Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Japanese guidelines for allergic rhinitis 2017.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

A Melanocytic Lesion Extending From the Right Ear to the Nasopharynx in a Pediatric Patient: A Case Report.

BACKGROUND: Blue nevus is a benign dermal melanocyte tumor that mainly arises from the skin. We report an extremely rare case of blue nevus in a pediatric patient with extensive progression from the middle ear and inner ear to the nasopharynx through the Eustachian tube. CASE REPORT: A 2-year-old girl with blue tympanum was referred to our department. Computed tomography scans and magnetic resonance imaging were performed, followed by a tissue biopsy and histopathologic evaluations. Radiologic examinations revealed that the lesion had progressed beyond the middle ear into the inner ear and the nasopharynx through the Eustachian tube. Subsequent histopathologic examinations indicated dermal dendritic melanocytic proliferations, but no evidence of malignancy. Based on the clinical and histopathologic findings, we concluded that the lesion was consistent with blue nevus. DISCUSSION: Blue nevus is a relatively common skin lesion. However, no prior reports have described the extension of blue nevus from the auditory organ to the nasopharynx in a pediatric patient. Despite the benign nature of the lesion, the patient experienced profound hearing loss in the affected ear, which necessitates continued monitoring as the lesion may expand with patient growth.

Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells.

Galanin and its receptors, GALR1 and GALR2, are known tumor suppressors and potential therapeutic targets in head and neck squamous cell carcinoma (HNSCC). Previously, we demonstrated that, in GALR1-expressing HNSCC cells, the addition of galanin suppressed tumor proliferation via upregulation of ERK1/2 and cyclin-dependent kinase inhibitors, whereas, in GALR2-expressing cells, the addition of galanin not only suppressed proliferation, but also induced apoptosis. In this study, we first transduced HEp-2 and KB cell lines using a recombinant adeno-associated virus (rAAV)-green fluorescent protein (GFP) vector and confirmed a high GFP expression rate (>90%) in both cell lines at the standard vector dose. Next, we demonstrated that GALR2 expression in the presence of galanin suppressed cell viability to 40-60% after 72 h in both cell lines. Additionally, the annexin V-positive rate and sub-G0/G1 phase population were significantly elevated in HEp-2 cells (mock vs GALR2: 12.3 vs 25.0% (P < 0.01) and 9.1 vs 32.0% (P < 0.05), respectively) after 48 h. These changes were also observed in KB cells, although to a lesser extent. Furthermore, in HEp-2 cells, GALR2-mediated apoptosis was caspase-independent, involving downregulation of ERK1/2, followed by induction of the pro-apoptotic Bcl-2 protein, Bim. These results illustrate that transient GALR2 expression in the presence of galanin induces apoptosis via diverse pathways and serves as a platform for suicide gene therapy against HNSCC.

Cytokine profiles in Japanese patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is classified in CRS without nasal polyp (CRSsNP) and CRS with nasal polyp (CRSwNP) in western countries, whereas this classification was not common so far in Japan. Studying inflammatory mediators in clearly defined disease subgroups may lead to a better differentiation of chronic sinus diseases. METHODS: Homogenates of sinonasal mucosal tissue from 14 controls, 9 CRSsNP patients, and 19 CRSwNP patients were assayed for transforming growth factor (TGF)-ß, interleukin (IL)-5, immunoglobulin E (IgE), Staphylococcus enterotoxin (SAE)-IgE, eosinophil-catioic protein (ECP), myeloperoxidase (MPO), IL-1ß, IL-6, and IL-8 by enzyme-linked immunosorbent assay or UNICAP system. RESULTS: CRSwNP had significantly higher levels of IL-5, IgE, SAE-IgE, and ECP compared with CRSsNP and controls. CRSsNP was characterized by high levels of TGF-ß, while CRSwNP showed a Th2 polarization and lower levels of TGF-ß. Especially, in CRSwNP samples, 68.4% were eosinophilic (ECP/MPO ratio >1), and 52.6% were SAE-IgE positive. On the other hand, in 9 CRSsNP patients, eosinophilic or SAE-IgE positive sample was only one sample respectively. Additionally, 31.6% of CRSwNP were asthmatic patients, while none of CRSsNP patient was suffering from bronchial asthma. CONCLUSIONS: This study is thought to be the first one that showed the cytokine profiles in Japanese CRSs/wNP similar to those of European CRS. Based on mediator profiles, we suggest that CRSsNP and CRSwNP are distinct disease entities within the group of chronic sinus diseases.

[Clinical 22-case study of hereditary hemorrhagic telangiectasia subjects undergoing nasal dermoplasty].

Hereditary hemorrhagic telangiectasia (HHT)-a systemic autosomal dominant disorder adversely affecting skin, mucous membranes, and visceral blood vessels-typically shows epistaxis. In this pathological condition, even minor stimulation may cause bleeding and hemostasis is unlikely to occur. Subjects with HHT showing severe nasal bleeding require nasal dermoplasty (ND). We report our experience in 22 cases of HHT undergoing ND seen from January 2000 to November 2009. Average age at surgery was 55.8 years. Since April 2008, we modified ND, cut the harvested skin graft from the lateral thigh in halves and spread each strip on the anterior halves of the nasal cavity. Placement was circumferential in the sequence of agger nasi, nasal valve, septum, floor, and inferior turbinate. Before this technique was used, bleeding could not be controlled in 3 of 14 cases. Two of the 3 had histories of arterial embolization. Subjects undergoing the new technique have enjoyed improved quality of life.

The morphological change of supporting cells in the olfactory epithelium after bulbectomy.

Transmission electron microscopy was used to study the responses of the supporting cells of the olfactory epithelium at 1-5 days after surgical ablation of the olfactory bulb (bulbectomy). In intact olfactory epithelium, lamellar smooth endoplasmic reticulum and rod-shaped mitochondria were distinctly observed in the supporting cells. On the first day after bulbectomy, bending of the microvilli and an increase in the smooth endoplasmic reticulum were observed. Cristae of the mitochondria became obscure, and the density of the mitochondrial matrix decreased. On the second day after bulbectomy, the number of microvilli decreased, broad cytoplasmic projections that contained cytoplasmic organelles protruded into the luminal side, and the mitochondria were swollen. On the fifth day after bulbectomy, microvilli seemed to be normal and some cells had large cytoplasmic projections that protruded toward the lumen of the nasal cavity. Within the cytoplasmic projections of the supporting cells, a large lamellar and reticular-shaped smooth endoplasmic reticulum was evident. Mitochondria exhibited almost normal morphology. The current findings demonstrate that morphological changes occur in the supporting cells after bulbectomy. This new evidence hypothesizes that these changes represent events that contribute to the regeneration of the olfactory epithelium after bulbectomy.

Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea.

Since standard aminoglycoside treatment progressively causes hearing disturbance with hair cell degeneration, systemic use of the drugs is limited. Adeno-associated virus (AAV)-based vectors have been of great interest because they mediate stable transgene expression in a variety of postmitotic cells with minimal toxicity. In this study, we investigated the effects of regulated AAV1-mediated glial cell line-derived neurotrophic factor (GDNF) expression in the cochlea on aminoglycoside-induced damage. AAV1-based vectors encoding GDNF or vectors encoding GDNF with an rtTA2s-S2 Tet-on regulation system were directly microinjected into the rat cochleae through the round window at 5 x 10(10) genome copies/body. Seven days after the virus injection, a dose of 333 mg/kg of kanamycin was subcutaneously given twice daily for 12 consecutive days. GDNF expression in the cochlea was confirmed and successfully modulated by the Tet-on system. Monitoring of the auditory brain stem response revealed an improvement of cochlear function after GDNF transduction over the frequencies tested. Damaged spiral ganglion cells and hair cells were significantly reduced by GDNF expression. Our results suggest that AAV1-mediated expression of GDNF using a regulated expression system in the cochlea is a promising strategy to protect the cochlea from aminoglycoside-induced damage.

Protection Against Aminoglycoside-induced Ototoxicity by Regulated AAV Vector-mediated GDNF Gene Transfer Into the Cochlea.

Since standard aminoglycoside treatment progressively causes hearing disturbance with hair cell degeneration, systemic use of the drugs is limited. Adeno-associated virus (AAV)-based vectors have been of great interest because they mediate stable transgene expression in a variety of postmitotic cells with minimal toxicity. In this study, we investigated the effects of regulated AAV1-mediated glial cell line-derived neurotrophic factor (GDNF) expression in the cochlea on aminoglycoside-induced damage. AAV1-based vectors encoding GDNF or vectors encoding GDNF with an rtTA2s-S2 Tet-on regulation system were directly microinjected into the rat cochleae through the round window at 5 × 1010 genome copies/body. Seven days after the virus injection, a dose of 333 mg/kg of kanamycin was subcutaneously given twice daily for 12 consecutive days. GDNF expression in the cochlea was confirmed and successfully modulated by the Tet-on system. Monitoring of the auditory brain stem response revealed an improvement of cochlear function after GDNF transduction over the frequencies tested. Damaged spiral ganglion cells and hair cells were significantly reduced by GDNF expression. Our results suggest that AAV1-mediated expression of GDNF using a regulated expression system in the cochlea is a promising strategy to protect the cochlea from aminoglycoside-induced damage.

[Cartilage palisade tympanoplasty for adhesive otitis media].

PURPOSE: We evaluated the clinical utility of cartilage palisade tympanoplasty (CRPT) in adhesive otitis media, a condition known to recur frequently with poor success in hearing gain. OBJECTIVE: Specimens were 9 ears having adhesive otitis media and undergoing CPT in January 2006 and December 2007. Cases of pars tensa cholesteatoma were excluded. Mean subject age was 35.2 years. Seven had total drum adhesion and 2 posterior half-adhesion. Preoperative pure-tone hearing averaged 20-102 dB (mean: 56 dB). METHODS: A small piece of cartilage harvested from the cymba was obliquely sectioned to yield wide, thin cartilage strips. Strips were overlapped slightly anteriorly to posteriorly parallel to the malleus handle when present. Tympanoplasty type 1 was conducted in 2 cases, type 3c in 6, and type 4c in 1. RESULTS: No ears undergoing CPT produced recurrent adhesion or perforation although 2 suffered transient partial erosion healed easily in topical management. An air-bone gap of <15 dB was achieved in 3 ears, a hearing gain exceeding 15 dB in 5, and a hearing level of less than 30 dB in 3. Conditions falling in at least 1 of the above categories are considered successful based on Japan Otological Society criteria. Seven of the 9 (78%) were regarded as audiologically successful. CONCLUSION: CPT conducted for adhesive otitis media appears worthwhile, given the present better-than-expected results in our cases, although further study is needed to confirm this conclusion.

[Community-based hearing screening project in Tochigi prefecture and results thorough audiometric test].

Community-based hearing screening projects have the objectives of screening hearing to identify early and intervene in cases of hearing-impaired infants and to consider how to implement mass screening, education, and support suitable. This project started in Tochigi prefecture in 2002. Of 6198 infants undergoing automatic auditory brainstem response (ABR), those rescreened accounted for 1.1% and those referred for diagnostic testing for 0.7%. After initial thorough audiometric testing, 20 infants were suggested to have bilateral hearing loss, although this was finally reduced to 17. Inconsistency between automatic and conventional ABR was found in 10 cases. Automatic ABR showed 7 false-positive and 3 false-negative cases, all of which finally proved to be within normal range hearing. Newborn-hearing screening enabled infants with hearing loss to be identified early. Japan has yet, however, to implement needed medical treatment and appropriate educational and support systems for hearing-impaired infants.

Rad9 modulates the P21WAF1 pathway by direct association with p53.

BACKGROUND: Previous studies suggest that human RAD9 (hRad9), encoding a DNA damage checkpoint molecule, which is frequently amplified in epithelial tumor cells of breast, lung, head and neck cancer, participates in regulation of the tumor suppressor p53-dependent transactivation of pro-survival P21WAF1. This study examined the exact mechanism of the hRad9 function, especially through the phosphorylation of the C-terminus, in the transcription regulation of P21WAF1. RESULTS: The transfection of phosphorylation-defective hRAD9 mutants of C-terminus resulted in reduction of the p53-dependent P21WAF1 transactivation; the knockdown of total hRad9 elicited an increased P21WAF1 mRNA expression. Immunoprecipitation and a ChIP assay showed that hRad9 and p53 formed a complex and both were associated with two p53-consensus DNA-binding sequences in the 5' region of P21WAF1 gene. The association was reduced in the experiment of phosphorylation-defective hRAD9 mutants. CONCLUSION: The present study indicates the direct involvement of hRad9 in the p53-dependent P21WAF1 transcriptional mechanism, presumably via the phosphorylation sites, and alterations of the hRad9 pathway might therefore contribute to the perturbation of checkpoint activation in cancer cells.

Palliative total pharyngo-laryngo-esophagectomy.

OBJECTIVE: To evaluate the outcomes of total pharyngo-laryngo-esophagectomy (TPLE) as a palliative procedure for achieving oral intake without tube placement. BACKGROUND: Patients with head and neck cancers require airway maintenance achieved by the placement of a tracheostomy tube and nutrition provided through a gastric fistula or a central vein, which may markedly decrease the quality of life (QOL) of the patients. CASES: Two patients with cervical esophageal cancer are described. The first patient was a 69-year-old male with cervical esophageal cancer with vertebral invasion, for which complete resection was not possible. Following TPLE, oral intake was initiated on post-operative day 9 and was maintained for 138 days. The second patient was a 73-year-old male with recurrent cervical esophageal cancer and unresectable lymph node metastasis for which lymph node dissection was not applicable. Following TPLE, oral intake was initiated on post-operative day 7 and was maintained for 199 days. Both patients were satisfied with the outcome. CONCLUSIONS: The QOL of the two patients was improved following the restoration of oral intake ability. Palliative TPLE may be appropriate for patients with advanced head and neck cancers.

[Fiberscopic reduction under local anesthesia for anterior arytenoid cartilage dislocation].

Arytenoid cartilage dislocation is a known complication of tracheal intubation and is also a type of laryngeal injury. Although spontaneous recovery has been reported, most patients require reduction via pharyngoscopy under general or neuroleptic anesthesia, and some must be treated by open reduction such as laryngoplasty. We report 8 cases of arytenoid cartilage dislocation between August 2003 and August 2004. Excluding 3 patients who recovered spontaneously, we conducted reduction under local anesthesia as an ambulatory procedure in the other 5 with anterior dislocation, i.e., 2 men and 3 women aged 53 to 75 years old. Of these 5, dislocation occurred after tracheal intubation in 4, and in 1 after wearing a laryngeal mask. The outcome was favorable in all 5. Surgery was conducteded after a fiberscope was inserted nasally and a urethral balloon catheter was inserted via the other nasal cavity under topical anesthesia with 4% lidocaine for both nasal cavities and the larynx. While monitoring the larynx, we expanded the balloon and pulled it away from the glottis. The expanded balloon was then placed at the arytenoid region for a few seconds. This procedure was repeated several times to achieve reduction. Three patients recovered well within 1 to 2 weeks of the first reduction, while 2 requierd a second reduction because of insufficient improvement after the first. These two both showed improved vocal cord movement and recovery from hoarseness within 1 to 2 weeks after the second reduction. We conducted 7 reductions without complications in any patient. Our approach is usable in the ambulatory setting, and is simple, minimally invasive, and effective. We consider it to be useful treatment for anterior arytenoid cartilage dislocation.

Temporal bone histopathologic abnormalities associated with mitochondrial mutation T7511C.

OBJECTIVES: We previously reported a mitochondrial T7511C mutation in the tRNA gene in a Japanese family with nonsyndromic hearing loss (HL). However, the temporal bone histopathology associated with T7511C has not been reported. The aim of the present study is to report histopathologic findings of a temporal bone from a patient in the Japanese family with this mutation. STUDY DESIGN: Single case study. METHODS: A temporal bone was obtained from the right ear of a male subject with progressive HL from 5 years of age and who died at 60 years of age from cerebral infarction. The bone was embedded, sectioned, and stained with hematoxylin-eosin for light microscopic study. Graphic reconstruction of the cochlea was performed using the method described by Schuknecht to determine loss of the stria vascularis and neurosensory elements including hair cells and spiral ganglion neurons. RESULTS: The most significant histopathologic finding was severe loss of spiral ganglion cells in all turns of the cochlea. Severe loss of neuronal filaments in Rosenthal's canal was also observed. The organ of Corti showed scattered loss of inner and outer hair cells in the basal turn. Partial atrophy of the stria vascularis was observed in all turns of the cochlea. CONCLUSION: Our results suggest that severe loss of spiral ganglion cells was the main cause of sensorineural HL associated with the T7511C mutation.

Multiple functions of rad9 for preserving genomic integrity.

DNA-damage checkpoints sense and respond to genomic damage. Human Rad9 (hRad9), an evolutionarily conserved gene with multiple functions for preserving genomic integrity, plays multiple roles in fundamental biological processes, including the regulation of the DNA damage response, cell cycle checkpoint control, DNA repair, apoptosis, transcriptional regulation, exonuclease activity, ribonucleotide synthesis and embryogenesis. This review examines work that provides significant insight into the molecular mechanisms of several individual cellular processes which might be beneficial for developing novel therapeutic approaches to cancerous diseases with genomic instability.

Nasal dermoplasty for Japanese hereditary hemorrhagic telangiectasia.

OBJECTIVE: While generally considered an effective treatment for moderate to severe epistaxis in hereditary hemorrhagic telangiectasia (HHT), nasal dermoplasty (ND) has not been well established in Japan. This prompted the present Japanese assessment of clinical efficacy and patient satisfaction following this procedure. METHODS: Retrospective analysis of clinical records of 15 patients with HHT undergoing ND between August 1991 and May 2004 and survey of these patients as to postsurgical conditions. Main outcome measures were skin graft "take" frequency after surgery (all patients), reported patient satisfaction (eight recent patients), and reported volume and frequency of epistaxis after versus before surgery (eight recent patients). RESULTS: Graft take rate was 100%. Most patients experienced reduced frequency and volume of bleeding. One patient required an additional operation, total closure of the external nares, 2 years later. Overall patients felt satisfied with ND, experiencing less nasal obstruction than expected. CONCLUSIONS: ND is effective in Japanese patients with moderate and severe nasal bleeding from HHT, reducing their risk of bleeding.

Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder.

A 19-year-old Japanese man exhibiting acute right sensorineural hearing loss and vertigo was referred to the Jichi Medical School Hospital in June 1994. Although he had no history of recurrent thrombosis and no family history of thrombosis, he had undergone reconstruction of a right foot joint fracture 4 months earlier. Screening studies for plasminogen activity demonstrated 10% of normal plasminogen activity and his plasminogen was diagnosed as "plasminogen Tochigi" by the gene analysis using restriction enzyme Fnu4HI. The patient's hearing returned to normal with administration of heparin, and he was prescribed warfarin for the prevention of thrombosis until October 1995. There was no recurrence of hearing loss during seven years of follow-up. The cause of this patient's hearing loss is believed to be associated with consumption of the already low levels of plasminogen as a result of his surgery as well as congenital plasminogen disorder.

[Only used unilateral transnasal approach applied endoscopic sinus surgery for pituitary adenomas].

Endoscope-assisted transnasal approach (TNA) for pituitary adenoma is a new alternative for Hardy's surgery (TSS). We performed TNA using only an endoscope through unilateral nostril. In our approach to sphenoid sinus, we apply method of endoscopic sinus surgery (ESS-TNA). We enter the sphenoid sinus directly through the natural ostium and do not brake the nasal septum nor vomer bone. Since September 2004 we had operated on 12 patients by endoscopic TNA. Six were non-functioning adenomas, and 6 were functioning adenomas. We are first to open the ethomoid sinus to make the space for middle concha to be displaced laterally. Secondary, we widen the natural ostium of the sphenoid sinus, retracting the middle concha laterally. The results were compared with those in 10 cases by TSS operated in our institute. Adenoma removal more than 80% was achieved in 58% by endoscopic TNA whereas in 50% by TSS. We had no case with postsurgical infection. Transient DI occurred in 4 cases and 1 case showed permanent. CSF rhinorrhea was seen in the case having small empty sellae in front of adenoma. For this case, we packed the fat tissue at the floor of the sella with endoscope under local anesthesia to close the fistula. Three cases that had hemianopsia before surgery showed the recovery postoperatively. In 6 functional adenoma, postoperative endocrinological examinations showed normalization in 3 cases and improvements in 3 cases. Postsurgical hospitalization days were 11.4 by endoscopic TNA whereas 15.4 by TSS. Our method showed same or better results than TSS in the removal rate and complication rate whereas the postoperative duration of nasal packing and hospitalization days were shorter than TSS.