Creutzfeldt-Jakob disease with dizziness initially presenting to the otolaryngology department.

Creutzfeldt-Jakob disease is a fatal transmissible prion disease of the central nervous system. Dizziness as an initial manifestation of Creutzfeldt-Jakob disease is rare. However, patients with Creutzfeldt-Jakob disease and dizziness may initially visit the otolaryngology department, but this is uncommon. We report the case of a 56-year-old woman with Creutzfeldt-Jakob disease who initially presented with dizziness as an emergency patient to the otolaryngology department. Primary position upbeat nystagmus was identified using a charge-coupled device camera with infrared illumination. Electronystagmography revealed impaired smooth pursuit and diminished optokinetic nystagmus. Based on these findings, we immediately suspected an intracranial cause of dizziness and reached a presumptive diagnosis of sporadic Creutzfeldt-Jakob disease, thus preventing severe transmission. This case emphasizes that Creutzfeldt-Jakob disease should be included as a differential diagnosis for patients with dizziness and abnormal eye movements, such as primary position upbeat nystagmus, which might be caused by intracranial disease.

Severe obstructive sleep apnea after concurrent chemoradiotherapy for laryngeal and hypopharyngeal cancer managed by CPAP.

Concurrent chemoradiotherapy (CCRT) is one of the most promising treatments for advanced head and neck cancer (HNC). On the other hand, CCRT may induce severe edema in laryngo-pharyngeal structures in association with radiation. This is a report of a 66-year-old man with severe obstructive sleep apnea (OSA) associated with edema in laryngo-hypopharynx after CCRT for advanced laryngeal and hypopharyngeal cancer. Tracheostomy was avoided and OSA was controlled by continuous positive airway pressure (CPAP). Subjective symptoms of sleepiness were improved. Though laryngeal edema appeared during the course of CCRT in this case, OSA was not evaluated until snoring had been pointed out and he complained of sleepiness. CCRT for laryngeal and hypopharyngeal cancer have a risk of occurrence of OSA due to irreversible mucous edema in the upper airway. Patients for whom CCRT is planned should be informed about the occurrence of OSA before the treatment because symptoms associated with OSA can negatively impact not only the daytime quality of life but also increase the risk of cardiovascular events. The OSA treatment for post CCRT would be expected to have a positive impact on not only cardiovascular and metabolic systems but also on the cancer treatment survival rate.

Effect of Spermidine on Biofilm Formation in Escherichia coli K-12.

Polyamines are essential for biofilm formation in Escherichia coli, but it is still unclear which polyamines are primarily responsible for this phenomenon. To address this issue, we constructed a series of E. coli K-12 strains with mutations in genes required for the synthesis and metabolism of polyamines. Disruption of the spermidine synthase gene (speE) caused a severe defect in biofilm formation. This defect was rescued by the addition of spermidine to the medium but not by putrescine or cadaverine. A multidrug/spermidine efflux pump membrane subunit (MdtJ)-deficient strain was anticipated to accumulate more spermidine and result in enhanced biofilm formation compared to the MdtJ+ strain. However, the mdtJ mutation did not affect intracellular spermidine or biofilm concentrations. E. coli has the spermidine acetyltransferase (SpeG) and glutathionylspermidine synthetase/amidase (Gss) to metabolize intracellular spermidine. Under biofilm-forming conditions, not Gss but SpeG plays a major role in decreasing the too-high intracellular spermidine concentrations. Additionally, PotFGHI can function as a compensatory importer of spermidine when PotABCD is absent under biofilm-forming conditions. Last, we report here that, in addition to intracellular spermidine, the periplasmic binding protein (PotD) of the spermidine preferential ABC transporter is essential for stimulating biofilm formation.IMPORTANCE Previous reports have speculated on the effect of polyamines on bacterial biofilm formation. However, the regulation of biofilm formation by polyamines in Escherichia coli has not yet been assessed. The identification of polyamines that stimulate biofilm formation is important for developing novel therapies for biofilm-forming pathogens. This study sheds light on biofilm regulation in E. coli Our findings provide conclusive evidence that only spermidine can stimulate biofilm formation in E. coli cells, not putrescine or cadaverine. Last, ΔpotD inhibits biofilm formation even though the spermidine is synthesized inside the cells from putrescine. Since PotD is significant for biofilm formation and there is no ortholog of the PotABCD transporter in humans, PotD could be a target for the development of biofilm inhibitors.

Generation of two iPSC lines from siblings of a homozygous patient with hearing loss and a heterozygous carrier with normal hearing carrying p.G45E/Y136X mutation in GJB2.

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Among them, the G45E/Y136X mutation in GJB2 is the third most prevalent in Japan. In this study, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of siblings with moderate-to-severe hearing loss (patient) or normal hearing (genetic carrier) carrying a homozygous or heterozygous G45E/Y136X mutation in GJB2 gene, respectively. These iPSC lines showed the expression of pluripotency markers and could differentiate into three germ layers. These disease-specific iPSC lines will be a powerful tool for investigating the pathogenesis of GJB2-related deafness.

Use of sound-elicited fetal heart rate accelerations to assess fetal hearing in the second and third trimester.

OBJECTIVES: We previously reported that fetal heart rate (FHR) accelerations could be obtained after fetal sound stimulation. We examined FHR accelerations during 20-37 weeks gestational age (GA) in order to assess the optimal time for the test. METHODS: The fetus was stimulated from the maternal abdomen with pure tone 2000 Hz, 90 dB, 5 s. Changes in the FHR before and after the sound stimulation were measured by a cardiotocometer. RESULTS: Compared with the positive rate of FHR accelerations at 20-21 weeks GA, significant increases were recognized in 26-27, 28 to 29, 30 to 31, and 34-35 weeks GA. Comparing the positive rate of FHR accelerations between the minimal and moderate variability of FHR baseline, no significant differences were observed at 20-27 weeks GA. On the other hand, at 28-37 weeks GA, the positive rate to detect FHR accelerations due to sound stimulation was 100% in moderate FHR baseline variability. CONCLUSION: Considering development of human fetal hearing, the method should be performed between 28 and 37 weeks GA and during moderate FHR variability corresponding to active sleep conditions. The method developed in the present study may provide a promising tool for evaluating the fetal hearing.

Generation of the induced pluripotent stem cell (hiPSC) line (JUFMDOi004-A) from a patient with hearing loss carrying GJB2 (p.V37I) mutation.

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Especially, V37I mutation in GJB2 is most prevalent in Southeast Asia including Thailand, Malaysia, and Indonesia. Furthermore, it is the second most prevalent cause in Japan and China, and exhibits an audiometric phenotype of mild-to-moderate hearing loss. In this study, we generated induced pluripotent stem cells (iPSC) from peripheral blood mononuclear cells (PBMCs) of patient with homozygous V37I mutation. This iPSC line will be a powerful tool for investigating the pathogenesis and for developing a treatment for GJB2-related hearing loss.

OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients.

The OTOF gene (Locus: DFNB9), encoding otoferlin, is reported to be one of the major causes of non-syndromic recessive sensorineural hearing loss, and is also reported to be the most common cause of non-syndromic recessive auditory neuropathy spectrum disorder (ANSD). In the present study, we performed OTOF mutation analysis using massively parallel DNA sequencing (MPS). The purpose of this study was to reveal the frequency and precise genetic and clinical background of OTOF-related hearing loss in a large hearing loss population. A total of 2,265 Japanese sensorineural hearing loss (SNHL) patients compatible with autosomal recessive inheritance (including sporadic cases) from 53 otorhinolaryngology departments nationwide participated in this study. The mutation analysis of 68 genes, including the OTOF gene, reported to cause non-syndromic hearing loss was performed using MPS. Thirty-nine out of the 2,265 patients (1.72%) carried homozygous or compound heterozygous mutations in the OTOF gene. It is assumed that the frequency of hearing loss associated with OTOF mutations is about 1.72% of autosomal recessive or sporadic SNHL cases. Hearing level information was available for 32 of 39 patients with biallelic OTOF mutations; 24 of them (75.0%) showed profound hearing loss, 7 (21.9%) showed severe hearing loss and 1 (3.1%) showed mild hearing loss. The hearing level of patients with biallelic OTOF mutations in this study was mostly severe to profound, which is consistent with the results of past reports. Eleven of the 39 patients with biallelic OTOF mutations had been diagnosed with ANSD. The genetic diagnosis of OTOF mutations has significant benefits in terms of clinical decision-making. Patients with OTOF mutations would be good candidates for cochlear implantation; therefore, the detection of OTOF mutations is quite beneficial for patients, especially for those with ANSD.

Frequency and clinical features of hearing loss caused by STRC deletions.

Sensorineural hearing loss is a common deficit and mainly occurs due to genetic factors. Recently, copy number variants (CNVs) in the STRC gene have also been recognized as a major cause of genetic hearing loss. We investigated the frequency of STRC deletions in the Japanese population and the characteristics of associated hearing loss. For CNV analysis, we employed a specialized method of Ion AmpliSeqTM sequencing, and confirmed the CNV results via custom array comparative genomic hybridization. We identified 17 probands with STRC homozygous deletions. The prevalence of STRC homozygous deletions was 1.7% in the hearing loss population overall, and 4.3% among mild-to-moderate hearing loss patients. A 2.63% carrier deletion rate was identified in both the hearing loss and the control population with normal hearing. In conclusion, our results show that STRC deletions are the second most common cause of mild-to-moderate hearing loss after the GJB2 gene, which accounts for the majority of genetic hearing loss. The phenotype of hearing loss is congenital and appears to be moderate, and is most likely to be stable without deterioration even after the age of 50. The present study highlights the importance of the STRC gene as a major cause of mild-to-moderate hearing loss.

Parapharyngeal Abscesses Caused by Group G Streptococcus.

Deep neck abscess is a life-threatening infection that causes laryngeal edema and upper airway occlusion. The predominant bacterial species involved in this disorder is group A streptococcus. Group G streptococcus (GGS) constitutes the normal commensal flora of the human upper airway. Although rarely, it can cause pharyngitis, tonsillitis, and peritonsillar abscess. Here, we report a case of a woman with parapharyngeal abscess caused by GGS. A 56-year-old woman presented to the emergency department with complaints of sore throat and cervical swelling, and a diagnosis of parapharyngeal abscess was established. She had upper airway occlusion, requiring urgent tracheostomy. Endoscopic incision and drainage of the abscess using a specially designed, rigid curved laryngoscope was successfully performed. Since a rigid curved laryngoscope creates a wide viewing field and working space, it was useful for incision and drainage of the parapharyngeal abscess.

Age-stratified sex differences in polysomnographic findings and pharyngeal morphology among children with obstructive sleep apnea.

BACKGROUND: Childhood obstructive sleep apnea (OSA) has important implications for growth, learning, behavior, cognition and cardiovascular health as well as snoring and OSA in adulthood. In this study, we elucidated the sex differences in polysomnographic (PSG) findings and pharyngeal radiographic data in pediatric OSA patients. METHODS: Sixty three children (age between 3 and 15 years old) with OSA [defined as apnea-hypopnea index (AHI) ≥1/h by polysomnography] were enrolled. Lateral neck radiographs were obtained from the patients. All subjects were separated by age: pre-adolescent group (3-8 years old) and adolescent group (9-15 years old). RESULTS: Overall, 45 patients in the pre-adolescent group (33 boys and 12 girls) and 18 patients in the adolescent group (10 boys and 8 girls) were enrolled, and sex differences were compared in each group. We found sex differences in craniofacial features and severity of OSA in the adolescent group, in which girls with OSA had more upper airway space, in addition to lower AHI, lower 3% oxygen desaturation index (ODI), higher minimum SO2 and better sleep efficiency than the boys. CONCLUSIONS: The present study found revealed sex differences in pediatric OSA patients in the adolescent group. Girls in the adolescent group had more upper airway space in addition to lower AHI, lower 3% ODI, higher minimum SO2 and better sleep efficiency than boys.

Piezoelectric vibrator-stimulated potential and heart rate accelerations detected from the fetus.

OBJECTIVES: The fetus is well known to have a substantial capacity for sound recognition in the uterine environment. The aim of this study was to develop a sound stimulus system equipped with a piezoelectric vibrator (PV), record the PV-stimulated potential (PVSP) of the fetus and monitor changes of the fetal heart rate (FHR) under PV stimulation. METHODS: The relationship between the input voltage applied to a piezoelectric vibrator and the sound pressure generated in the uterus was calibrated based on a model of the maternal abdomen. Fourteen fetuses for the measurement of the PVSP and 22 fetuses for the measurement of the heart rate changes from low-risk pregnant women were recruited. RESULTS: The PVSP responses were obtained in 9 out of 14 fetuses. All the tested fetuses accelerated the FHR after the 2 kHz tone stimulation at 70 dB intensity generated by PV from 32 to 37 weeks gestational age. CONCLUSIONS: Using a newly developed sound stimulus system equipped with PV, the electric responses of a fetus recorded from electrodes placed on the mother's abdomen may be closely related to the auditory evoked response. Significant accelerations of FHR were objectively, accurately and readily obtained after the sound stimulation.

POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.