A PROSPECTIVE STUDY ON LIFESTYLE GUIDANCE AND USE OF MANAGEMENT FORMS FOR FOOD ALLERGY IN LICENSED NURSERY SCHOOLS.

BACKGROUND: 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. OBJECTIVES: The contents of lifestyle management guidance forms obtained in Sagamihara city from licensed nurseries were investigated prospectively. SUBJECTS AND METHODS: 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. RESULTS: 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). CONCLUSION: Using a life management guidance form will make it easier to manage food allergies in children.

Spatiotemporal expression of TRPM4 in the mouse cochlea.

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.

Notch signaling and the developing inner ear.

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.

Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens-Johnson syndrome and toxic epidermal necrolysis.

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.

Bone marrow-derived cells are not the origin of the cancer stem cells in ultraviolet-induced skin cancer.

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.

Notch-Hes1 pathway contributes to the cochlear prosensory formation potentially through the transcriptional down-regulation of p27Kip1.

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.

Increased soluble Fas ligand levels in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis preceding skin detachment.

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-alpha, IFN-gamma, 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.

Endoscopic endonasal management of recurrent maxillary mucoceles using biliary T-tube stenting.

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.

Mapping of notch activation during cochlear development in mice: implications for determination of prosensory domain and cell fate diversification.

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."

Endolymphatic hydrops as a cause of audio-vestibular manifestations in relapsing polychondritis.

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.

Endoscopic Transseptal Approach to Frontal Sinus Disease.

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.

Expression of Musashi1, a neural RNA-binding protein, in the cochlea of young adult mice.

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.

Subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil.

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.

Soluble Fas ligand: is it a critical mediator of toxic epidermal necrolysis and Stevens-Johnson syndrome?

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 in TEN and SJS.