Saiko Sugiura

Intratumoral injection of herpes simplex virus HF10 in recurrent head and neck squamous cell carcinoma

We have developed a novel replication-competent, oncolytic herpes simplex virus (HSV), named HF10, and have evaluated its anticancer efficacy in a variety of animal models. We report a pilot study of intratumoral injection of HF10 into subcutaneous nodules in patients with head and neck squamous cell carcinoma (HNSCC). HF10 efficiently infected human HNSCC cells and caused extensive tumor cell death without any significant adverse effects, suggesting that HF10 represents a promising therapy for HNSCC in humans. To assess the therapeutic potential of HF10 in human HNSCC, we performed a preliminary study of toxicity and efficacy in two patients with recurrent metastatic HNSCC. For each patient, a metastatic skin nodule was injected with HF10 once a day for 3 days. They were monitored for systemic adverse effects, and the injected nodules were excised at day 13 (patient 1) or day 15 (patient 2) after injection for histochemical examination. HF10 replicated, spread well in the tumor nodules, and caused cell death in a considerable population of tumor cells without any significant adverse effects.

Association of interleukin‐1 gene polymorphisms with sudden sensorineural hearing loss and Ménière’s disease

Sudden sensorineural hearing loss (SSNHL) and Ménière’s disease are the most common inner ear diseases in which the causes are unknown. As recent magnetic resonance imaging has demonstrated disruption of the blood–labyrinth barrier in these inner ear diseases, inflammatory reaction associated with increased permeability of the blood vessels may be involved. The genotypes of interleukin 1A (IL1A) (−889C/T; rs1800587) and interleukin 1B (IL1B) (−511C/T; rs16944) were determined using an allele‐specific primer–polymerase chain reaction method in 72 patients with SSNHL, 68 patients with Ménière’s disease, and 2202 control subjects living almost in the same area as the patients. A significantly higher prevalence of the IL1A−889T allele was observed in SSNHL and Ménière’s disease compared with controls, although no significant difference in distribution of IL1B−511C/T genotypes was observed between the patients and controls. Adjusted odd ratios for SSNHL and Ménière’s disease risks in the −889TT genotypes were 25.89 (95% confidence interval (CI) 12.19–54.98) and 18.20 (95% CI 7.80–42.46), respectively, after age and gender were taken as moderator variables. Our results suggested that IL1A is closely associated with susceptibility of SSNHL and Ménière’s disease.

Molecular genetic epidemiology of age-related hearing impairment

Genetic epidemiology focuses on the genetic determinants in the etiology of disease among populations and seeks to elucidate the role of genetic factors and their interaction with environmental factors in disease occurrence. In recent years, genetic epidemiological research has become more focused on complex diseases, and human genome analysis technology has made remarkable advances. Age-related hearing impairment (ARHI) is a complex trait, which results from a multitude of confounding intrinsic and extrinsic factors. Although the number of genetic investigations of ARHI is increasing at a surprising rate, the etiology of ARHI is not firmly established. In this article, we review (1) the methodological strategies used to analyze genetic factors that contribute to human ARHI, (2) several representative investigations, and (3) specific genetic risk factors for human ARHI identified in previous work.

Association of the C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene With Sudden Sensorineural Hearing Loss

To investigate the recently reported association of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with sudden sensorineural hearing loss (SSNHL), we analyzed data from a community‐based Japanese population.

Endothelin-1 gene polymorphism and hearing impairment in elderly Japanese.

To investigate the association between the Lys198Asn (G/T) polymorphism (rs5370) in the endothelin‐1 gene (EDN1) and hearing impairment in middle‐aged and elderly Japanese.

Polymorphisms in Genes Involved in Inflammatory Pathways in Patients with Sudden Sensorineural Hearing Loss

Abstract: Although the etiology of idiopathic sudden sensorineural hearing loss (SSNHL) remains unclear, the pathologically increased permeability of blood vessels, elucidated by gadolinium-enhanced magnetic resonance imaging (MRI), suggests the involvement of inflammation. Because SSNHL is considered a multifactorial disease, possibly caused by interactions between genetic factors and environmental factors, the authors investigated the associations of polymorphisms of inflammatory mediator genes with susceptibility to SSNHL. The authors compared 72 patients affected by SSNHL and 2010 adults (1010 men and 1000 women; mean age 59.2 years; range 40–79) who participated in the National Institute for Longevity Sciences Longitudinal Study of Aging. Multiple logistic regression was used to obtain odds ratios (ORs) for SSNHL in subjects with polymorphisms in the genes IL-6 C − 572G, IL-4R G1902A, IL-10 A − 592C, TNFα C − 863A, TNFRSF1B G593A, VEGF C936T, VEGF C − 2578A, and VEGF G − 1154A, with adjustment for age, gender, and any history of hypertension, diabetes, or dyslipidemia. The per-allele OR for the risk of SSNHL in subjects bearing IL-6 C − 572G was 1.480 (95% confidence interval [CI], 1.037–2.111) in model 1 (no adjustment), 1.463 (CI, 1.022–2.094) in model 2 (adjusted for age and gender), and 1.460 (CI, 1.016–2.097) in model 3 (adjusted for age, gender, and a history of hypertension, diabetes, or dyslipidemia). Under the dominant model of inheritance, the ORs were 1.734 (CI, 1.080–2.783) in model 1, 1.690 (CI, 1.050–2.721) in model 2, and 1.669 (CI, 1.035–2.692) in model 3. The remaining seven polymorphisms failed to show any associations with the risk of SSNHL. These data need to be confirmed on larger series of patients. In conclusion, the IL-6 C − 572G polymorphism is associated with a risk of SSNHL. Because permeability of blood vessels in the inner ear is frequently increased in patients with SSNHL, inflammation of the inner ear might be involved.

The association between gene polymorphisms in uncoupling proteins and hearing impairment in Japanese elderly

Abstract Conclusion: This study illustrates that UCP2 Ala55Val polymorphisms exhibit a significant association with age-related hearing loss in the Japanese population. Objectives: Mitochondrial uncoupling proteins (UCPs) have been suggested to play a protective role against neuron oxidative damage and a thermal signaling role in neuron modulation in the inner ear. In the current study, we examined the relationship between gene polymorphisms in UCP1 and UCP2 and hearing impairment (HI) in Japanese elderly. Methods: A total of 1547 subjects aged 40–79 years and living in Aichi prefecture, Japan, were entered into this study. Subjects were followed up every 2 years, and the cumulative number of subjects for 3 sequential examinations in 6 years was 4942 persons. Detailed questionnaires, pure-tone audiometry measurements, and UCP1 A-3826G and UCP2 Ala55Val polymorphisms were examined. Using generalized estimating equations, associations between HI and gene polymorphisms in UCP1 and UCP2 with age, sex, history of occupational noise exposure, and body mass index were analyzed under dominant, recessive, and additive models. Results: UCP1 A-3826G polymorphism did not exhibit any significant association with HI. However, UCP2 Ala55Val polymorphism did exhibit a significant association with HI under all the dominant (p = 0.0167), recessive (p = 0.0411), and additive (p = 0.0061) models.

Hearing impairment risk and interaction of folate metabolism related gene polymorphisms in an aging study

BackgroundRecent investigations demonstrated many genetic contributions to the development of human age-related hearing impairment (ARHI), however, reports of factors associated with a reduction in the ARHI risk are rare. Folate metabolism is essential for cellular functioning. Despite the extensive investigations regarding the roles of folate metabolism related gene polymorphisms in the pathophysiology of complex diseases, such as cancer, cardio-cerebrovascular disease, and atherosclerosis, little is known about the association with ARHI. The aim of this study is to investigate the effects of the methionine synthase (MTR) A2756G and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms on the risk of hearing impairment in middle-aged and elderly Japanese.MethodsData were collected from community-dwelling Japanese adults aged 40-84 years who participated in the Longitudinal Study of Aging biennially between 1997 and 2008. We analyzed cumulative data (5,167 samples in accumulated total) using generalized estimating equations.ResultsThe MTHFR 677T allele was significantly associated with a reduced risk of hearing impairment only when the subjects were wild-type homozygotes for MTR A2756G. The per-T allele odds ratio of MTHFR for the risk of developing hearing impairment was 0.7609 (95% CI: 0.6178-0.9372) in the MTR AA genotype. In addition, a subgroup analysis demonstrated that the favorable effect of the MTHFR 677T allele on the risk of developing hearing impairment was independent of folate and homocysteine level, whereas plasma total homocysteine level was independently associated with an increased risk of developing hearing impairment. The interactive effect of gene polymorphisms associated with folate metabolism may modify the risk of developing hearing impairment after middle age. These results contribute to the elucidation of the causes of ARHI.ConclusionsThe present study has found that the MTHFR 677T allele has a favorable effect on a risk of hearing impairment in the middle-aged and elderly population, only when the individuals were wild-type homozygotes for MTR A2756G.

The impact of arterial sclerosis on hearing with and without occupational noise exposure: A population-based aging study in males

OBJECTIVES Arterial sclerosis contributes to inadequate blood supply to multiple organs, suggesting that general atherosclerosis may play an important role in the inner ear. Since noise is a major etiology for hearing loss, the aim of this study was to evaluate both the respective and the combined effects of arterial sclerosis and occupational noise exposure on hearing after accounting for age in middle-aged and elderly men. METHODS The evaluation was conducted using 773 subjects from a population-based sample of 1189 men, aged 40-83 years. The impact of carotid atherosclerosis (CA) or retinal arteriolosclerosis (RA) on hearing was assessed according to history of occupational noise exposure (Noise) obtained in a questionnaire. Differences in the mean pure-tone thresholds at each frequency, between the CA (+) and CA (-) groups or between the RA (+) and RA (-) groups, based on noise exposure were compared using the general linear model (GLM) Procedure in SAS, with adjustments for age. Then, the main effect of CA or RA, and the interactive effect of noise and either CA or RA on pure-tone threshold at seven frequencies were analyzed using an analysis of covariance (ANCOVA), after adjusting for age. RESULTS In the Noise (+) group, a statistically significant deterioration in hearing was found in the CA (+) group compared with the CA (-) group at 500 and 1000 Hz. The results in RA were significant at even lower frequencies than in CA. In the results from ANCOVA, the significant main effect of CA was shown in the pure-tone threshold at 8000 Hz, but not in the analysis of RA. A significant interactive effect of either CA or RA and Noise was observed in hearing at the range from 125 to 1000 Hz. CONCLUSIONS The present study suggests that the impact of arterial sclerosis on hearing is limited but significantly hazardous in middle-aged and elderly men, and that arterial sclerosis exacerbates the deleterious effects of noise on hearing. Early recognition of arterial sclerosis might be contributory to the hearing prognosis after middle age, especially for noise-exposed men.

Detection of Herpesvirus DNAs in Perilymph Obtained from Patients with Sensorineural Hearing Loss by Real‐Time Polymerase Chain Reaction

Objectives/Hypothesis: Perilymph and peripheral blood mononuclear cells (PBMCs) from patients with bilateral severe sensorineural hearing loss (SNHL) were evaluated for the presence of DNA from cytomegalovirus (CMV), herpes simplex virus (HSV), and human herpesvirus (HHV)6.