JAK/STAT Dysregulation With SOCS1 Overexpression in Acquired Cholesteatoma-Adjacent Mucosa.

IMPORTANCE: Surgery remains the gold standard in cholesteatoma treatment. However, the rate of recurrence is significant and the development of new nonsurgical treatment alternatives is warranted. One of the possible molecular pathways to target is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. OBJECTIVE: To investigate the JAK/STAT pathway in the middle ear mucosa in patients with acquired cholesteatoma compared with middle ear mucosa from healthy controls. DESIGN: Case-control study. SETTING: Linköping University Hospital, Sweden, and Karolinska Institutet, Stockholm, Sweden. Sampling period: February 2011 to December 2016. PARTICIPANTS: Middle ear mucosa from 26 patients with acquired cholesteatoma undergoing tympanoplasty and mastoidectomy, and 27 healthy controls undergoing translabyrinthine surgery for vestibular schwannoma or cochlear implantation was investigated. MAIN OUTCOMES/MEASURES: The expression of Interleukin-7 receptor alpha, JAK1, JAK2, JAK3, STAT5A, STAT5B, and suppressor of cytokine signaling-1 (SOCS1) were quantified using quantitative polymerase chain reaction. In addition, expression level of cyclin D2, transforming growth factor beta 1, thymic stromal lymphopoietin, CD3, and CD19 was evaluated. RESULTS: In cholesteatoma-adjacent mucosa, SOCS1 was significantly upregulated (p= 0.0003) compared with healthy controls, whereas STAT5B was significantly downregulated (p = 0.0006). The expression of JAK1, JAK2, JAK3, and STAT5A did not differ significantly between groups. CONCLUSIONS AND RELEVANCE: To the best of our knowledge, this is the first article reporting dysregulation of the JAK/STAT pathway in cholesteatoma-adjacent mucosa. The main finding is that important players of the aforementioned pathway are significantly altered, namely SOCS1 is upregulated and STAT5B is downregulated compared with healthy controls.

Extensive qPCR analysis reveals altered gene expression in middle ear mucosa from cholesteatoma patients.

The middle ear is a small and hard to reach compartment, limiting the amount of tissue that can be extracted and the possibilities for studying the molecular mechanisms behind diseases like cholesteatoma. In this paper 14 reference gene candidates were evaluated in the middle ear mucosa of cholesteatoma patients and two different control tissues. ACTB and GAPDH were shown to be the optimal genes for the normalisation of target gene expression when investigating middle ear mucosa in multiplex qPCR analysis. Validation of reference genes using c-MYC expression confirmed the suitability of ACTB and GAPDH as reference genes and showed an upregulation of c-MYC in middle ear mucosa during cholesteatoma. The occurrence of participants of the innate immunity, TLR2 and TLR4, were analysed in order to compare healthy middle ear mucosa to cholesteatoma. Analysis of TLR2 and TLR4 showed variable results depending on control tissue used, highlighting the importance of selecting relevant control tissue when investigating causes for disease. It is our belief that a consensus regarding reference genes and control tissue will contribute to the comparability and reproducibility of studies within the field.

The Outcome of Unilateral Cochlear Implantation in Adults: Speech Recognition, Health-Related Quality of Life and Level of Anxiety and Depression: a One- and Three-Year Follow-Up Study

Abstract Introduction Hearing impairment is a common disease worldwide, with a comprehensive impact, and cochlear implantation (CI) is an intervention for profound hearing impairment. Objective To study the outcome one and three years after unilateral CI on hearing, health-related quality of life and level of depression and anxiety, and the correlation between the outcomes. Second, to study whether age, gender, etiology, operated side, residual hearing or cognitive performance can predict the outcome. Methods A prospective longitudinal study including adults with profound postlingual hearing impairment, with respect to hearing (speech recognition), health-related quality of life (Health Utilities Index 3) and level of depression and anxiety (Hospital Anxiety and Depression scale), pre-CI, and one and three years post-CI. The total sample was composed of 40 participants (40% of men), with a mean age of 71 years. Results Speech recognition and the overall health-related quality of life improved one year post-CI (p= 0.000), without correlation (ρ= 0.27), and with no difference three years post-CI. The hearing attribute (in the health-related quality of life instrument) improved one and three years post-CI (p= 0.000). The level of anxiety did not change one and three years post-CI. The level of depression improved one year post-CI (p= 0.036), and deteriorated three years post-CI (p= 0.031). Age, etiology, operated side, residual hearing and cognitive performance did not predict the outcome, but the female gender did significantly improve speech recognition compared with men (p= 0.009). Conclusion The CI significantly improved speech recognition, health-related quality of life and level of depression one year post-CI without mutual correlation, and women performed significantly better than men. There were no further improvements three years post-CI, apart from the hearing attribute.

The evaluation of canal wall up cholesteatoma surgery with the Glasgow Benefit Inventory.

PURPOSE: The aim of the study was to investigate the change in health-related quality of life (HRQoL) after canal wall up cholesteatoma surgery, using the Glasgow Benefit Inventory (GBI). METHODS: Data from a consecutive group of 47 adults scheduled for primary cholesteatoma surgery using canal wall up (CWU) with obliteration, from January 2005 to December 2009, were analysed. Information was extracted from a medical database, and complementary data from patient files and audiograms were collected and recorded retrospectively. The GBI questionnaire was used for the assessment of HRQoL after surgery. RESULTS: There was no finding of residual or recurrent cholesteatomas in the study group. Hearing was improved at 1 and 3 years postoperatively. No patient suffered a total hearing loss. The overall GBI scores showed an improved HRQoL after surgery. Twenty-nine (85%) patients benefitted from surgery, 1 (3%) had no change, and 4 (12%) expressed deterioration. CONCLUSIONS: Cholesteatoma surgery using CWU with obliteration gives an improved HRQoL for the majority of patients. The GBI questionnaire provides complementary information to hearing and healing results after cholesteatoma surgery.

Cholesteatoma surgery with the canal wall up technique combined with mastoid obliteration: results from primary surgery in 230 consecutive cases.

OBJECTIVE: To evaluate the canal wall up (CWU) technique combined with mastoid obliteration used in cholesteatoma surgery from the aspects of safety and function. STUDY DESIGN: Retrospective chart review. Information was extracted from a medical database and complementary data from patient files and audiograms were collected and recorded retrospectively. SETTING: A tertiary-stage hospital and a secondary-stage hospital. Surgeons of various levels of experience. METHOD: Data from a consecutive group of 230 primary operations for cholesteatoma surgery using CWU with obliteration employing the combined approach tympanoplasty (CAT) technique, from January 1994 to December 2009 were analyzed. RESULTS: In 90% of the ears, the anatomy was normalized with an intact ear drum. The frequency of residual cholesteatoma was 1% and the frequency of recurrent cholesteatoma 8%. Hearing was improved one year postoperatively and remained improved three years postoperatively. No patient suffered a total hearing loss. CONCLUSIONS: CWU procedure comprising CAT with obliteration of the mastoid is a safe surgical method with a low frequency of residual and recurrent disease and a good hearing preservation.

Hearing impairment among adults: the impact of cardiovascular diseases and cardiovascular risk factors.

OBJECTIVE: To investigate the influence of cardiovascular diseases on hearing impairment (HI) among adults. Furthermore, to seek other potential risk factors for HI, such as smoking, obesity, and socioeconomic class. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Cardiovascular diseases did not increase the risk for HI in a propensity-score adjusted logistic regression model: OR 1.24, 95% CI 0.79 to 1.96 for HI defined by better ear hearing level (BEHL), and OR 1.48, 95% CI 0.96 to 2.28 for HI defined by worse ear hearing level (WEHL), in the 0.5-4 kHz frequency range. Heavy smoking is a risk factor for HI among men (BEHL: OR 1.96, WEHL: OR 1.88) and women (WEHL: OR 2.4). Among men, obesity (BEHL, OR 1.85) and lower socioeconomic class (BEHL: OR 2.79, WEHL: OR 2.28) are also risk factors for HI. CONCLUSION: No significant association between cardiovascular disease and HI was found.

Occupational noise, smoking, and a high body mass index are risk factors for age-related hearing impairment and moderate alcohol consumption is protective: a European population-based multicenter study.

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children.

OBJECTIVE: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland. METHODS: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously. RESULTS: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with heteroplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016). INTERPRETATION: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation.

An office procedure to detect vestibular loss in children with hearing impairment.

As coexisting vestibular and cochlear lesions are of etiological importance, evaluation of children with congenital or early acquired hearing impairment (HI) should include vestibular assessment. A rotation test requires specific equipment and allows only detection of bilateral vestibular impairment. An impulse or head thrust test allows assessment of one ear at a time, detects more pronounced caloric side differences and can be performed without any equipment. We report a consecutive series of children with profound sensorineural HI investigated at a tertiary hospital unit. Age at taking first steps without help, the results of temporal bone images (CT/MRT) and vestibular tests were collected retrospectively from patient files. The children were 12 to 90 months old at the time they attended both a rotation and an impulse test. All 14 children cooperated in the impulse test, and 12 completed the vestibular rotation test successfully. Three out of 14 children tested so far have been confirmed to have a bilaterally pathological vestibulo-ocular reflex confirmed both in the rotation test and the impulse test. Our results show that both the rotation test and the vestibular impulse test can be successfully performed on small children at a regular outpatient appointment.