry j1-galactomannan conjugate immunotherapy for Japanese cedar pollen allergy".

Surgical approaches to jugular foramen schwannomas: An anatomic study.

BACKGROUND: The variety of surgical approaches to jugular schwannomas makes selection of an approach difficult. The purpose of this study was to define the anatomic elements of these approaches. METHODS: Ten adult cadaveric heads were examined. RESULTS: There are lateral, posterior, and anterior routes that access various parts of the jugular foramen. Removal of the jugular process of the occipital bone provides access to the posterior aspect of the foramen, the infralabyrinthine mastoidectomy provides access to the lateral edge and dome of the jugular bulb, and the preauricular approaches provide access to the anterior margin of the bulb and foramen. Additions to these approaches may include cervical and vertebral artery exposure, facial nerve transposition, foramen magnum exposure, and external canal and condylar resection. CONCLUSION: An understanding of the anatomy of the jugular foramen is crucial in achieving total tumor removal while minimizing risk. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1041-E1053, 2016.

Dual gain of HER2 and EGFR gene copy numbers impacts the prognosis of carcinoma ex pleomorphic adenoma.

We investigated the potential roles of HER2 and EGFR and evaluated their prognostic significance in carcinoma ex pleomorphic adenoma (CXPA). We analyzed HER2 and EGFR overexpression status using immunohistochemistry (IHC) and gene copy number gain by chromogenic in situ hybridization (CISH) in 50 cases of CXPA (40 ductal-type and 10 myoepithelial-type CXPAs). Salivary duct carcinoma was the most common histologic subtype of malignant component (n = 21). Immunohistochemistry positivity and chromogenic in situ hybridization positivity were closely correlated in both HER2 and EGFR. HER2 CISH positivity (mostly gene amplification) and EGFR CISH positivity (mostly gene high polysomy) were present in 19 (40%) and 21 (44%) cases, respectively, and were each significantly correlated with poor outcome (P = .0009 and P = .0032, respectively). Dual gain of HER2 and EGFR gene copy numbers was present in 11 cases (23%) and was the most aggressive genotype. HER2 CISH positivity was more frequently present in ductal-type CXPAs (47%) than in myoepithelial-type CXPAs (10%), whereas the prevalence of EGFR CISH positivity was similar in both histologic subtypes (42% and 50%, respectively). Our results suggest that HER2 and EGFR gene copy number gains may play an important role in the progression of CXPA, in particular ductal-type CXPAs. HER2 CISH-positive/EGFR CISH-positive tumors may be the most aggressive subgroup in CXPA. The molecular subclassification of CXPA based on the HER2 and EGFR status may be helpful for prognostic prediction and decisions regarding the choice of therapeutic strategy.

Molecular architecture of the stria vascularis membrane transport system, which is essential for physiological functions of the mammalian cochlea.

Stria vascularis of the mammalian cochlea transports K(+) to establish the electrochemical property in the endolymph crucial for hearing. This epithelial tissue also transports various small molecules. To clarify the profile of proteins participating in the transport system in the stria vascularis, membrane components purified from the stria of adult rats were analysed by liquid chromatography tandem mass spectrometry. Of the 3236 proteins detected in the analysis, 1807 were membrane proteins. Ingenuity Knowledge Base and literature data identified 513 proteins as being expressed on the 'plasma membrane', these included 25 ion channels and 79 transporters. Sixteen of the former and 62 of the latter had not yet been identified in the stria. Unexpectedly, many Cl(-) and Ca(2+) transport systems were found, suggesting that the dynamics of these ions play multiple roles. Several transporters for organic substances were also detected. Network analysis demonstrated that a few kinases, including protein kinase A, and Ca(2+) were key regulators for the strial transports. In the library of channels and transporters, 19 new candidates for uncloned deafness-related genes were identified. These resources provide a platform for understanding the molecular mechanisms underlying the epithelial transport essential for cochlear function and the pathophysiological processes involved in hearing disorders.