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Mucoceles of the paranasal sinus can be managed endoscopically with an extremely low recurrence rate. Frontal sinus mucoceles can sometimes be prevented from closing and reforming by stenting, which to the best of our knowledge has not yet been reported in the maxillary sinus. We describe the cases of 5 patients—3 men and 2 women, aged 47 to 75 years (mean; 59.6)—with a recurrent and intractable maxillary sinus mucocele that was managed with biliary T-tube stenting. The indications for stenting included recurrent episodes of mucocele with or without a lateral location with a relatively thick bony wall. A latex rubber pediatric biliary T-tube was endoscopically inserted through a window opening into the marsupialized mucocele. The stent was removed 6 to 14 months postoperatively in 4 cases; in the other case, the stent remained adequately positioned for 35 months. None of the patients experienced signs or symptoms of recurrence. We conclude that a T-tube stent can be used successfully to maintain long-term patency in patients with a recurrent and intractable maxillary mucocele, with patency being maintained even after removal of the stent.

Background Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. Methods This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. Results We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. Conclusion We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

There have been no reports on the use of "foods allergy disease lifestyle guidance and management forms at day care centers" (life management guidance forms) for understanding details of pupils with food allergies.The contents of lifestyle management guidance forms obtained in Sagamihara city from licensed nurseries were investigated prospectively.We compared and analyzed for the use of life management guidance forms initially in 2013 and in the fiscal year of 2014 in Sagamihara city licensed nurseries.In all, in 2013 and 2014, 9,567 and 10,069 pupils were included in licensed nurseries, and 426 (4.5%) and 447 (4.4%) pupils had food allergies, 61 (0.6%) and 61 (0.6%) had anaphylaxis, respectively.The causative foods in 2013 and 2014, respectively, included unheated hen's egg in 71.6% and 69.6%; heated hen's egg in 54.2% and 54.8%; milk in 23.0% and 23.3%; peanuts in 17.8% and 17.0%; buckwheat in 7.3% and 8.5%; and wheat in 6.3% and 8.3%. There are no significant differences in the distribution of causative foods between 2013 and 2014.Immediate-type food allergy was significantly more frequent in 2014 than in 2013 (73.0% and 78.8%, respectively; p=0.040).Using a life management guidance form will make it easier to manage food allergies in children.

We present herein on two cases of fungal rhinosinusitis infiltrating the adjacent structures. The first case was zygomycosis in the sphenoid sinus infiltrating the superior orbital fissure and clivus, developed in an old but immunocompetent female. Endoscopic sinus surgery followed by systemic administration of liposomal amphotericin B (L-AMB) rapidly relieved the symptoms of severe headache and high fever. The accompanying abducens palsy also recovered 3 months after the treatment. The second case was aspergillosis extending into the orbit and cavernous sinus in a 66 years old male with diabetes mellitus. While L-AMB treatment showed limited effect, alteration to voriconazole and micafungin administration dramatically improved the signs and symptoms. Oral administration of voriconazole was continued for 4 months until negative serum βD glucan confirmed. These two cases were successfully treated with endoscopic surgery and antifungal agents, but invasive fungal rhinosinusitis remians a challenging clinical state for otolaryngologists. Treatment plans should be based on the histological identification of the causal fungus.

Acute invasive fungal sinusitis frequently occurs in immunocompromised hosts suffering from diabetes mellitus, liver diseases, using steroids or antibiotics and in the elderly. Invasive fungal sinusitis can destroy bones, muscles and tissues and cause orbital and cranial complications, and increases the mortality rate. Recently, however, antifungal drugs have been reported to be effective against invasive fungal sinusitis. We report on a patient with acute invasive fungal sinusitis who died from drug-related side effect. The patient was 72-year-old man who had diabetes mellitus, hepatitis C and cerebral infarction. He complained of right visual loss. He was treated with steroids, but his visual activity decreased. He was referred to our hospital because of the presence of an invasive soft tissue density in the right sphenoid sinus on CT imaging. We performed an endonasal endoscopic biopsy to confirm the diagnosis. The diagnosis was invasive paranasal aspergillosis. He was treated with antifungal drugs, but he died of liver failure caused by the drugs. In the case of an underlying disease, it is necessary to pay special attention to drug-associated side effects.

We clinically examined 32 subjects—25 men and 7 women (median age: 65 years)—with inverted nasal and paranasal sinus papilloma seen between 1997 and 2010. Krouse classification confirmed, 6 as T1, 7 as T2, 18 as T3, and 1 as T4. The 31 subjects with T1, T2 and T3 underwent surgery, and the remaining T4 subject chemoradiation. Recurrence occurred in 6 of the surgical cases (recurrence rate: 19%). Reducing post operative recurrence requires that magnetic resonance imaging and computed tomography, identify tumor origin and extent and that endoscopic examination confirm total surgical excision.

Eighteen new eremophilanes (dimeric lactones, lactams, carboxylic acid, methyl ester, tetranor- and dinor-ketones, furanoeremophilane, enoleremophilanolide, epoxyeremophilanolide, and hydroxy- or methoxyeremophilanolides) have been isolated from the methanol extract of fresh rhizomes of Farfugium japonicum (Compositae), and their structures have been determined on the basis of high-resolution 2D NMR and X-ray crystallographic analyses as well as by chemical transformations.

The Notch signaling pathway has a crucial role in the differentiation of hair cells and supporting cells by mediating "lateral inhibition" via the ligands Delta-like1 (Dll1) and Jagged2 (Jag2) and the effectors Hes1 and Hes5 during mammalian inner ear development. Recently, another Notch ligand, Jagged1 (Jag1)-dependent Notch activation, has been revealed to be important for the determination of the prosensory region in the earlier stage before cell differentiation. However, little is known about the effectors of the Notch pathway in this context. P27(Kip1), a cyclin-dependent kinase inhibitor, is also known to demarcate the prosensory region in the cochlear primordium, which consists of the sensory progenitors that have completed their terminal mitoses. Hes1 reportedly promotes precursor cell proliferation through the transcriptional down-regulation of p27(Kip1) in the thymus, liver, and brain. In this study, we observed Hes1 as a mediator between the Notch signaling pathway and the regulation of proliferation of sensory precursor cells by p27(Kip1) in the developing cochlea. We showed that Hes1, but not Hes5, was weakly expressed at the time of onset of p27(Kip1). The expression pattern of Hes1 prior to cell differentiation was similar to that of activated Notch1. P27(Kip1) was up-regulated and BrdU-positive S-phase cells were reduced in the developing cochlear epithelium of Hes1 null mice. These results suggest that the Notch-Hes1 pathway may contribute to the adequate proliferation of sensory precursor cells via the potential transcriptional down-regulation of p27(Kip1) expression and play a pivotal role in the correct prosensory determination.

Several lines of evidence have demonstrated that various cancers are derived from cancer stem cells (CSCs), which are thought to originate from either tissue stem or progenitor cells. However, recent studies have suggested that the origin of CSCs could be bone marrow-derived cells (BMDCs); for example, gastric cancer, which follows persistent gastric inflammation, appears to originate from BMDCs. Although our previous research showed the capability of BMDCs to differentiate into epidermal keratinocytes, it has yet to be determined whether skin CSCs originate from BMDCs. To assess the possibility that BMDCs could be the origin of CSCs in skin squamous cell carcinoma (SCC), we used a mouse model of UVB-induced skin SCC. We detected a low percentage of BMDCs in the lesions of epidermal dysplasia (0.59%), SCC in situ (0.15%), and SCC (0.03%). Furthermore, we could not find any evidence of clonal BMDC expansion. In SCC lesions, we also found that most of the BMDCs were tumor-infiltrating hematopoietic cells. In addition, BMDCs in the SCC lesions lacked characteristics of epidermal stem cells, including expression of stem cell markers (CD34, high alpha6 integrin) and the potential retention of BrdU label. These results indicate that BMDCs are not a major source of malignant keratinocytes in UVB-induced SCC. Therefore, we conclude that BMDCs are not the origin of CSCs in UVB-induced SCC.

Relapsing polychondritis (RP) is characterized by inflammation and subsequent degeneration of cartilage. We report a 61-year-old woman who had RP with audio-vestibular manifestations. She was also diagnosed as having a myelofibrosis with myeloid metaplasia (MMM). Bilateral endolymphatic hydrops (EH) was confirmed by dominant -SP/AP of the electrocochleogram (ECochG). When thalidomide and prednisolone were prescribed for the treatment of MMM, symptoms of RP -- including the inner ear dysfunction -- were ameliorated. Isosorbide, one of the osmotic diuretics commonly used for the treatment of Meniere's disease (MD) in Japan, was also effective in keeping her free from inner ear dysfunction. This is the first report to confirm the existence of EH in a patient with RP with audio-vestibular manifestations. We suppose that an immunological imbalance due to MMM, in conjunction with a specific immunogenetic background, may have played a role in the pathogenesis of RP and the formation of EH in this patient.

Musashi1 (Msi1) is an RNA-binding protein expressed in neural stem/progenitor cells, astroglial progenitor cells and astrocytes in the vertebrate central nervous system. We hypothesized that Msi1 is expressed in only some of the supporting cells in the cochlea, which could become hair cell progenitors under special circumstances after an injury. To observe this, we investigated Msi1 expression in young adult mouse cochlea by immunohistochemistry using monoclonal antibody against Msi1. Msi1 immunostaining was found in a variety of supporting cells but not in outer hair cells in the organ of Corti. Although an immunoreactive ring was found around the inner hair cells, it also seemed to originate from the supporting cells. We suppose that this wide expression of Msi1 in supporting cells indicates that those cells might have the potential to become hair cell progenitors if injured, but that some other mechanisms strictly inhibit this ability.

Background: Adult nasolacrimal sac mucocele, dacryocystocele, is a rare complication of chronic dacryocysitis. Study design and methods: Case report Case presentation: We report two adult cases in which epiphora and a bluish cystic mass was located inferior to medial canthus. Nasolacrimal sac mucocele in both cases was successfully cured by endoscopic marsupialization. Conclusions: The successful outcomes were obtained by endoscopic marsupialization of the nasolacrimal sac mucocele.

This paper describes an endoscopic transseptal approach to identify and access the frontal sinus and reviews the clinical cases. Between May 2004 and July 2010, endoscopic modified Lothrop procedure (EMLP) with transseptal approach was performed on sixteen patients. The indications for EMLP were complicated frontal sinusitis or cyst, revision surgery for failed frontal sinusotomy or Lynch procedure, or trauma cases. The first step of this procedure was to open a window in the bilateral anterior portion of the middle turbinates and nasal septum. The nasal septum, which could be observed through the window, should be the landmark of the midline during the surgery. A drill bur was raised up just behind the nasal bone along the midline of the nose. After the bilateral frontal sinuses and their posterior walls were confirmed, the interfrontal septum was removed superiorly. We reviewed the clinical records of patients who underwent the EMLP with transseptal approach. We have managed sixteen patients in this fashion. Neither intracranial nor orbital complications were encountered during or after surgery. Endoscopic transseptal frontal sinus surgery is simple to perform, and does not cause severe complications.

© 2014 The Authors. doi: 10.2340/00015555-1806 Journal Compilation © 2014 Acta Dermato-Venereologica. ISSN 0001-5555 Lymphomatoid papulosis (LyP) is characterised by a chronic course of years to decades of recurrent papulonodular lesions, each of which undergoes spontaneous regression after weeks or months (1). Recently LyP type D was identified as a new histolopathological variant simulating a primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (pCAE-CD8+ CTCL) (2). Despite histologically alarming features, the patients have a clinical presentation and indolent course that are similar to those with typical cases of LyP.

A linoleic acid ester of an alcohol possessing two triple bonds (trans-lachnophyllol) has been isolated from the root ofAster tataricus, and its structure determined based on the spectroscopic evidence.

Because profound bilateral hearing impairment is a catastrophic event, the management and care of an individual with an 8th nerve lesion in an only/better hearing ear remains a significant challenge for both patient and physician. Current options regarding the treatment of the acoustic tumor in an only/better hearing ear include: observation, attempted hearing preservation surgery and stereotactically guided radiation therapy. In this article, we present 3 cases of acoustic tumor within the internal auditory canal in an only/better hearing ear diagnosed by gadolinium-enhanced MRI and discuss the recommendations, especially observation, available in the care of these cases. In one patient, hearing disturbance caused by the tumor in a better hearing ear made the patient quite depressive and desperate. One of the most important consideration is for the physician to provide the patient with adequate informed consent regarding the possibility of profound bilateral hearing loss caused by either the natural growth or surgical removal of the tumor in the future, and alternative methods of communication with others such as: hearing aid and lip reading, cochlear implant and brainstem implant.

We experienced 52 patients with idiopathic sudden deafness with vertigo treated at our hospital between 1992 and 1997. In order to investigate influences of long-term canal paresis (CP) on the patients' hearing prognosis and activity in their daily life, we examined caloric test, audiometry and several questionnaires with 30 out of 52 patients over long-term intervals (14-75 months) after the onset. These examinations revealed that 20 out of 30 patients had persistent CP and poor prognosis of hearing. Those with persistent CP also had a handicap in their everyday life because of the dizziness induced by head and body movements, resulting in disturbance of their mood. It is notable that hearing level of those with persistent CP was worsened during long-term follow up (more than 5 years).

The purpose of the present study was to investigate the clinical features of cases of cholesteatoma with labyrinthine fistulas, and in particular the pre and post-operative bone-conduction (BC). Cholestatoma patients with bone erosion or a defect found in the first stage operation were analyzed. The operations were conducted between 1992 and 1996. The patients were classified into four types, I, IIa, IIb, and III, according to Dornhoffer and Milewski's classification, which is based on different stages in the bone defect. A type I fistula is an erosion of the bony labyrinth with an intact endosteum. Type IIa is accompanied by an opened perilymphatic space with undisturbed perilymph while type IIb has a disturbed perilymph. A Type III fistula is an opened perilymphatic space with a disturbance of the underlying membranous labyrinth. Only 24 patients with type II and type III fistulas were included in this study. The location of the fistulas was the semicircular canals (SCCs) or/and the vestibula in 21 patients and in the cochlea in 3 patients. We examined the fistula by high-resolution computed tomography scan (CT scan) with 1 mm slice and 1 mm width axial-sections in 14 patients. A bone defect in the labyrinth was detected in 10 cases (71.5%) pre-operatively. Pre-operative BC was worse in the patients with cochlear fistulas than in those with fistulas located in SCCs or the vestibula. Within this latter group there were 13 type IIa (group IIa), patients and 8 type IIb or III (group IIb or III) patients. However, there was no difference in the pre-operative BC between these two sub-groups Tympanoplasty was conducted in all 24 patients. The postoperative BC of group IIa and group IIb or III were compared. Two of the 13 patients in group II a (15.4%) and 3 of 8 in group IIb or III (37.5%) had a deteriorated postoperative BC. Statistical analysis revealed that the postoperative BC was more inclined to become worse in patients with advanced stage IIb or III fistulas.

In this paper, a very rare case of vasculo (angio)-Behcet's disease initiated with hoarseness due to inflammatory aortic aneurysm, is presented. A 35 year-old male with persistent hoarseness for half a month was revealed to have left recurrent laryngeal nerve palsy. Chest X-ray films showed slight enlargement of the aortic arch. CT demonstrated direct evidence of a saccular type aortic aneurysm at the branched area of the left subclavian artery. Aortic angiography demonstrated two additional aortic aneurysms at the right subclavian artery and in the lower abdominal area. The patient subsequently underwent emergency surgery for treatment of these aneurysms. The histopathological characteristics of the representative aortic aneurysmal lesions suggested a diagnosis of “vasculo-Behcet's disease”. Behcet's disease is usually characterized by oral and genital ulceration, folliculitis and uveitis. This patient, however, displayed no previous evidence of these symptoms. We would like to emphasize that some cases of left recurrent laryngeal nerve palsy require urgent management.

An 84-year-old female with profound hearing loss in her left ear since her childhood, complained of vertigo attack with right fluctuating hearing loss and tinnitus. The clinical picture suggested a diagnosis “contralateral delayed endolymphatic hydrops”. On serological test, however, this patient showed moderately positive serology for syphilis. Precise re-inquiry indicated that she was infected with syphilis during pregnancy in her twenties. Thus, we treated this case with isosorbide dehydration, steroids and anti-syphilitic medication. As the result, vertigo attack was suppressed, hearing level became stable, and the rate of syphilitic serology was reduced. It is rare but noteworthy that this case of syphilitic labyrinthitis showed clinical course similar to delayed endolymphatic hydrops. In this paper, we would like to emphasize the necessity of excluding syphilitic labyrinthitis from the differential diagnosis of other vestibular diseases including delayed endolymphatic hydrops.

A 46-year-old Japanese woman pr esented with vesicles on her nose and the dosal aspect of her hands since 3 months. Physical examination revealed tense blisters and atrophic erythematous plaques on her arms and the dosal side of her hands (Fig. 1a). Erosions were also scattered on the face (Fig. 1b). She also had hypertrichosis on her face. The patient was first diagnosed as having systemic lupus erythematosus (SLE) in 1997 at the age of 41 years, when she presented with alopecia, fever, arthralgia, Raynaud’s phenomenon, hemolytic anemia and lymphadenopathy. Liver transamirase levels were slightly elevated. She had no sign of hepatitis including autoimmune hepatitis, drug-rela ted hepatotoxity, al coholic hepatitis, or viral infection. Systemic lupus eryhtematosus was well-controlled with a daily 5-mg dose of prednisolone (PSL). At age of 43 years she developed erythematous plaques with scaling on the back of her hands. Clinically the skin erupution at that time appeared to be discoid lupus erythematodes. She was treated with a steroid ointment and her eruptions gradually improved, but new skin lesions repeatedly appeared on her hands. Laboratory investigations at age 46 years while taking PSL 5mg disclosed the following results: white cell count 3.9 ×10

三環系抗うつ薬は心血管系に対して著明な作用を及ぼすが,麻酔薬との相互作用は明らかではない.うつ病のため三環系抗うつ薬のイミプラミン,アミトリプチリンをそれぞれ30mg/日服用中の49歳の男性患者に対して,大動脈弁閉鎖不全に対する弁置換術が予定された.患者の強い希望で投薬を継続した.体外循環からの離脱は順調であったが,術直後より高度の心機能低下が認められた.さらに三環系抗うつ薬の再開後,I度房室ブロックや心室性頻脈などの不整脈が認められ,恒久的ペースメーカーの植え込みを行なった.開心術症例では手術操作による心機能低下も加わるため,周術期の三環系抗うつ薬の継続および再開は心機能も考慮したうえで決定すべきである.

The present study was conducted to elucidate the presence of the transient receptor potential cation channel subfamily M member 4, TRPM4, in the mouse inner ear. TRPM4 immunoreactivity (IR) was found in the cell body of inner hair cells (IHCs) in the organ of Corti in the apical side of marginal cells of the stria vascularis, in the apical portion of the dark cells of the vestibule, and in a subset of the type II neurons in the spiral ganglion. Subsequently, changes in the distribution and expression of TRPM4 in the inner ear during embryonic and postnatal developments were also evaluated. Immunohistochemical localization demonstrated that the emergence of the TRPM4-IR in IHCs occurs shortly before the onset of hearing, whereas that in the marginal cells happens earlier, at the time of birth, coinciding with the onset of endolymph formation. Furthermore, semiquantitative real-time PCR assay showed that expressions of TRPM4 in the organ of Corti and in the stria vascularis increased dramatically at the onset of hearing. Because TRPM4 is a Ca(2+) -activated monovalent-selective cation channel, these findings imply that TRPM4 contributes to potassium ion transport, essential for the signal transduction in IHCs and the formation of endolymph by marginal cells.

Objectives/Hypothesis Japanese patients with chronic rhinosinusitis with nasal polyps (CRSwNP), differing from European and U.S. patients, are suggested to show two distinct phenotypes: Th2-polarized and Th1-shifted immunity. The purpose of this study was to conduct clinical subgrouping of CRSwNP based on inflammatory cell infiltration, which was evaluated and supported by clinical backgrounds and immunological characteristics. Study Design A cross-sectional study. Methods One hundred thirty Japanese patients with CRSwNP were classified by the infiltration of eosinophils and neutrophils in nasal polyps. Immunohistochemical analysis was performed in 42 patients. Results The patients were classified into three groups: 1) 42 patients with eosinophilic type, 2) 27 patients with neutrophilic type, and 3) 61 patients with noneosinophilic nonneutrophilic type. Both the number of serum eosinophils and the recurrence rates were significantly higher in the eosinophilic group compared to the other two groups. The IgE value was significantly higher in the eosinophilic group, followed by the noneosinophilic nonneutrophilic and neutrophilic groups. Both the symptomatic and CT scores were significantly greater in the eosinophilic group than in the neutrophilic group. The expressions of eotaxin, IL-17A, MUC5AC, and CD68 were greater in the eosinophilic group than in the other two groups. Conclusion The eosinophilic CRSwNP phenotype is clinically characterized by serum eosinophilia, atopy, extensive disease, and poor prognosis compared to the neutrophilic and the noneosinophilic nonneutrophilic groups. We clearly demonstrated that all three subgroups of CRSwNP had characteristic differences in those inflammatory markers, which allows for pathophysiologically meaningful differentiations with likely therapeutic consequences. Level of Evidence 3b. Laryngoscope, 123:E1–E9, 2013

Sensory hair cells (HCs) and their associated nonsensory supporting cells (SCs) exhibit a typical mosaic pattern in each of the sensory patches in the inner ear. Notch signaling has been considered to conduct the formation of this mosaic pattern through one of its famous functions, known as 'lateral inhibition'. The two Notch ligands Delta-like1 and Jagged2 are believed to act synergistically at the stage of cell diversification in mammals. In addition, many current studies suggest that Notch signaling has another inductive, but not inhibiting, role in the determination of the prosensory region, which precedes the cell diversification of HCs and SCs and Jagged1 is thought to be an essential ligand in this process. Earlier in ear development, the first cell fate determination begins with the delamination of the neuroblasts from the otic epithelium. The delaminated neuroblasts migrate and coalesce to form cochleovestibular ganglion. Notch signaling pathway is thought to function during the delamination through its lateral inhibitory mechanism. Recently, many experiments examining Notch-related gene expression patterns and direct functional analyses of genes have revealed multiple important functions of Notch in inner ear development. Here, we survey a series of studies and discuss the issues that remain to be elucidated in the future.

Sensory hair cells (HCs) and their associated nonsensory supporting cells (SCs) exhibit a typical mosaic pattern in each of the sensory patches in the inner ear. Notch signaling has been considered to conduct the formation of this mosaic pattern through one of its famous functions, known as ‘lateral inhibition’. The two Notch ligands Delta-like1 and Jagged2 are believed to act synergistically at the stage of cell diversification in mammals. In addition, many current studies suggest that Notch signaling has another inductive, but not inhibiting, role in the determination of the prosensory region, which precedes the cell diversification of HCs and SCs and Jagged1 is thought to be an essential ligand in this process. Earlier in ear development, the first cell fate determination begins with the delamination of the neuroblasts from the otic epithelium. The delaminated neuroblasts migrate and coalesce to form cochleovestibular ganglion. Notch signaling pathway is thought to function during the delamination through its lateral inhibitory mechanism. Recently, many experiments examining Notch-related gene expression patterns and direct functional analyses of genes have revealed multiple important functions of Notch in inner ear development. Here, we survey a series of studies and discuss the issues that remain to be elucidated in the future.

Background Life-threatening adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) sometimes start with clinical features of ordinary drug-induced skin reactions (ODSRs) and it may be difficult to make a correct diagnosis before severe mucocutaneous erosions occur. We have reported that serum granulysin levels are elevated (cut off: 10 ng/mL) in patients with SJS/TEN before generalized blisters form. Objective We sought to develop a rapid detection system for elevated serum granulysin to predict the progression from ODSRs. Methods Serum samples from 5 patients with SJS/TEN at 2 to 4 days before mucocutaneous erosions formed were analyzed. Sera from 24 patients with ODSRs and 31 healthy volunteers were also investigated as control subjects. We developed a rapid immunochromatographic assay for the detection of high levels of serum granulysin using two different antigranulysin monoclonal antibodies. Results The immunochromatographic test showed positive results for 4 of 5 patients with SJS/TEN but only one patient of 24 with ODSRs. The results correlated closely with those of enzyme-linked immunosorbent assays. Limitations The validation of the long-time stability in this test strip has not been investigated. Conclusion This novel test enables the prediction of SJS/TEN occurrence in patients even when only features of ODSRs are noted clinically.

Background It is difficult to distinguish the early phase of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) from other ordinary types of drug-induced skin reactions (ODSRs). Levels of several serum soluble factors, including soluble Fas ligand (sFasL), have been reported to be increased in patients with SJS/TEN; however, the marker to predict the onset of SJS/TEN before the development of skin detachment or mucosal lesions has not been identified. Objective We sought to determine whether sFasL might be a useful marker in the early stages of SJS/TEN. Methods Sera of 19 patients with SJS and 16 patients with TEN at 1 or multiple time points were obtained from Japanese multiple hospitals. The disease onset (day 1) was defined when erosion/ulceration of the mucocutaneous or ocular lesion first developed. For the investigation of soluble factors, including sFasL, TNF-α, IFN-γ, IL-6, and sCD40 ligand, we used ELISAs and Cytometric Bead Arrays. Results Before disease onset (day −4 to approximately −2), 7 samples were available, and we detected the highest concentrations of sFasL in 5 (71.4%) of 7 patients. Increased sFasL levels decreased rapidly within 5 days of disease onset. In all 32 patients with ODSRs and 33 healthy control subjects, no increase of sFasL levels was detected. Other soluble factor concentrations did not show significant difference with those seen in patients with SJS/TEN before disease onset and ODSRs. Conclusion The sFasL levels of sera in patients with SJS/TEN are significantly increased before development of skin detachment, mucosal lesions, or both.

Recent chick experiments have shown that Notch signaling plays context-dependent distinct roles in inner ear development: initially, Notch activity confers a prosensory character on groups of cells by "lateral induction"; subsequently, it is involved in the establishment of fine-graded patterns of hair cells and supporting cells by "lateral inhibition." However, the spatiotemporal pattern of Notch activation in situ during mammalian inner ear development has not been investigated. In this study, we detected the expression patterns of the activated form of Notch1 (actN1) as well as those of endogenous Notch1, Jagged1 (Jag1), and Math1. ActN1 was detected by immunohistochemistry using an antibody that specifically recognizes the processed form of the intracellular domain of Notch1 cleaved by presenilin/gamma-secretase activity. Between embryonic days (E)12.5 and E14.5, actN1 was weakly detected mainly in the medial region of cochlear epithelium, where Jag1-immunoreactivivty (IR) was also observed. Jag1-IR gradually became stronger in a more sharply defined area, finally becoming localized in supporting cells, while actN1 was detected in an overlapping area. Thus, a positive feedback loop was assumed to exist between the expression of Jag1 and actN1. In addition, actN1 started to be strongly expressed in the cells surrounding Math1-positive hair cell progenitors between E14.5 and E15.5. Strong actN1-IR continued in both a supporting cell lineage and in the greater epithelial ridge during the perinatal stage but ended by P7, suggesting that Notch1 activation may initially demarcate a prosensory region in the cochlear epithelium and then inhibit progenitor cells from becoming hair cells via classical "lateral inhibition."

Structure and function of the marginal cell in the stria vascularis were studied by freeze-fracture, cytochemistry and immunohistochemistry with special regard to the ion transport of potassium. Freeze-fracture showed that marginal cells were connected by tight junctions beneath the scala media K(+)-NPPase cytochemistry showed that Na+, K(+)-ATPase was abundant on the basolateral infoldings of the marginal cell. Immunohistochemistry of a rat Isk protein, which has a property of a potassium channel, revealed that the rat Isk protein was localized at the endolymphatic surface of the marginal cell. These findings supported the 'one-pump' theory (Offner et al. Hear Res 1987; 29: 117-24).

Understanding the appearance of vestibular symptoms during periods of convalescence after surgery for the treatment of Meniere's disease is important for determining when a patient can return to work as well as the long-term results of the operation. We have treated 20 cases of intractable Meniere's disease with endolymphatic sac drainage & steroid-instillation surgery (EDSS) [Kitahara T, et al., Ann Otol Rhlnol Laryngol in press, 2000] and observed the subjective symptoms and objective vestibular findings using electronystagmogram (ENG) during the subsequent period of convalescence. The average postoperative durations of subjective static and evoked vestibular symptoms were 1.7 and 6.7 days, respectively. Those of spontaneous, positional and positioning nystagmus observed using ENG were 1.2, 2.0 and 7.9 days, respectively. In cases with a long history of Meniere's disease, postoperative static vestibular sensation and positional nystagmus lasted significantly longer than in cases with short histories. In cases with poorly developed temporal bony pneumatization in the area behind the posterior semicircular canal, postoperative evoked vestibular sensations and positioning nystagmus lasted significantly longer than in cases with well developed temporal bony pneumatization. Vestibular symptoms resulting from direct invasion during EDSS were considered to be slighter than those resulting from vestibular neurectomy or gentamicin treatment and almost the same as those resulting from endolymphatic sac surgery.

Although soluble Fas ligand (sFasL) is an important candidate in toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS), Stur and colleagues report that elevated sFasL has been detected in maculopapular rashes. In addition to sFasL, other factors, including predisposing genetic factors, should also be investigated to determine their precise pathogenesis inTEN and SJS.