Quantification of Mastoid Air Cells and Opacification of the Middle Ear in Primary Ciliary Dyskinesia.

OBJECTIVE: To evaluate pneumatization and opacification of the temporal bone on computed tomography (CT) images in patients with primary ciliary dyskinesia (PCD). STUDY DESIGN: Retrospective case-control study. SETTING: Tertiary referral center. PATIENTS: Fifteen patients with PCD (30 ears) and 45 age-matched individuals without PCD (90 ears) as controls. INTERVENTION: Diagnostic only. MAIN OUTCOME MEASURES: Quantification of mastoid air cells in the PCD and control groups and comparison between them. Degree of middle ear opacification on CT images of the temporal bone in the PCD group. RESULTS: The volume of the mastoid air cells was 30% smaller in the PCD group than in the control group ( p < 0.05). The suppression ratio, which is defined to indicate how much the average volume of mastoid air cells in the PCD group is suppressed relative to the control group, was 64% lower in the PCD group ( p < 0.05). Opacification was noted in 47% of the mastoid air cells and 63% of the tympanic cavity on CT images of the temporal bone in the PCD group, which were significantly higher frequencies than in the control group (1.1% and 1.1%, respectively). CONCLUSIONS: Compared with individuals without PCD, those with PCD showed a significantly smaller volume of mastoid air cells and a significantly higher frequency of opacification of mastoid air cells and tympanic cavity on temporal bone CT. Otitis media raises suspicion for PCD, and the otological manifestations of PCD reported here could help to narrow the differential diagnosis and facilitate early treatment.

[Evaluation of the Accuracy of the Displayed Average Glandular Dose in Mammography].

PURPOSE: We aimed to clarify the error of displayed value against the measured value of the average glandular dose (AGD) in two-dimensional (2D) mammography and digital breast tomosynthesis (DBT) and evaluate the accuracy of the displayed AGD as an index to estimate AGD. METHODS: Polymethyl methacrylate (PMMA) phantoms with thicknesses varying from 20 to 80 mm were imaged, and the values displayed on the mammography system were used as the displayed AGD. The incident air kerma and the half-valued layer were measured, and the measured AGD in 2D mammography was calculated using the equation by Dance et al. On the other hand, the measured AGD in DBT was calculated by correcting for different projection angles. The relative error to the PMMA thickness was evaluated by assessing the relative error of the displayed AGD against the measured AGD. RESULTS: The maximum relative error of the displayed AGD against the measured AGD was 17.3% in 2D mammography, 19.1% in the standard (ST) mode, and 19.8% in the high-resolution (HR) mode. CONCLUSION: The relative error of the displayed AGD against the measured AGD tended to increase with increase in PMMA thickness. This tendency was especially noticeable for PMMA with thicknesses of 70 and 80 mm in DBT.

A Case of IgG and IgA Anti-Laminin-332 Antibody-Positive Mucous Membrane Pemphigoid with IgG and IgA Anti-Envoplakin and Anti-Periplakin Antibodies.

A 76-year-old Japanese man presented with a 6-year history of a sore throat. He was treated at several clinics without any improvement before being referred to us. Physical examination revealed widespread erosions and ulcers from the palate to the larynx. Approximately 25 × 15 mm in size, erosive lesions were present on the retroauricular regions, forearms, and glans penis. Pseudomembranous conjunctivitis was also observed. The skin biopsy revealed a partial cleft formation below the epidermis, suggesting subepidermal bullous disease. Immuno-serological tests were negative for anti-desmoglein 1 (Dsg1), anti-Dsg3, anti-BP180, and anti-BP230 antibodies by ELISAs. A whole-body examination revealed gastric cancer. The possibility of mucous membrane pemphigoid (MMP) or paraneoplastic pemphigus (PNP) was considered. Indirect immunofluorescence using rat bladders showed positive IgG reactivity with cell surfaces on the transitional epithelia. Immunoblotting using recombinant proteins of laminin-332 showed both IgG and IgA reactivities with laminin-α3, and immunoblotting using normal human epidermal extract showed double-positive reactivities with envoplakin and periplakin for both IgG and IgA antibodies. Based on the clinical and histopathological features and results of various immuno-serological tests, our case was diagnosed as anti-laminin-332-type MMP with serological findings of PNP. Twenty days after laparoscopic gastrectomy, treatment with oral methylprednisolone 32 mg/day was initiated, and mucosal and skin lesions improved.

A Perihilar Variant of Focal Segmental Glomerulosclerosis Due to De novo Branchio-oto-renal Syndrome.

Branchio-oto-renal syndrome is an autosomal dominant disorder characterized by branchial anomalies, hearing loss, and renal urinary tract malformations. We herein report a 32-year-old Japanese man with a right preauricular pit, bilateral mixed hearing loss, and malposition of the right kidney who presented with proteinuria. The findings of a left kidney biopsy were compatible with a perihilar variant of secondary focal segmental glomerular sclerosis. A trio exome analysis conducted among the patient and his parents failed to identify the causal gene variant, despite a sporadic pattern. His kidney function remained stable for 11 years with an angiotensin II receptor blocker.

Primary cytomegalovirus infection during pregnancy and congenital infection: a population-based, mother-child, prospective cohort study.

OBJECTIVE: This study assessed maternal cytomegalovirus antibodies, and the occurrence of primary and congenital cytomegalovirus infections, and risk factors of congenital infection after a maternal primary infection. STUDY DESIGN: We included 19,435 pregnant women in Japan, who were tested for serum cytomegalovirus antibodies before 20 gestational weeks. Immunoglobulin (Ig) G avidity was evaluated in women with both IgG and IgM antibodies; tests were repeated at ≥28 gestational weeks among women without IgG and IgM antibodies. RESULT: Primary and congenital infections were 162 and 23 cases, respectively. The risk ratios for congenital infection were 8.18 (95% confidence interval: 2.44-27.40) in teenage versus older women, and 2.25 (95% confidence interval: 1.28-3.94) in parity ≥ 2 versus parity ≤ 1. Of 22 live birth congenital infection cases, three had abnormal neurological findings. CONCLUSION: We demonstrated teenage and parity ≥ 2 pregnant women as risk factors of post-primary congenital infection.

Retrospective study of cochlear implantations at a single facility focusing on postoperative complications.

OBJECTIVE: Although cochlear implantation (CI) is a relatively safe operation, postoperative complications sometimes occur. We reviewed the frequency and severity of complications of CI at our hospital. We compared our results with previously reported complications and considered measures to improve patient outcomes. METHODS: This retrospective study examined the medical records of 70 patients who received CI between March 2005 and December 2018. We collected the following data: age at the time of the first surgery, etiology of hearing impairment, date of implantation, type of implanted devices, and complications. Surgical complications were divided by time into perioperative, early, and late, and by severity into major or minor. RESULTS: Records of 38 adults and 32 children were analyzed. Bilateral CI was performed in 16 patients, 8 of whom were sequential, and unilateral CI was performed in 54 patients. The total number of operations was 78 for 86 CI. Complications were observed in 15 of 78 operations (19%), and the rates of minor and major complications were 15% and 4%, respectively. Complication rates were 21% (8/39) for children and 10% (4/39) for adults. All of the perioperative and early complications were minor. There were three major complications, all of which were infections presenting with mastoiditis and subcutaneous or subperiosteal abscesses. One case required reimplantation twice because of recurrent mastoiditis and temporal abscess. CONCLUSIONS: There was no significant difference in the incidence of complications between children and adults, but all major complications were infection in pediatric cases. Careful attention is needed to prevent postoperative infection.

Copy number variation in DRC1 is the major cause of primary ciliary dyskinesia in the Japanese population.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The involvement of copy number variation (CNV) in the development of PCD is largely unknown. METHODS: We examined 93 Japanese patients with clinically suspected PCD from 84 unrelated families. CNV was examined either by exome sequencing of a PCD gene panel or by whole-exome sequencing (WES). The identified alterations were validated by PCR and Sanger sequencing. Nasal ciliary ultrastructure was examined by electron microscopy. RESULTS: Analysis of CNV by the panel or WES revealed a biallelic deletion in the dynein regulatory complex subunit 1 (DRC1) gene in 21 patients, which accounted for 49% of the PCD patients in whom a disease-causing gene was found. Sanger sequencing of the PCR product revealed a 27,748-bp biallelic deletion including exons 1-4 of DRC1 with identical breakpoints in all 21 patients. The ciliary ultrastructure of the patients with this CNV showed axonemal disorganization and the loss or gain of central microtubules. CONCLUSION: The deletion of DRC1 is the major cause of PCD in Japan and this alteration can cause various ciliary ultrastructural abnormalities.

A targeted next-generation sequencing panel reveals novel mutations in Japanese patients with primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The early diagnosis of PCD is important for the prevention of long-term sequelae; however, this is often challenging because of the phenotypic heterogeneity of PCD and difficulty in genetic analysis. The majority of PCD patients in Japan are not diagnosed properly. To diagnose PCD more accurately, we developed a targeted next-generation sequencing (NGS) panel. METHODS: We examined 46 patients (age range, 1-64 years; 23 male and 23 female) who were clinically suspected of PCD. First, mutation hotspots in DNAH5 and DNAI1 were sequenced by the Sanger method. Next, exome sequencing was performed in 32 known PCD genes using our novel NGS panel with the Ion Torrent PGM system. Variant annotation was generated by Ion Reporter Version 5.0 (Life Technologies). Mutations found in the panel were validated by Sanger sequencing. RESULTS: Disease-causing gene mutations were found in 10 patients from 7 families: DNAH5 in 4 families, and DNAI1, CCDC40, and RSPH4A in 1 family each. Heterozygous mutations were found in 1 patient. The majority of the mutations found in the present analysis were novel. CONCLUSION: Japanese PCD patients have novel mutations in cilia-related genes. This targeted NGS panel can identify disease-causing mutations in patients with PCD.

A Time Limit for Initiating Anti-Inflammatory Treatment for Improved Olfactory Function after Head Injury.

We previously reported that treatment with an anti-inflammatory drug, specifically a steroid, is effective in improving recovery during the acute phase of head injury. Clinically, however, patients with head injury usually become aware of their olfactory loss several weeks or months after the injury, which may be a critical factor in poor recovery from olfactory dysfunction. This raises an important question: When should steroid administration begin in order to achieve optimum improvement of olfactory dysfunction? The present study was designed to reveal the time limit for starting anti-inflammatory treatment for better improvement of post-traumatic olfactory dysfunction. Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP)-tau-lacZ mice and subcutaneous injections of dexamethasone sodium phosphate for 5 consecutive days was started at 7, 14, 28, and 42 days after the NTx (7-, 14-, 28-, and 42-day time-points). Histological assessment of olfactory nerve recovery in the olfactory bulb was made at 5, 14, and 42 days after the start of drug treatment. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential testing also were performed. Animals treated at 7 days post-injury had less injury-associated tissue with fewer astrocytes and macrophages and better histological and functional nerve recovery, compared with control mice. However, those treated at 14, 28, or 42 days post-injury did not show significant histological or functional differences between saline control and treatment groups. These findings suggest that an anti-inflammatory treatment using steroids for traumatic olfactory dysfunction may be effective if started at least by 7 days, but may be ineffective at 14 days or later after head injury.

Analysis of Otologic Features of Patients With Primary Ciliary Dyskinesia.

OBJECTIVE: To evaluate otologic features of primary ciliary dyskinesia (PCD), especially eardrum features, audiometric findings, and clinical course. STUDY DESIGN: Retrospective patient review. SETTING: Tertiary referral center. PATIENTS: Fifteen patients (mean age, 16.9 years [range, 1-32 yr]; 8 males and 7 females) diagnosed with PCD at our university hospital in the last 12 years. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Electron microscopy of nasal cilia, gene mutation analysis, endoscopy of 30 eardrums, pure-tone audiometry, and tympanometry. RESULTS: All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The remaining patient had chronic otitis media. Pure-tone audiometry revealed the mean air conduction thresholds to be 25.0 and 26.4 dB in the right and left ears, respectively. In the ears with better hearing and worse hearing, the mean air conduction thresholds were 22.3 and 29.0 dB respectively. CONCLUSION: Otologic disease among patients with PCD essentially comprised otitis media with effusion, and the patients' eardrums showed a variety of findings. Knowledge of these otologic features may lead to the early detection of PCD.

Endoscopic electrocauterization of pyriform sinus fistula.

To determine the efficacy of endoscopic electrocauterization for pyriform sinus fistula (PSF) using a flexible Bugbee cautery electrode. From 2009 to 2016, a total of eight patients with acute suppurative thyroiditis or cervical abscess secondary to PSF were retrospectively registered in our study (three males, five females; median age 6.5 years). All patients underwent endoscopic electrocauterization as treatment for PSF. Six of eight patients had no recurrence after the initial endoscopic electrocauterization of PSF. One patient with recurrence developed symptoms 9 days after cauterization and another experienced recurrence after 2 years. Mean follow-up for the eight patients was 50 months (range 5-96 months). No post-operative complication was reported. Endoscopic electrocauterization appears to be a less-invasive, safe, and effective method for the treatment of PSF.

Novel syndrome with conductive hearing loss and congenital glaucoma in three generations.

The objective of this paper was to describe the clinical and otological findings in multiple members of a family with congenital glaucoma, cardiac anomaly, and conductive hearing loss due to ossicular chain anomalies. We performed a retrospective review of the medical charts and otological materials of multiple members of the same family. Congenital glaucoma and hearing loss were inherited by the proband and her daughter, son, and mother, suggesting autosomal dominant inheritance. The son and daughter also showed atrial septal defects. Exploratory tympanotomies revealed anomalies of the long process of the incus in the proband and her daughter, and tympanoplasty improved hearing loss in both patients. This represents the first description of coexisting congenital glaucoma and conductive hearing loss due to ossicular chain anomalies in multiple members of a single family.

Interleukin-33 induces mucin gene expression and goblet cell hyperplasia in human nasal epithelial cells.

We investigated whether IL-33 is involved in mucus overproduction and goblet cell hyperplasia in eosinophilic chronic rhinosinusitis (ECRS). IL-33 mRNA was significantly higher in the eosinophilic CRS group than in the non-eosinophilic CRS group from human nasal polyps. IL-33 induced MUC5AC mRNA and MUC5AC protein, and also goblet cell hyperplasia at air liquid interface culture in human nasal epithelial cells. In addition to that, IL-33 induced MUC5B and FOXA3, and reduces FOXJmRNA. In conclusion, our present study demonstrated that the direct evidence of IL-33 which lead to increase mucin gene and protein expression, as well as goblet cell hyperplasia. This study provides novel insights into the role of IL-33 on mucus overproduction in eosinophilic inflammation of human airways.

Recent advances in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease inherited in an autosomal recessive manner. The prevalence of PCD is estimated to be 1 in 20,000 live births. Congenital abnormality of the primary cilia results in situs inversus in 50% of patients. Decreased function of motile cilia causes chronic rhinosinusitis, otitis media with effusion, bronchiectasis and infertility. Cases with situs inversus are considered to show "Kartagener's syndrome", and diagnosis is not difficult. However, in cases without situs inversus, the diagnosis is much more troublesome. PCD without situs inversus is thus probably underdiagnosed. Prolonged chronic cough represents an important symptom that is seen in most patients. The diagnosis of PCD requires the presence of the characteristic clinical phenotypes and either: (1) specific ciliary ultrastructural defects identified by transmission electron microscopy in biopsy samples of respiratory epithelium; or (2) identification of mutation in one of the genes known to be associated with PCD. Nasal nitric oxide concentration is extremely low in PCD, and this could be useful for screening of the disease. At present, no fundamental therapies are available for PCD. Diagnosis in the early stages is important to prevent progression of bronchiectasis and deterioration of lung function by guidance for daily life, immunization, cessation of smoking and prompt therapy at the time of respiratory tract infection. Since PCD is inherited in an autosomal-recessive manner, genetic counseling is necessary after definite diagnosis.

Descending necrotizing mediastinitis from deep neck infection.

This study aims to identify predisposing characteristics of descending necrotizing mediastinitis (DNM) arising from deep neck infection (DNI) and to determine appropriate therapeutic intervention strategies. We retrospectively reviewed 54 patients (male, n = 34; female, n = 20; mean age, 64.5 years) who had been treated at Mie University Hospital for DNI between April 2001 and October 2011. Eight of nine patients who developed DNM confirmed by computed tomography of the neck and chest, underwent mediastinal drainage (video-assisted thoracic surgical drainage, n = 6; mediastinoscopy-assisted drainage, n = 2). A patient developed uncontrolled acute respiratory distress syndrome after aggressive surgery, resulting in a mortality rate of 12 %. High blood CRP values, and the pharynx and tonsils as origins of infection were factors involved in the development of DNM arising from DNI. In conclusion, DNM remains a destructive and fatal disease that requires aggressive treatment including mediastinal exploration.

Applicability of the cross-culturally modified University of Pennsylvania Smell Identification Test in a Japanese population.

BACKGROUND: The University of Pennsylvania Smell Identification Test (UPSIT) is a popular olfactory function test used throughout the world. In Japan, however, it is not widely used because it is written in English and some of the test odorants are unfamiliar to the Japanese population. Recently, a cross-culturally modified UPSIT was developed. This study was designed to determine if the Japanese version of the UPSIT (UPSIT-J) is effective in Japanese populations. METHODS: We administered the UPSIT-J to 50 normosmic Japanese subjects and 54 Japanese patients with known olfactory dysfunction. Subjects were also administered the Japanese standard olfactory threshold test (T&T olfactometry), the Odor Stick Identification Test for Japanese (OSIT-J) and i.v. olfactometry (the Alinamin test). Test results from the UPSIT-J and subjects' opinions were compared with the standard Japanese tests of olfactory function. RESULTS: Most subjects reported that the UPSIT-J was easy and interesting compared with OSIT-J and easier and more interesting than the T&T olfactometry and Alinamin test. Identification rates for nine of the UPSIT-J odorants were found to be <80% for normal subjects. UPSIT-J scores correlated with subjects' self-reported levels of olfactory function (r(s) = 0.85), OSIT-J score (r(s) = 0.86), recognition threshold of the T&T olfactometry (r(s) = 0.80), and Alinamin test results (r(s) = 0.38 for latency; r(s) = 0.52 for duration time). CONCLUSION: Although a cultural bias was detected for some test odorants, this study indicates that the UPSIT-J is effective for use in the clinic to assess olfactory function in the Japanese population.

[Increased throat symptoms in Japanese cypress pollinosis].

BACKGROUND: Seasonal allergic rhinitis caused by Japanese cypress pollen is highly associated with that by Japanese cedar pollen, due to the similar antigen of the two pollens. Clinically, patients with cypress pollinosis complain of strong throat symptoms. METHOD: Weekly nasal and throat symptoms during the pollen season in patients with Japanese cedar-cypress pollinosis were measured using a visual analog scale (VAS). Symptoms other than rhinoconjuctivitis by Japanese rhinitis quality of life questionnaire No2 were compared in two different pollen scattering-seasons. RESULT: VAS showed that nasal symptoms appeared parallel with pollen scattering, and that they were severe in the cedar season more than in the cypress season. On the other hand, throat disco,fort and cough were worse in the cypress season, even though this study took place of during a year when there was only a small amount of cypress-pollen scattering. The severity of symptoms other than rhinoconjunctivitis in cedar pollinosis depended on the total amount of pollen, however, cypress pollinosis showed severe throat symptoms in both a small and a mass scattering year. CONCLUSION: Although cypress and cedar pollinosis is considered as the same disease, cypress pollinosis showed more severe symptoms other than rhinoconjunctivitis. Throat symptoms in particular are more severe in cypress pollinosis, even in the year of a small amount of scattering.

Effects of clarithromycin and dexamethasone on mucus production in isografted rat trachea.

OBJECTIVES: The purpose of this study was to develop an animal model for the study of mucus overproduction and to assess the effect of a 14-membered macrolide antibiotic and a glucocorticoid on lipopolysaccharide (LPS)-induced mucus production. METHODS: Tracheas from donor rats were homografted to recipient rats for 4 weeks, and the usefulness of this tracheal homograft model in the study of mucus production was examined. RESULTS: Oral administration of clarithromycin (CAM) to recipient rats for 4 weeks significantly reduced LPS-induced mucus production in the homografted trachea. Dexamethasone administered for 4 weeks also significantly reduced the mucus volume in LPS-treated homografted trachea compared with that in the control rats. The implanted trachea containing control medium was not histologically different from normal trachea. When the medium instilled into the implanted trachea contained 1 µg/ml LPS, the volume and spinability of mucus produced in the tracheal lumen were significantly increased compared to those in the trachea instilled with control medium. Goblet cell metaplasia was also observed in the implanted trachea containing LPS. CONCLUSIONS: The present study shows that LPS-administered homografted trachea is a good animal model of chronic hypersecretory diseases of the upper and lower airways. CAM and dexamethasone could be treatment choices in such hypersecretory diseases.

[Clinical usefulness of smell identification test card: Open Essence].

Since the Odor Stick Identification Test for Japanese (OSIT-J) has proved clinically useful in Japan, the Open Essence (OE) smell identification test card has been developed to amend OSIT-J deficits. To determine its clinical effectiveness, we administered the OE to 93 Japanese subjects reporting olfactory dysfunction. They scored their olfactory dysfunction on levels one to five, i.e., normal to anosmic, using the Japan Rhinologic Society Self-Administered Odor Questionnaire (SAOQ) and the visual analog scale (VAS). They also took the Japanese standard olfactory test (T & T olfactometry) and intravenous olfactometry (Alinamin test). Opinions on the OE and OSIT-J were recorded from those previously administered the OSIT-J and testers familiar with OSIT-J administration. The OE took 5.1+/- 1.6 minutes to administer. Scores correlated significantly for the OE, self-reported olfactory function, SAOQ, VAS, T & T olfactometry recognition threshold, and Alinamin latency and duration time. Subjects and testers reported the OE to be easier, shorter, more interesting, and more convenient, indicating its utility in clinical olfactory dysfunction evaluation and its convenience for both subjects and testers.