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Tight junctions (TJs) are necessary for salivary gland function and may serve as indicators of salivary gland epithelial dysfunction. IgG4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition which disrupts the TJ associated epithelial barrier. The salivary glands are one of the most frequently involved organs in IgG4-RD, however, changes of the TJ associated epithelial barrier in salivary gland duct epithelium is poorly understood. Here, we investigated the regulation and function of TJs in human submandibular gland ductal epithelial cells (HSDECs) in normal and IgG4-RD. We examined submandibular gland (SMG) tissue from eight control individuals and 22 patients with IgG4-RD and established an HSDEC culture system. Immunohistochemistry, immunocytochemistry, western blotting, and measurement of transepithelial electrical resistance (TER) were performed. Claudin-4, claudin-7, occludin, and JAM-A were expressed at the apical side of the duct epithelium in submandibular gland (SMG) tissue and at the cell borders in HSDECs of normal and IgG4-RD. The expression and distribution of TJs in SMG tissue were not different in control individuals and patients with IgG4-RD in vivo and in vitro. Although interferon-gamma (IFNγ) generally disrupts the integrity and function of TJs, as manifested by decreased epithelial barrier function, IFNγ markedly increased the epithelial barrier function of HSDECs via upregulation of claudin-7 expression in HSDECs from patients with IgG4-RD. This is the first report showing an IFNγ-dependent increase in epithelial barrier function in the salivary gland duct epithelium. Our results provide insights into the functional significance of TJs in salivary gland duct epithelium in physiological and pathological conditions, including IgG4-RD.

Changes in interferon (IFN)-stimulated gene (ISG) expression in cells infected with measles virus (MeV), four wild strains (belonging to different genotypes), and the laboratory strain Edmonston were examined. ISGs [MxA, 2'-5'-oligoadenylate synthetase, and interferon regulatory factor-1] were upregulated in an MeV-infection-induced manner and in an IFN-induced manner. In MeV-infected SiHa cell lines, the MeV infection-induced expression levels were in the order of A>H1>D8>D5>D3. On the other hand, all infected cell lines abolished type I and III IFN-induced ISG expression. However, partial type II IFN-mediated induction was observed in the MeV-infected cells. The wild strain of genotype D3 was the most potent inhibitor of MeV infection-induced and IFN-induced ISG expression and generated the highest titer of infectious viral particles. Edmonston triggered the highest levels of MeV infection-induced ISG expression in SiHa cells and produced the lowest titer of infectious particles. Expression of the viral C protein was associated with suppression of MeV infection-induced and type II IFN-induced ISG expression.

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B-cell lymphoma-6 and Blimp-1 determine lineages of Tfh cells and other types of effector CD4(+) T cells, respectively, suggests that there are unique mechanisms to establish Tfh-cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B-cell lymphoma-6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1(-/-) mice were much higher than those in wild-type (WT) mice. In addition, expansion of Tfh cells within Bob1(-/-) CD4(+) T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T-cell-intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1(-/-) Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3-induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1-related mechanism to restrict numerical frequency against stimulation of TCRs., (© 2016 The Authors. European Journal of Immunology published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Adrenergic receptors (ARs) include four general types (α1, α2, β1 and β2), which are found in different target tissues. α-AR agonists are commonly used for decongestant therapy of upper airway diseases. In order to clarify the roles of AR subtypes in the upper airways, we investigated the localization of these receptors by immunohistochemistry., Methods: Human turbinates were obtained after turbinectomy from 12 patients with nasal obstruction refractory to medical therapy. The specific cells expressing α- and β-AR proteins were identified by immunostaining using an anti-human AR subtype-specific antibodies (α1A-, α1D-, α2C- and β2-ARs) antibody., Results: Immunohistochemical analysis revealed that immunoreactivities for α1D- and β2-ARs were densely distributed in submucosal glands. In contrast, immunoreactivities for α1A- and 2C-ARs were densely distributed in vascular smooth muscle., Conclusion: Our results suggested that adrenergic receptor (AR) subtypes had different roles in upper airway diseases, such as allergic rhinitis and nonallergic rhinitis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Junctional adhesion molecule-A (JAM-A), which belongs to the IgG superfamily, is one of the tight junction molecules. JAM-A is dysregulated in various cancers and is closely associated with the invasion and metastasis of cancers such as breast cancer, lung cancer and pancreatic cancer. In the present study, we found a high expression of JAM-A in head and neck squamous cell carcinoma (HNSCC) as well as β-catenin in immunohistochemistry. The expression of JAM-A and β-catenin was of a low level in differentiation-induced cancer pearl regions of HNSCC. Real-time PCR showed the high expression of JAM-A mRNA through all differentiated stages (well, moderate, poor) of HNSCC. When we performed ELISA using the serum of HNSCC patients to measure plasma-soluble JAM-A, it was found to be higher in HNSCC patients than healthy subjects. These results indicate that JAM-A is one of the malignancy markers of HNSCC as well as β-catenin in histopathology, and the plasma-soluble JAM-A may contribute to a serum diagnosis of HNSCC. JAM-A is a promising molecular target for diagnosis and therapy in HNSCC., (© 2016 S. Karger AG, Basel.)

Pneumolabyrinth is a rare condition with air bubbles existing in the vestibule and/or cochlea. We report a case of pneumolabyrinth without trauma that was suspected to be caused by labyrinthitis. A 65-year-old man presented with vertigo and hearing loss in the left ear after catching a cold. Computed tomography performed after there had been no improvement in the patient's symptoms showed the presence of air bubbles in the vestibule, semicircular canals and cochlea. The patient was transferred to our hospital with suspected perilymphatic fistula. Bacterial infection was suspected after the laboratory tests had indicated a severe inflammatory response, and the patient was treated with antibiotics. However, no bacteria were detected in a bacterial culture of the otorrhea. An exploratory tympanotomy was performed to improve the patient's staggering gait and to examine the middle ear, with no obvious fistula being observed. Subsequent fenestration of the round window revealed a white mass that appeared to contain bacteria which was collected from the cochlea and submitted for analysis and bacterial culture. However, no bacteria were detected and the mass contained white blood cells. We suspected pneumolabyrinth following labyrinth infection. However, the cause of air bubble formation remains unclear and needs to be validated with further research., (© 2016 S. Karger AG, Basel.)

In the sensory hair cells of the mammalian cochlea, the primary cilia in the planar cell polarity as well as the tight junctions in the epithelial cell polarity and the barrier are important to maintain normal hearing. Temperature-sensitive mouse cochlear precursor hair cells were used to investigate the behavior of primary cilia and tricellular tight junction proteins during the differentiation of sensory hair cells. In undifferentiated cells (incubated at 33°C), many acetylated tubulin-positive primary cilia were observed, and each was accompanied with an x03B3;-tubulin-positive basal body. The primary cilia had a '9 + 0' architecture with nine outer microtubule doublets but lacking a central pair of microtubules. In differentiated cells (incubated at 39°C), acetylated tubulin-positive primary cilia as well as acetylated tubulin-positive cilia-like structures were partially observed on the cell surface. In differentiated cells, the number of primary cilia was markedly reduced compared with undifferentiated cells, and innumerable cilia-like structures with no ciliary pockets were partially observed on the cell surface. In undifferentiated cells, few tricellulin molecules and lipolysis-stimulated lipoprotein receptors (LSRs) were observed in the cytoplasm. In differentiated cells, many tricellulin molecules and LSRs were observed on the membranes and within the cytoplasm. Conditional immortalized mouse cochlear precursor hair cells may be useful to investigate the roles of primary cilia and tricellular tight junctions during cellular differentiation and degeneration such as apoptosis., (© 2016 S. Karger AG, Basel.)

Anisakidosis is a nematode infection caused by the ingestion of larvae-infected raw or undercooked fish. Although gastric anisakiasis is a common disease in Japan due to the popularity of eating raw and undercooked fish, reports of anisakiasis in the tonsils are extremely rare. A 68-year-old man presenting with clinical features of peritonsillitis was admitted for examination. The right peritonsillar region exhibited slight edematous swelling and rash, and a white foreign body was observed. This foreign body was removed, and pathological examination revealed Anisakis., (© 2016 S. Karger AG, Basel.)

We report a retrospective study of 26 patients with maxillary sinus squamous cell carcinoma who were treated at the Sapporo Medical University between January 2002 and December 2008. The 5-year local control rate was 85.7% in patients with stage T2-3 disease and 61.0% in patients with stage T4a disease. The overall 5-year survival rate was 71.3% and the 5-year disease-specific survival rate was 79.9%. The 5-year disease-specific survival rate was 100% in patients with T2-3 disease and 44.4% in patients with T4 disease. The 5-year disease-specific survival rate was 76.3% in patients with N0 disease and 87.5% in patients with N+ disease. Five patients died of stage T4a disease. Two died of uncontrolled tumors at the primary site and 3 patients died of lung metastasis. We should consider another approach for the treatment of patients with advanced maxillary sinus carcinoma in the future., (© 2016 S. Karger AG, Basel.)

Seventy-three children who underwent plastic surgery for their external ear malformations between December 2010 and May 2013 at the Sapporo Medical University Hospital were evaluated. The predominance of right-sided malformation (62%) in males (71%) was similar to that reported previously, but the number of bilateral cases (9.3%) was lower than that in previous reports. We classified patients' ears using Marx's classification. The pure-tone average (average air conduction thresholds measured at 500, 1,000 and 2,000 Hz) was used as the representative value for the hearing level, which was compared with a patient's Marx classification. We evaluated the facial nerve position using high-resolution computed tomography scans. A thorough understanding of anatomical variations and complications, as well as performing appropriate treatments, is required for otolaryngologists to effectively manage congenital microtia., (© 2016 S. Karger AG, Basel.)

Sleep is important for children pertaining to their physical and mental growth. Obstructive sleep apnea syndrome (OSAS) in children has been shown to have different effects as compared to OSAS in adults, including deficits in cognition and neuropsychological functions, hyperactivity, ADHD, behavior problems, aggressive behavior, learning problems and nocturnal enuresis. Hypertrophy of the adenoids and tonsils is a major cause of OSAS in children; therefore, adenotonsillectomy may decrease the effects of OSAS pertaining to physical and mental growth. It is important to accurately diagnose and appropriately treat OSAS in children to prevent OSAS in their adulthood., (© 2016 S. Karger AG, Basel.)

In an aging society, the number of patients suffering from vertigo and dizziness is increasing. Vertigo is mostly thought to occur owing to otorhinolaryngologic disease. In contrast, it is difficult to diagnose dizziness, because of its varied causes, and we believe that the number of elderly patients suffering from dizziness is increasing. Here, we evaluated the relationship between canal paralysis and symptoms at the first medical examination and age-related changes in caloric response, and obtained the following 3 main findings: (a) 41.3% of the patients with canal paralysis complained of dizziness at the first medical examination, with an increased tendency in patients aged >70 years; (b) the slow-phase eye velocity (SPEV) of patients aged >70 years was lower than that of patients aged ≤69 years, and the SPEV of patients complaining of vertigo was higher than that of patients who complained of dizziness during a caloric test, and (c) the percentage of patients complaining of dizziness and those not complaining of symptoms during a caloric test increased with age. In conclusion, patients with canal paralysis tend to complain of dizziness at the first medical examination, and the percentage of patients without vertigo during a caloric test increased with age., (© 2016 S. Karger AG, Basel.)

Defensins are small antimicrobial peptides and effector components of innate immune responses. Recent studies have shed light on their beneficial functions for the prevention of infection and potential for development of new drugs. Here, we showed the expression profiles of human defensins in palatine tonsils with 3 different diseases: tonsillar hypertrophy, recurrent tonsillitis and focal infection of the tonsil. RT-PCR analysis and immunofluorescence revealed that the expression of human α-defensin 4 and β-defensin 3 (β3) in palatine tonsils with tonsillar hypertrophy was lower than that in recurrent tonsillitis and focal infection of the tonsil, suggesting that chronic inflammation induces defensin expression. Interestingly, β2 and β3 mRNAs were specifically expressed by palatine tonsil tissues but not in human peripheral blood mononuclear cells and mucosa of the small intestine. Additionally, we observed that exposure to a Toll-like receptor 4 ligand, lipopolysaccharide, which is used as a bacterial infection model, increases the production of β2 in culture supernatants from tonsillar epithelial cells in a dose-dependent manner. Taken together, these results indicate that β2 produced by tonsillar epithelial cells plays an important role in the innate immune response for bacterial infections., (© 2016 S. Karger AG, Basel.)

Cysteinyl leukotrienes (CysLTs) are lipid mediators that have been implicated in the pathogenesis of allergic rhinitis. Pharmacological studies using CysLTs indicate that two classes of receptor exist: CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R). The CysLT1R is a high-affinity leukotriene D4 receptor with lower affinity for leukotriene C4 that is sensitive to the CysLT1R antagonist currently used to treat asthma and allergic rhinitis. Our previous immunohistochemical and autoradiographic studies have demonstrated the presence of anti-CysLT1R antibodies labeled in eosinophils, mast cells, macrophages, neutrophils and vascular endothelial cells in human nasal mucosa. Furthermore, we have revealed that the novel radioactive CysLT1R antagonist [3H]-pranlukast bound specifically to CysLT1R in human inferior turbinates and its binding sites were localized to vascular endothelium and the interstitial cells. These data suggest that the major targets of CysLT1R antagonists in allergic rhinitis are the vascular bed and infiltrated leukocytes such as mast cells, eosinophils and macrophages. Clinical trials have demonstrated that CysLT1R antagonists are as effective as antihistamines for the treatment of allergic rhinitis; however, they are less effective than intranasal steroids. The use of CysLT1R antagonists in combination with antihistamines has generally resulted in greater efficacy than when these agents were used alone., (© 2016 S. Karger AG, Basel.)

It is necessary for the surgeon to be familiar with frontal recess anatomy during an endoscopic approach to the frontal sinuses. The aim of this study was to evaluate the prevalence of frontal recess cells in Japanese adults as well as the association between the frontal recess and the location of the anterior ethmoidal artery (AEA). The frontal recess cells and the AEAs were retrospectively evaluated in CT scans of the nasal and paranasal sinuses for 89 patients. The prevalence of agger nasi cells was 90.7%. The frequency of frontal cell types 1, 2, 3 and 4 was 28.8, 0.6, 2.6 and 0%, respectively. Suprabullar cells (SBCs) and frontal bullar cells (FBCs) were identified in 78/96 sides (81.3%) and 24/96 sides (24%), respectively. The prevalence of the medial group of frontal recess cells (interfrontal sinus septal cells) was 12.4%. In 42/61 sides (68.9%), the AEAs were located within the posterior margin of the SBCs or the FBCs. Therefore, SBCs, FBCs and the vertical portion of the middle turbinate are reliable landmarks for the identification of AEAs., (© 2016 S. Karger AG, Basel.)

Nose- or nasopharynx-associated lymphoid tissue (NALT) has a unique role that is distinct from that of other lymphoid tissues. During upper airway mucosal immune response, NALT induces a variety of responses, including cytokine and chemokine production and innate immune response, to establish acquired immunity. NALT consists of epithelial cells, epithelium-associated lymphoid tissues such as IgA-committed B cells, innate lymphocytes, T helper cells and dendritic cells. Intranasal immunization has recently been shown to effectively induce a proactive immune response in the local mucosa in addition to a systemic immune response. A variety of factors can cause otitis media, including Eustachian tube dysfunction, inflammation, allergy and viral and bacterial infections. However, the detailed pathogenesis of otitis media is not yet completely understood. In this report, we provide evidence suggesting that adenoid tissue as a component of NALT in children may play an important role in inducing innate immunity following viral infection., (© 2016 S. Karger AG, Basel.)

The epithelium of upper respiratory tissues such as the human nasal mucosa forms a continuous barrier via tight junctions (TJs). The development of a drug delivery system for use across the nasal mucosa is being reconsidered. In intranasal administration across the nasal mucosa, the paracellular pathway regulated by TJs is extremely important. It is known that the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the TJ protein claudin and disrupts the tight junctional barrier without inducing a cytotoxic effect. We investigated the effects of C-CPE mutants on the function of TJs of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across HNECs treated with C-CPE 194 and C-CPE m19. We recently reported that C-CPE mutants 194 and m19 can regulate the permeability of insulin across HNECs via the MAPK pathway and may play a crucial role in therapy for various diseases via direct intranasal insulin administration. On the other hand, microRNAs (miRNAs) are known to regulate the expression of TJs as direct or indirect targets in genes to maintain barrier function. We investigated the effects of miRNAs on the epithelial barrier of HNECs and found that miRNA-146a plays crucial roles in the maintenance of the TJ barrier and innate immune response against invading pathogens. This chapter reviews a novel drug delivery system across the nasal mucosa from the point of view of the epithelial barrier function., (© 2016 S. Karger AG, Basel.)

More than 20 years have passed since cochlear implantation (CI) was first introduced in Japan. We began CI at the Sapporo Medical University Hospital in 1988; since then, up to the first half of 2015, we have performed CI on 280 ears. In patients aged less than and those aged over 18 years, 121 and 159 ears, respectively, have undergone surgery. This report presents typical cases of CI, such as an adult case, a bilateral case, a case where both hearing and vision were impaired, a pediatric case, a case with multiple handicaps, a case with a genetic mutation leading to severe hearing loss, and a complicated case. In addition, complications with CI cases experienced during extended follow-up periods are also summarized., (© 2016 S. Karger AG, Basel.)

The tonsils are located at the entrance of the pharynx as a cardinal constituent of Waldeyer's ring, taking part not only in local immune responses, but also in systemic immunity. Functional deficits of tonsils primarily underlie the pathogenesis of various characteristic disorders, including tonsillar focal infections such as palmoplantar pustulosis and IgA nephropathy, in addition to the highly prevalent sleep disorder called obstructive sleep apnea syndrome. Although the mechanisms underlying these disorders remain unknown, the tonsils have long been postulated as a unique and enigmatic immune organ. Lymphoid cells and tissues from surgically resected tonsils are often employed to analyze the human immune response from a retrospective view. This approach has provided much new fundamental evidence for understanding innate and acquired immune responses, thereby facilitating further studies in the fields of mucosal immunity and specific humoral immunity originating in the germinal center. Future studies of the tonsils in basic and clinical research are expected to reveal the mechanisms of tonsil-related disorders as well as the nature of human immunity. In this review, which is primarily based on our original research over the past 3 decades, we summarize our findings and discuss the future prospects of studies focusing on the tonsils., (© 2016 S. Karger AG, Basel.)

The nasal allergic response is a complex process involving interactions between many chemical mediators such as histamine, bradykinin, cysteinyl leukotrienes, platelet-activating factor, prostaglandin D2 and thromboxane A2. The actions of these chemical mediators are facilitated by specific cell surface receptors that are coupled to G-proteins. Current therapeutic strategies against nasal allergic responses are mainly based on drugs that target these chemical mediators. To understand the role of these chemical mediators in allergic rhinitis, determining the identity and distribution of their receptors is of considerable interest. We have examined the expression and localization of the receptors for these chemical mediators in human nasal mucosa. Here, we review our data on the expression and localization of these receptors in allergic rhinitis, and we discuss the roles of chemical mediators in allergic rhinitis., (© 2016 S. Karger AG, Basel.)

Thyroid cancer is a disease that affects 8,000 new individuals a year, a number that has increased approximately 3-fold in the past 30 years. The increase in the incidence of thyroid cancer can be related to various factors. The evolution of diagnostic technology has distinctly occurred in the fields of diagnostic imaging, cytology and immunochemistry. For example, liquid-based cytology, developed to assess gynecological lesions, has improved diagnostic accuracy over conventional smear cytology. This technique can also be positively applied to cytological analyses of thyroid cancer. In the field of tumor biomarkers, thyroglobulin and trefoil factor-1 are well known and useful. On the other hand, a new specific biomarker of thyroid cancer has been developed. Furthermore, definitive diagnosis of follicular thyroid tumors is extremely difficult or impossible with current tumor biomarkers and cytological methods. Although the standard treatment for thyroid cancer is a basic surgical resection, iodine adjuvant therapy after surgery is a well-known treatment. Here we present a treatment strategy for thyroid cancer according to the statistics obtained at our facility., (© 2016 S. Karger AG, Basel.)

Cochlear implantation (CI) has proven to be an effective treatment for severe bilateral sensorineural hearing loss (SNHL). Inner ear malformation is a rare anomaly and occurs in approximately 20% of cases with congenital SNHL. In cases with cochlear malformation, CI can be successfully performed in nearly all patients, the exceptions being those with complete labyrinthine and cochlear aplasia. It is important to evaluate the severity of inner ear deformity and other associated anomalies during the preimplantation radiological assessment in order to identify any complication that may potentially occur during the surgery and subsequent patient management., (© 2016 S. Karger AG, Basel.)

Inflammasomes, large protein complexes typically consisting of a Nod-like receptor (NLR), adapter protein apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1, are postulated to be activated in response to danger signals arising from tumors. Inflammasomes are thought to have critical but contrasting roles through facilitating antitumor immunity and inducing oncogenic factors. However, the role and function of inflammasomes in oropharyngeal carcinoma remain unclear. We analyzed nine specimens of oropharyngeal squamous cell carcinoma (SCC) and determined the expression of NLRP3, ASC, interleukin (IL)-1β, IL-18 and caspase-1 in the specimens with and without human papilloma virus (HPV) infection using immunohistochemistry, and analyzed the correlations between the altered expression of these proteins and clinicopathological factors of oropharyngeal SCC. We found strong expression of NLRP3, ASC, IL-1β, IL-18 and caspase-1 in human oropharyngeal SCC and weak or no expression of these proteins in normal tonsils. Furthermore, the distribution of mindbomb E3 ubiquitin protein ligase 1 and inflammasome-associated proteins in oropharyngeal SCC was not significantly different; there was no correlation between the expression of inflammasome-associated proteins and HPV infection. These findings suggest that inflammasomes in oropharyngeal SCC play a key role through facilitating antitumor immunity and the possibility of new roles for inflammasomes in the oropharynx., (© 2016 S. Karger AG, Basel.)

Recently, the prevalence of allergic rhinitis has been dramatically increasing worldwide. As conventional therapies for allergic rhinitis, such as antihistamines, leukotriene receptor antagonists, nasal sprays and allergen immunotherapy, have limitations, the development of new drugs is required. Recent studies have revealed that epithelial cell-derived cytokines, including thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, are able to control immune cells, such as dendritic cells and T cells, thereby acting as 'master switches' in allergic disease. In addition, new roles have been identified for follicular helper T cells and regulatory B cells in allergic disease, and they are considered to be promising targets for new therapies. Thus, crosstalk between epithelial and immune cells, the epimmunome, underlies the pathogenesis of allergic rhinitis. Greater understanding of the epimmunome may lead to breakthroughs in the development of new treatments for allergic rhinitis and will help us cure many patients suffering from its severe symptoms in the future., (© 2016 S. Karger AG, Basel.)

Allergic rhinitis is a chronic inflammatory disease of the upper airways caused by Th2 cell-type cytokines in response to allergen exposure. The inducible costimulator (ICOS), the third member of the CD28/CTLA4 family, plays an important role in immune response. In this study, adenovirus vectors containing ICOSIg (Adex1CAICOSIg) were administered to effectively inhibit the ICOS/ICOSL interaction, and the effects of Adex1CAICOSIg on allergic rhinitis were examined. Intranasal administration of Adex1CAICOSIg attenuated airway inflammation, as demonstrated by a decrease in nasal symptoms and infiltration of eosinophils into the nasal mucosa, as well as by a decrease in local IL-5 expression. Therefore, the ICOS/ICOSL pathway significantly contributes to the progression of allergic rhinitis., (© 2016 S. Karger AG, Basel.)

Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease entity characterized by elevated serum IgG4 and extensive IgG4-positive plasma cell infiltration of various organs. Patients with IgG4-RD show nasal manifestations with chronic rhinosinusitis. The objective of this study was to evaluate the clinical characteristics of sinonasal lesions in patients with IgG4-RD., Methods: We evaluated radiological findings of sinonasal lesions in 79 patients with IgG4-RD who were divided into 3 groups according to severity. We also compared serological findings, including serum IgG4 and IgE levels, and eosinophil counts., Results: Rhinosinusitis was found in 41 patients (51.9%). Although there were no significant differences in the serum IgG4 and IgE levels of the groups, there was a significant increase in eosinophil counts (445 ± 311.9/mm³) in Group C. Furthermore, 14 of the 41 patients with rhinosinusitis (34.1%) showed improvement after prednisolone administration. Patients with IgG4-RD and serum eosinophilia tend to also have sinonasal lesions., Conclusions: Rhinosinusitis is common in patients with IgG4-RD, and its pathogenesis can be similar to eosinophilic chronic rhinosinusitis., (© The Author(s) 2015.)

Background: Persons allergic to birch pollen often report oral and pharyngeal hypersensitivity to fruit and vegetables, due to immunological cross-reactivity between pollen and foods. This phenomenon is referred to as the oral allergy syndrome (GAS). Such cross-reactive antigen reactions mainly involve Bet v 1, which is the major birch-pollen allergen, and partially involve birch-pollen profilin Bet v 2. Soybean contains Bet v 1-related antigen (Gly m 4), and soy milk often causes the OAS with severe symptoms such as precordial and abdominal burning sensation because soy milk undergoes little denaturation, and this water-soluble liquid is consumed by most people rather quickly. We evaluated the frequency of the oAS after ingestion of soymilk and examined IgE antibodies to various allergens., Methods: A total of 167 patients [122 women, 45 men; age range, 4-72 years (mean age, 32 years)], who had experienced GAS episodes and had IgE birch--pollen antibodies, were interviewed. Using the CAP system, we examined IgE antibodies to birch pollen and other allergens. Of 167 patients, 161 were examined for IgE antibodies to Bet v 1, Bet v 2, Gly m 4, and soybean. We evaluated the frequency of the GAS after soy milk ingestion based on reports by GAS patients with birch pollen allergy, and evaluated the positive rates of some of the IgE antibodies., Results: Among the 167 patients with birch-pollen allergy and GAS on ingestion of any of the foods, there were 16 cases (10%) with OAS following soy milk ingestion. In addition, the foods that caused OAS most often were apples (123 cases, 74%), peaches (67%), and cherries (55%), followed by pears (37%) and kiwi (37%). A higher CAP class for birch pollen, Bet v 1, Gly m 4, and soybean was associated with a higher prevalence of OAS to soy milk. Of 15 patients who had GAS on ingestion of soy milk and had birch-pollen allergy, 47% (7cases) were CAP class 1 for soybean and only 7% (case) was CAP class c2, whereas 93% (14cases) were CAP class 1 for Gly m 4, and 87% (3cases) were CAP class ≥ 2 for Gly m 4., Conclusion: Among the birch-pollen allergic OAS patients, 10% had the OAS on ingestion of soy milk, and among these with birch-pollen allergy and the OAS on ingestion of soy milk, the positive rate for soy milk CAP was low, whereas that for Gly m 4 CAP was high.

Human nasal epithelial cells (HNECs) are important in the tight junctional barrier and innate immune defense protecting against pathogens invading via Toll-like receptors (TLRs). MicroRNAs (miRNAs) regulate expression of tight junctions as direct or indirect targeting genes and maintain the barrier function. However, the roles of miRNAs in the epithelial barrier of HNECs via TLRs remain unknown. In the present study, to investigate the effects of miRNAs on the epithelial barrier of HNECs via TLRs, primary cultured HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs), were treated with the TLR3 ligand poly(I:C) and miRNA array analysis was performed. In the miRNA array of the cells treated with poly(I:C), upregulation of miR-187, -146a, -574, -4274, -4433, -4455 and -4750, and downregulation of miR-4785 by more than twofold compared to the control were observed. When control HNECs were treated with mimics and inhibitors of these miRNAs, an miR-146a mimic induced expression of tight junction proteins claudin-1, occludin and JAM-A together with an increase of the epithelial barrier function. The poly(I:C)-induced miR-146a was regulated via the distinct TLR3-mediated signal pathways PI3K, JNK and NF-κB. Furthermore, the miR-146a mimic prevented downregulation of claudin-1 and JAM-A and the secretion of proinflammatory cytokines IL-8 and TNF-α induced by poly(I:C) by targeting TRAF6. These findings indicate that, in HNECs, miRNA-146a plays crucial roles in maintenance of the tight junction barrier and innate immune defense protecting against invading pathogens., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Progressively transformed germinal centers (PTGC), a lymph node process unfamiliar to most otolaryngologists, is a morphological variant of reactive lymphofollicular hyperplasia of lymph nodes. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a newly identified condition, characterized by hyper-IgG4-γ-globulinemia and mass-forming or hypertrophic lesions associated with infiltration of IgG4(+) plasma cells in the affected organs. Recently, a case study of PTGC was reported that fulfilled the diagnostic criteria of IgG4-RD (IgG4(+) PTGC) [1]. A 68-year-old male was referred to our hospital with swelling in the left submandibular region. Palpation revealed swollen lymph nodes, the largest of which measured 5cm in diameter. (18)F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography identified lymphadenopathy with high (18)F-FDG uptake in the left submandibular region. We strongly suspected malignant lymphoma, and excisional biopsy of the submandibular lymph node was performed under general anesthesia. Pathological findings were consistent with IgG4(+) PTGC, and serological examination demonstrated elevated levels of IgG4. These findings were consistent with IgG4-RD. The patient did not have systemic lesions; therefore, he has not undergone corticosteroid therapy. IgG4(+) PTGC should be considered as a differential diagnosis for cervical lymphadenopathy by otolaryngologists as well as pathologists., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Benign vascular tumors are frequently found in the head and neck, however, such tumors of the external auditory canal are extremely rare. We report three cases of benign vascular tumors limited to the external auditory canal., Case Description: A 50-year-old woman was diagnosed during an episode of ear fullness and hearing loss. A 10-year-old boy consulted our department about an episode of recurrent otorrhagia. A 20-year-old man found a bulge of his external auditory canal by chance. Complete surgical resection was performed for the first patient. The second patient underwent electro-coagulation of the lesion. In the third patient, to exclude the possibility of a malignant tumor, a biopsy was performed under local anesthesia. Histopathological analysis demonstrated the characteristic of vascular tumors. The lesion showed remarkable reduction during his treatment with antibiotics and cleaning. He remains under careful observation., Discussion and Evaluation: In diagnosis, there is sometimes confusion between vascular tumors and malformations. Generally, vascular malformations can be differentiated from vascular tumors since they are present at birth and are generally stable., Conclusion: Decision making about treatment of benign vascular tumors is sometimes confusing because of the difficulty in diagnosis. We performed biopsy for only one of our three cases because we regard that informal biopsy should not be conducted for lesions with difficult hemostic conditions and locations.

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypersecretion of mucin in the airway epithelium is an important feature of allergic airway diseases. Of the 3 cysteinyl leukotrienes (CysLTs; LTC4 LTD4 and LTE4), only LTE4 is sufficiently stable to be detectable in extracellular fluids. However, LTE4 has received little attention because it binds poorly to the CysLT1 and CysLT2 receptors; therefore, little is known about the effects of LTE4 on mucous secretion. Recently, studies have focused on the P2Y12 receptor as a potential receptor for LTE4, because this receptor is required for LTE4-mediated pulmonary inflammation. In our previous study, we confirmed the expression of P2Y12 receptor in human airway epithelial cells. To clarify the roles of LTE4 in airway epithelial cells, we investigated mucus secretion by LTE4 in vitro., Methods: Confluent NCI-H292 cells were stimulated with LTE4 (0.01-1 μM) for 24 h. The release and production of MUC5AC protein, a gel-forming mucin, were evaluated with an enzyme-linked immunosorbent assay., Results: Western blot analysis revealed that NCI-H292 cells expressed P2Y12 receptor protein. LTE4 significantly induced the release of MUC5AC mucin in a dose-dependent manner. Th2 cytokines such as IL-4 (10 ng/mL) and IL-13 (10 ng/mL) accelerated the LTE4-induced release of MUC5AC protein. MRS2935, a P2Y12 receptor antagonist, partially inhibited the LTE4-induced release of MUC5AC protein in the airway. In contrast, MK571, a CysLT1 receptor antagonist, did not affect the release of MUC5AC protein elicited by LTE4., Conclusions: These results suggest that LTE4 may play some important roles in allergic mucus secretion partially via activation of P2Y12 receptor., (Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The airway epithelium of the human nasal mucosa acts as the first physical barrier that protects against inhaled substances and pathogens. Irsogladine maleate (IM) is an enhancer of gastric mucosal protective factors via upregulation of gap junctional intercellular communication (GJIC). GJIC is thought to participate in the formation of functional tight junctions. However, the effects of IM on GJIC and the epithelial barrier in human nasal epithelial cells (HNECs) remain unknown. To investigate the effects of IM on GJIC and the tight junctional barrier in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were treated with IM and the GJIC inhibitors oleamide and 18β-GA. Some cells were pretreated with IM before treatment with TLR3 ligand poly(I:C) to examine whether IM prevented the changes via TLR3-mediated signal pathways. In hTERT-HNECs, GJIC blockers reduced the expression of tight junction molecules claudin-1, -4, -7, occludin, tricellulin, and JAM-A. IM induced GJIC activity and enhanced the expression of claudin-1, -4, and JAM-A at the protein and mRNA levels with an increase of barrier function. GJIC blockers prevented the increase of the tight junction proteins induced by IM. Furthermore, IM prevented the reduction of JAM-A but not induction of IL-8 and TNF-α induced by poly(I:C). In conclusion, IM can maintain the GJIC-dependent tight junctional barrier via regulation of GJIC in upper airway nasal epithelium. Therefore, it is possible that IM may be useful as a nasal spray to prevent the disruption of the epithelial barrier by viral infections and exposure to allergens in human nasal mucosa.

A spiral phenomenon is sometimes noted in the plots of CO₂ output (VCO₂) against O₂ uptake (VO₂) measured during cardiopulmonary exercise testing (CPX) in patients with heart failure with oscillatory breathing. However, few data are available that elucidate the clinical significance of this phenomenon. Our group studied the prevalence of this phenomenon and its relation to cardiac and cardiopulmonary function. Of 2,263 cardiac patients who underwent CPX, 126 patients with a clear pattern of oscillatory breathing were identified. Cardiopulmonary indexes were compared between patients who showed the spiral phenomenon (n = 49) and those who did not (n = 77). The amplitudes of VO₂ and VCO₂ oscillations were greater and the phase difference between VO₂ and VCO₂ oscillations was longer in the patients with the spiral phenomenon than in those without it. Patients with the spiral phenomenon also had a lower left ventricular ejection fraction (43.4 ± 21.4% vs 57.1 ± 16.8%, p <0.001) and a higher level of brain natriuretic peptide (637.2 ± 698.3 vs 228.3 ± 351.4 pg/ml, p = 0.002). The peak VO₂ was lower (14.5 ± 5.6 vs 18.1 ± 6.3, p = 0.002), the slope of the increase in ventilation versus VCO₂ was higher (39.8 ± 9.5 vs 33.6 ± 6.8, p <0.001), and end-tidal PCO₂ both at rest and at peak exercise was lower in the patients with the spiral phenomenon than in those without it. In conclusion, the spiral phenomenon in the VCO₂-versus-VO₂ plot arising from the phase difference between VCO₂ and VO₂ oscillations reflects more advanced cardiopulmonary dysfunction in cardiac patients with oscillatory breathing., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Abstract Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians. Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse. Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment. Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.

Objectives: Inducting clinical remission by glucocorticoid treatment is relatively easy in IgG4-related disease (IgG4-RD), but relapse also occurs easily with tapering of the steroid dose. The present study tried to analyse the cases to extract predictors of relapse present at the diagnosis of IgG4-RD., Methods: Subjects comprised 79 patients with IgG4-related dacryoadenitis and sialadenitis, known as Mikulicz's disease, who were diagnosed between April 1997 and October 2013 and followed-up for >2 years from the initial induction treatment. They were applied to Cox proportional hazard modelling, based on the outcome of interval to relapse. We performed multivariate analysis for the clinical factors of these cases and identified predictors of relapse., Results: Identified factors were male sex and younger onset in cases without organ involvement at diagnosis and low levels of serum IgG4 in cases with organ dysfunction at diagnosis. Complication with autoimmune pancreatitis and low steroid dose at initial treatment also tended to be associated with recurrence., Conclusion: Follow-up is important in cases with recognized risk factors for relapse, including male sex and younger onset in cases without organ damage., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Conclusions: Tracheoesophageal diversion (TED) and laryngotracheal separation (LTS) can prevent aspiration pneumonia and improve the morbidity of patients with severe motor and intellectual disability (SMID). By improving hospitalization rates and care needs, the quality-of-life can be improved for the patients and their parents., Objectives: This study evaluated the clinical outcomes of TED and LTS in patients with intractable aspiration and SMID., Methods: This study retrospectively reviewed patients with SMID and intractable aspiration pneumonia who underwent TED or LTS at the institution between January 2008 and January 2015. It assessed the frequency of sputum suctioning, the number of pre-operative and post-operative hospitalizations, the operative time, and complications., Results: Forty patients were identified during the study period. After surgery, there were significant reductions in the frequency of secretion suctioning (from 165.0 times/day to 33.0 times/day) and the number of hospitalizations because of aspiration pneumonia (from 5.4 times/year to 0.2 times/year). A tracheocutaneous fistula occurred in one (2.5%) patient, and two (5.4%) patients developed tracheoinnominate artery fistulas. In the latter group, the innominate arteries were successfully ligated and endovascular embolization was performed.

The current clinical study was performed on 311 cases of pars flaccida and 89 cases of pars tensa cholesteatoma which were treated with canal wall reconstructed tympanoplasty between 1991 and 2012. The average follow-up time of these patients was 5.3 years. Since follow-up periods were different in each case and some censored patients were involved, we used survival analysis on this study to discuss the cumulative rates of disease-free successful cases and the rates of recurrent cholesteatoma throughout the postoperative course. The disease-free successful cases were defined as those cases in which patients were both out of re-operation with recurrent and residual cholesteatoma and out of revision operation with another problem, furthermore, maintained good hearing outcome. Based on the criteria set by the Japan Otological Society (2010), the cases that satisfied the following were evaluated as good hearing results; (a) a successful case in which preoperative bone conduction was used, and (b) a case in which the postoperative air-bone gap was within 20dB after tympanoplasty for chronic otitis media. The analysis results were shown for each of (a) and (b). 1. In pars flaccida cholesteatoma, the 5-year survival rate of successful case was (a) 76.1% and (b) 83.9%, the 10-year survival rate was (a) 58.9% and (b) 73.0%. In pars tensa cholesteatoma, the 5-year survival rate of successful cases was (a) 57.7% and (b) 63.5%, the 10-year rate was (a) 42.1% and (b) 56.9%. A significant difference was seen between pars flaccida and pars tensa cholesteatoma (p < 0.001). 2. In pars flaccida cholesteatoma, the 5-year recurrence rate was 7.6% and the 10-year rate was 15.3%, and the recurrence rate increased gradually throughout the follow-up period. On the other hand, in pars tensa cholesteatoma, the increase in the recurrence rate reached a peak 15.8% at 5.5 years after the surgery. A long-term follow-up is necessary when evaluating the clinical results after tympanoplasty.

The newly comprehensive diagnostic criteria in 2011 emphasize the importance of IgG4-positive plasmacyte infiltration along with storiform or swirling fibrosis and obliterative phlebitis in diagnosing IgG4-related disease(RD). Although labial salivary gland (LSG) biopsy is a minimally invasive and convenient procedure for obtaining tissues, LSG fibrosis is thought to be inconspicuous or absent in IgG4-RD cases. In this study we evaluated 15 patients with IgG4-RD, in whom both submandibular gland (SMG) and LSG biopsies were performed at the same time. Histological evaluation revealed fibrosis in all the SMG specimens but in only one LSG specimen (6.7%). The diagnosis of IgG4-RD is primarily based on its morphological appearance on biopsy. The results of this study demonstrated that although more invasive than LSG biopsy, SMG biopsy is recommended for accurate diagnosis of IgG4-related MD and to exclude malignant diseases.

Objectives: Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease (MD), is a chronic inflammatory disease. However, little is known about its pathogenesis and pathological condition. In the present study, we used immunohistological techniques to compare the roles of cytotoxic T lymphocytes (CTLs) in MD and primary Sjogren's syndrome (SS). We examined the state of CTLs [cytotoxic granule-positive rate and programmed death-1 (PD-1) expression rate] in the salivary glands., Methods: The study samples comprised 12 submaxillary glands from untreated MD patients and 12 labial glands from SS patients. We performed immunofluorescence and multicolor immunofluorescence to stain CD8, perforin (PRF), granzyme B (GZMB), and PD-1. We measured the total number of CTLs as well as the PRF(+)CTLs, GZMB(+)CTLs, and PD-1(+)CTLs., Results: We found that the degree of infiltration of CTLs was equal in MD and SS, but the rate of CTLs with cytotoxic granules, especially PRF, in MD was less than in SS. In addition, the frequency of PD-1(+)CTLs in MD was higher than that in SS., Conclusions: Cytotoxic granule-positive CTLs were in the minority in D salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.

Objectives: Mikulicz's disease (MD) is an immunoglobulin (Ig) G4-related disease with systemic symptoms. Submandibular gland (SMG) biopsy is recommended for patients with possible IgG4-related MD for accurate differential diagnosis; however, it is difficult for certain patients to undergo this procedure. In contrast, labial salivary gland (LSG) biopsy is more convenient. Here we present an analysis of patients with IgG4-related MD whose LSG specimens were infiltrated with abundant IgG4-positive plasma cells., Methods: Sixteen patients diagnosed with IgG4-related MD underwent simultaneous SMG and LSG biopsies. We evaluated patients' serological and (18)F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) and grouped them as LSG+ (LSG specimens with > 40% IgG4-positive plasma cells/IgG-positive plasma cells, 11 patients) or LSG- (LSG specimens with < 40% IgG4-positive plasma cells/IgG-positive plasma cells, 6 patients)., Results: There were not significant differences in serum IgG and IgG4 levels between the two groups; however, serum concentrations of soluble interleuikin-2 receptor (sIL-2R) were significantly higher in the LSG+ group. All patients with increased (18)F-FDG uptake in their parotid glands were a part of the LSG+ group., Conclusions: When a SMG biopsy is not possible, the serum concentration of sIL-2R and (18)F-FDG-PET/CT findings may predict whether LSG biopsy will facilitate the diagnosis of IgG4-related MD.

Tight junctions (TJs), which are the most apically located of the intercellular junctional complexes, have a barrier function and a fence function. Recent studies show that they also participate in signal transduction mechanisms. TJs are modulated by intracellular signaling pathways including protein kinase C, mitogen-activated protein kinase, and NF-ϰB, to affect the epithelial barrier function in response to diverse stimuli. TJs are also regulated by various cytokines, growth factors, and hormones via signaling pathways. To investigate the regulation of TJ molecules via signaling pathways in human epithelial cells under normal and pathological conditions, we established a novel model of human telomerase reverse transcriptase-transfected human epithelial cells. In this review, we describe the recent progress in our understanding of the role of TJs for signal transduction under normal conditions in upper airway epithelium, pancreatic duct epithelial cells, hepatocytes, and endometrial epithelial cells, and in pathological conditions including cancer and infection.

Objectives: Recent studies revealed that Mikulicz's disease (MD) should be considered as an immunoglobulin (Ig) G4-related disease with aspects of systemic disorders involving the orbit. This study aimed to analyze the relationship between Immunoglobulin G4 (IgG4)-related MD and infraorbital nerve thickness., Methods: We measured infraorbital nerve thickness in 68 patients diagnosed as IgG4-related MD at our hospital and performed computed tomography scans of the head and neck region before treatment and compared these scans with those of the control group., Results: The mean infraorbital nerve diameter (± standard deviation) was 3.2 ± 1.2 mm in patients with IgG4-related MD, and 2.6 ± 0.3 mm in the control group. Infraorbital nerves were significantly thicker in patients with IgG4-related MD. Nerve swelling was found in 20 of 68 patients (29.4%) with a cutoff value of 3.3 mm because this value was obtained from diameter of nerves in the control group + 2 standard deviation mm. No patients in the control group showed nerve swelling. In addition, we found significant correlations between infraorbital nerve swelling and serum IgG4 levels as well as the existence of multiple organ lesions., Conclusions: We found that significant infraorbital nerve swelling occurred in patients with IgG4-related MD and was thought to be a part of IgG4-related disease.

In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63(lo/-)). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.

Osteosarcoma is a rare but highly malignant tumor occurring most frequently in adolescents. The prognosis of non-responders to chemotherapy is still poor, and new treatment modalities are needed. To develop peptide-based immunotherapy, we previously identified autologous cytotoxic T lymphocyte-defined osteosarcoma antigen papillomavirus binding factor (PBF) in the context of HLA-B55 and the cytotoxic T lymphocyte epitope (PBF A2.2) presented by HLA-A2. PBF and HLA class I are expressed in ∼90 and 70% of various sarcomas, respectively. However, the expression status of peptide PBF A2.2 presented by HLA-A2 on osteosarcoma cells has remained unknown because it is difficult to generate a specific probe that reacts with the HLA·peptide complex. For detection and qualification of the HLA-A*02:01·PBF A2.2 peptide complex on osteosarcoma cells, we tried to isolate a single chain variable fragment (scFv) antibody directed to the HLA-*A0201·PBF A2.2 complex using a naïve scFv phage display library. As a result, scFv clone D12 with high affinity (KD = 1.53 × 10(-9) M) was isolated. D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA·peptide complex was expressed on osteosarcoma cells. In conclusion, scFv clone D12 might be useful to select candidate patients for PBF A2.2 peptide-based immunotherapy and develop antibody-based immunotherapy., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Tracheo-innominate artery fistula (TIF) is a rare but life-threatening complication following tracheostomy or tracheoesophageal diversion (TED). Although successful surgical intervention for TIF has been reported, few studies have been performed in patients with severe motor and intellectual disability (SMID). Therefore, we aimed to analyze TIF in patients with SMID to clarify the clinical variables predicting the occurrence and adequate management for lifesaving of TIF., Methods: We retrospectively reviewed the records of patients with SMID undergoing surgical tracheostomy and TED between 2006 and 2012 and identified those with TIF. When TIF occurred, we obtained the clinical status and emergency management., Results: Of 70 patients who underwent tracheostomy or TED during the study period, three patients had TIFs; in one case, TIF was avoided by ligation of the innominate artery before TED. The incidence of TIF in those undergoing tracheostomy and TED was 2.3% and 7.4%, respectively. The interval between tracheostomy and TIF was 14-50 months., Conclusions: Patients with SMID may have an increased risk of TIF. Prompt diagnosis and surgical intervention to control the bleeding is the only effective management at present., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Human respiratory syncytial virus (RSV) is a major causative agent of respiratory infections. Common cold syndrome caused by RS virus, which is prevalent in winter, occasionally develops into bronchitis, bronchiolitis and pneumonia. In particular, severe RS virus infections in infants with underlying cardiopulmonary diseases and with low-birth weight baby have been a problem. Furthermore, repetitive RS virus infections occur for the entire lifetime, and the relationship between RS virus infections and exacerbation of COPD and bronchial asthma is also indicated mainly in elderly individuals. Various immunomodulatory effects other than antimicrobial activity of macrolides, including clarithromycin, have been reported, and their clinical usefulness is shown mainly in respiratory diseases. This review describes the findings of action of macrolides on RS virus infections.