Three years later: report on the state of well-being of patients with chronic tinnitus who underwent modified tinnitus retraining therapy.

Successful management of patients with chronic tinnitus is an important health issue. One of the tinnitus management strategies used at our Tinnitus Center is a combination of tinnitus retraining therapy (TRT) with physiotherapy and psychological management [called modified TRT (MTRT)]. We have used this type of management for over a decade and have described the protocol in detail elsewhere. In the present study, we wanted to determine the effect of MTRT on the well-being of tinnitus patients 3 years after treatment onset. One hundred and thirty patients with chronic tinnitus were assessed using psychometric instruments immediately before 7-day MTRT, immediately after the therapy and 3 years later. Patients with very severe tinnitus-related distress associated with major depression and a risk of suicide were excluded from this study. MTRT resulted in a sustained reduction of tinnitus-related distress. Moreover, the quality of life of patients had increased, as assessed by a separate questionnaire. The effect of MTRT was influenced by the degree of tinnitus-related distress and by the patients' age, the latter being gender dependent. Hearing loss and tinnitus duration had only a minor influence on the therapeutic effect. Taken together, we report a positive change in the state of well-being of patients with chronic tinnitus measurable with various psychometric instruments 3 years after the onset of MTRT.

Biological correlates of tinnitus-related distress: an exploratory study.

During the process of tinnitus diagnostics, various psychometric instruments are used to measure tinnitus-related distress. The aim of present work was to explore whether candidates for biological correlates of the tinnitus-related distress could be found in peripheral blood of patients and if so, whether there was association between them and psychometric scores that reflect tinnitus-related distress. The concentrations of interleukin-1ß (IL1ß), interleukin-6 (IL6), tumor necrosis factor-α (TNFα) and a brain-derived neutrotrophic factor (BDNF) were measured in serum of 30 patients diagnosed with chronic tinnitus and tested for correlation with psychometric scores collected on the same day. Spearman's correlation analyses detected significant positive association between the concentrations of tumor necrosis factor α and tinnitus loudness, total perceived stress, tension and depression and a negative association between tumor necrosis factor α and a psychometric score "joy". Concentrations of interleukin-1ß correlated with the awareness grade of tinnitus. The correlation between visual analogue scale (VAS) "loudness" and tumor necrosis factor α as well as between "joy" and tumor necrosis factor α retained their significance (p < 0.00167) after the application of Bonferroni correction for multiple testing. Partial correlations removing the effects of age, hearing loss and the duration of tinnitus verified the results obtained using Spearman correlation. We conclude that measuring the concentrations of selected circulating cytokines could possibly become an additional objective element of tinnitus diagnostics in the future.

Gender and chronic tinnitus: differences in tinnitus-related distress depend on age and duration of tinnitus.

OBJECTIVE: Conflicting data about the role of gender in tinnitus distress exist in the literature. In addition, little is known about gender differences regarding age and duration of tinnitus. Tinnitus was shown to be related to stress and impairment of coping, sense of coherence, and personal resources. There are known differences in the aforementioned psychological parameters between man and women or among different age groups. The authors hypothesized that this may also be true for patients with chronic tinnitus in addition to gender- and age-related differences in tinnitus annoyance. Therefore, using a large number of patients with chronic tinnitus, the authors analyzed pretherapeutic scores of tinnitus annoyance, perceived stress, proactive coping strategies, sense of coherence, and personal resources in addition to hearing loss and tinnitus pitch and loudness in respect to gender and age of the patients as well as duration of tinnitus. DESIGN: The study group included 607 female and 573 male patients who reported tinnitus for longer than 3 months. The age of the patients ranged from 17 to 81 years in both gender groups. Pretherapeutic scores of tinnitus annoyance, perceived stress, proactive coping strategies, sense of coherence, and personal resources as well as the degree of hearing loss and tinnitus pitch and loudness were analyzed. RESULTS: Irrespective of age and tinnitus duration, women were more annoyed by tinnitus and perceived more stress than men did. In addition, women scored lower than men in proactive coping, sense of coherence, and personal resources but had lower levels of hearing loss and tinnitus loudness than men did. The differences were small, but statistically significant. Analysis of three age groups revealed significant differences between older female and male patients. Tinnitus annoyance was stronger in the middle-age groups of women and men (45-59 years of age) than in younger patients and decreased again in older men (≥60 years of age), but not in older women. Women, but not men, had cognitive distress scores that progressed with age. Older women (≥60 years of age) reported more sleep disturbances than older men. Women had more somatic complaints and coped less efficiently than men, except for younger patients (<45 years of age). The scores of perceived stress decreased whereas scores of sense of coherence and self-efficacy increased in older men and women (≥60 years of age). However, women scored worse than men did in this age group. Hearing loss was found to be correlated with tinnitus loudness and age in both gender groups. The duration of tinnitus affected subjective hearing problems, intrusiveness of tinnitus, and proactive coping. This association was in part age-dependent. CONCLUSIONS: The authors found gender differences regarding tinnitus-related distress in patients with chronic tinnitus; however, these differences depended on age and in part on duration of tinnitus. Addressing these differences could result in improved, tailored therapy approaches. For instance, applying physical exercise and relaxation techniques could be of special help for older women to reduce their somatic complaints and sleep disturbances. Similarly, cognitive behavioral therapy could reduce their cognitive distress. Therapy for younger patients should in particular include stress management.

Exposure of Wistar rats to 24-h psycho-social stress alters gene expression in the inferior colliculus.

Recently, we have demonstrated that the exposure of Wistar rats to psycho-social stress results in a transient auditory hypersensitivity. Here, to learn more about modifications occurring in auditory brainstem, we have analyzed gene expression pattern in inferior colliculus using quantitative RT-PCR. As targets, we have chosen genes associated with: neural activity (FBJ osteosarcoma viral oncogene, cFos), hypoxia (nitric oxide synthase inducible, iNos; superoxide dismutase 2, Sod2), neuroprotection (nerve growth factor beta, Ngfb; heat shock factor 1, Hsf1; heat shock protein 70, Hsp70) and inflammation (tumor necrosis factor alpha, Tnfa; tumor necrosis factor alpha receptor, Tnfar; substance P, Sp; cyclooxygenase 2, Cox2). We found that the expression of all genes was modified following stress, as compared to the controls. Immediately after stress, the number of transcripts encoding iNos, Sod2, Hsf1, Ngfb, Tnfa, Tnfar and Sp was significantly increased, suggesting possible modulation during exposure to stressor. Interestingly, we found that expression of Hsf1 and Ngfb at this particular time was left-right asymmetrical: there were more transcripts of both genes found in the left colliculi, as compared to the right colliculi. Three hours post-stress, iNos, Hsf1, Tnfa and Tnfar were still upregulated, Sod2, Ngfb and Sp went back to baseline and Cox2 was upregulated. Six hours post-stress, cFos mRNA became downregulated. The number of Hsp70 mRNA increased 24h post-stress. Except for the reduced number of cFos transcripts, expression of all other genes tested reached the baseline seven days post-stress. Presented results corroborate the concept of auditory system responding to the psycho-social stress. Post-stress changes in the IC gene expression could likely indicate shift from allostasis to homeostasis in the auditory brainstem.

Extra benefit of a second cochlear implant with respect to health-related quality of life and tinnitus.

OBJECTIVE: To evaluate whether the second cochlear implant (CI) provides any extra benefit with respect to health-related quality of life, tinnitus, and auditory abilities. DESIGN: The data were evaluated using validated questionnaires before and after the first and second CI supply. Preimplantation data were collected retrospectively. PATIENTS: Forty postlingually deafened adults, 11 male and 29 female subjects were included in this study. All patients were sequentially bilaterally implanted with a multi-channel CI for at least 6 months. RESULTS: The health-related quality of life assessed with the Nijmegen Cochlear Implant Questionnaire further increased after the second CI. In patients with initially higher level of tinnitus annoyance measured with the Tinnitus Questionnaire, the scores decreased after the first CI and remained steady after the second CI. Patients with initially lower level of tinnitus annoyance had a further decrease of the Tinnitus Questionnaire score after the second CI. Additionally, the second CI induced further improvement of auditory abilities, as assessed by the Oldenburg Inventory and the Freiburg monosyllable test in quiet and the HSM and Oldenburg sentence tests in noise. The quality of life scores correlated with the auditory abilities, especially after the second CI. CONCLUSION: The present study provides evidence that the second CI leads to further increase in quality of life and reduction of tinnitus annoyance in addition to improvement of auditory abilities as compared with the first CI. Patients with bilateral CIs benefit from additional positive effects in all these fields.

Stress and tinnitus-from bedside to bench and back.

The aim of this review is to focus the attention of clinicians and basic researchers on the association between psycho-social stress and tinnitus. Although tinnitus is an auditory symptom, its onset and progression often associates with emotional strain. Recent epidemiological studies have provided evidence for a direct relationship between the emotional status of subjects and tinnitus. In addition, studies of function, morphology, and gene and protein expression in the auditory system of animals exposed to stress support the notion that the emotional status can influence the auditory system. The data provided by clinical and basic research with use of animal stress models offers valuable clues for an improvement in diagnosis and more effective treatment of tinnitus.

The impact of cochlear implantation on tinnitus, stress and quality of life in postlingually deafened patients.

Tinnitus is a common complaint in the candidates for cochlear implantation (CI). Tinnitus-related distress has often been measured in these patients using categorical ratings, which lack information about tinnitus severity, stress and health-related quality of life or their correlation. Here, using 4 validated questionnaires, we evaluated psychometric parameters and the quality of life of 32 postlingually deafened patients before and after CI. The data regarding pre-CI were collected retrospectively. Of all patients included in this study, 28 (87.5%) suffered from tinnitus before implantation. Following a mean of 24 months after surgery, these patients reported a significant decrease (39.2%) of tinnitus impairment, as measured by the Tinnitus Questionnaire. In none of the 28 patients has tinnitus worsened. Moreover, the 4 tinnitus-free patients remained so after the CI surgery. In addition, the implant supply resulted in 36.7% reduction in perceived stress and in 15.4% reduction in evasive coping. In addition, the focus on positive coping has improved by 12.3%, whereas the health-related quality of life improved by 53.4% in all patients. Tinnitus impairment and stress were reduced more strongly in patients who had initially higher scores. Interestingly, a significant correlation between the psychometric scores was found mainly after CI. Our results indicate that patients with higher tinnitus-related distress have a lower quality of life, lesser coping abilities and perceive more stress, but before implantation it is masked by deafness. We conclude that tinnitus-related screening of patients before and after CI is an important step in the identification of individuals who would benefit from specific fitting and/or tinnitus therapy after implantation.

Elderly patients benefit from cochlear implantation regarding auditory rehabilitation, quality of life, tinnitus, and stress.

OBJECTIVES/HYPOTHESIS: To determine the effect of cochlear implantation on quality of life, speech performance, tinnitus, perceived stress, and coping strategy in patients aged≥70 years in comparison with younger patients. STUDY DESIGN: Retrospective study. METHODS: A total of 55 postlingually deafened adults who were unilaterally implanted with a multichannel cochlear implant for at least 6 months were included in the study. Twenty patients were aged≥70 years (70-84 years), and 35 patients were <70 years (19-67 years). Speech perception was measured using the Freiburg monosyllable test in quiet and the Hochmair-Schulz-Moser sentence test. In addition, the patients filled in six validated questionnaires. RESULTS: Speech perception and subjectively assessed auditory ability were similar in the two age groups after implantation. Disease-specific quality of life was improved in patients aged≥70 years and even to a higher extent as compared to younger patients. Tinnitus annoyance and perceived stress were reduced in elderly patients to the same extent as in younger patients in the case of high initial severity level. The scores for the coping subdomain "seeking support" were reduced in elderly patients. CONCLUSIONS: The present study provides evidence that cochlear implantation constitutes a very successful procedure of auditory rehabilitation, even for patients aged ≥70 years. In addition, elderly patients benefit from implantation, with increased quality of life and reduced tinnitus and stress.

In vitro protection of auditory hair cells by salicylate from the gentamicin-induced but not neomycin-induced cell loss.

Salicylate has been shown to protect animals and people from the gentamicin-induced hearing loss. The objective of our study was to determine if salicylate is otoprotective in vitro. In this fashion, we wanted to validate the use of explant culture system for future studies on the ototoxicity prevention. In addition, we wanted to find out if salicylate protects from the ototoxicity of other aminoglycosides. As a model, we used the membranous cochlear tissues containing the organ of Corti, spiral limbus and spiral ganglion neurons dissected from the cochleas of p3-p5 Wistar pups. The explants were divided into apical, medial and basal parts and cultured in presence or absence of 100µM gentamicin, 100µM neomycin and 5mM salicylate. Following the tissue fixation and staining with phalloidin-TRITC, the number of inner and outer hair cells (IHCs, OHCs) was scored under the fluorescent microscope. Presence of 5mM salicylate in explants cultures exposed to 100µM gentamicin significantly reduced the loss of IHCs and OHCs, as compared to explants exposed to gentamicin alone. In contrast, neomycin-induced auditory hair cell loss remained unaffected by the presence of salicylate. Our results corroborate earlier in vivo findings and validate the use of cochlear explants for future studies on ototoxicity and its prevention. Moreover, the inability of salicylate to prevent neomycin-induced ototoxicity implies possible differences between the mechanisms of auditory hair cell loss induced by gentamicin and neomycin.

Cochlear implantation has a positive influence on quality of life, tinnitus, and psychological comorbidity.

OBJECTIVES: To determine the effect of cochlear implantation (CI) on health-related quality of life (HRQoL), tinnitus, and psychological comorbidity in patients with severe to profound postlingual hearing loss and to analyze the relationship between these parameters. STUDY DESIGN: Prospective study. METHODS: Using six validated questionnaires, we evaluated the pre-CI and post-CI scores of HRQoL, tinnitus, perceived stress, symptoms of depression and anxiety, and coping strategies in 43 patients implanted unilaterally with a multichannel implant for at least 6 months. RESULTS: In addition to improvements in hearing, speech understanding, and disease-specific HRQoL, psychological comorbidity was reduced and coping strategies were improved following CI. In the 39 tinnitus patients, their tinnitus was reduced. We found negative correlations between HRQoL and stress, depression, and anxiety. Pre-CI, tinnitus severity did not correlate with HRQoL and psychological comorbidity. However, patients with a high-level tinnitus had lower HRQoL as well as a higher level of perceived stress and anxiety symptoms than patients with a low-level tinnitus and no/incidental tinnitus before CI. Moreover, patients with severe hearing loss had a higher level of perceived symptoms of stress and depression than patients with profound hearing loss before CI. CONCLUSIONS: The present study provides evidence that tinnitus and psychological comorbidity may play an important role in the rehabilitation of CI patients, and that there is a correlation between HRQoL and these parameters. In addition to hearing tests, tinnitus, stress, and psychological comorbidity should be assessed using validated questionnaires before and after CI. This will help to improve the rehabilitation process.

Salicylate modulates Hsp70 expression in the explanted organ of Corti.

Heat shock protein 70 (Hsp70, Hspa1a) is known to play a protective role in the inner ear and in the nervous system. Our recent study demonstrated that the induction of Hsp70 by geldanamycin protected the auditory hair cells against ototoxic insult. Here, using the explanted organ of Corti (OC), we characterized the effect of sodium salicylate on the expression of Hsp70. Using the real-time RT-PCR; after 27 h in standard culture, we observed an increase in the Hsp70 transcript number. After 48 h in culture, the number of Hsp70 transcripts increased further, as compared to the freshly isolated tissues or explant cultured for 27 h. Three hours after the addition of 2.5mM sodium salicylate, the expression of Hsp70 mRNA increased significantly. Interestingly, Hsp70 protein level remained unaffected by the addition of salicylate, as shown by immunoblotting and Hsp70-ELISA. Confocal microscopy imaging demonstrated predominant localization of Hsp70 protein with or without salicylate exposure to the fibrocytes of spiral limbus. Our results suggest that in the OC, explanting process induces expression of Hsp70 in limbal fibrocytes and that this expression can be enhanced by salicylate but only on mRNA and not on the protein level.

Expression of genes implicated in oxidative stress in the cochlea of newborn rats.

Oxidative stress is an important mechanism inducing ototoxicity-, age- and noise-induced hearing loss. To better understand this phenomenon, we examined cochlear tissues for the expression of following genes involved directly or indirectly in the oxidative stress response: glyceraldehyde-3-phosphate dehydrogenase (Gapdh); solute carrier family-2 (facilitated glucose transporter), member-1 (Slc2a1); heme oxygenase-1 (Hmox1); heme oxygenase-2 (Hmox2); inducible nitric oxide synthase-2 (Nos2); transferrin (Tf); transferrin receptor (Tfrc); glutathione S-transferase A3 (Gsta3) and metallothionein-1a (Mt1a). Cochlear tissues were dissected from the p3-p5 Wistar rats, divided into the organ of Corti (OC), modiolus (MOD) and stria vascularis together with spiral ligament (SV + SL) and processed immediately or cultured under normoxic conditions or a short-term, mild hypoxia followed by re-oxygenation. After 24 h, explants were collected and total RNA isolated, transcribed and amplified in the real time RT-PCR. We found all genes listed above expressed in the freshly isolated cochlear tissues. In the OC and MOD, Slc2a1, Tf, and Mt1a were expressed on a lower level than in the SV + SL. In the OC, Hmox1 was expressed on a lower level than in the MOD and SV + SL. Hypoxic and normoxic cultures increased the transcript number of Gapdh, Slc2a1 and Hmox1 in all cochlear tissues. The expression of Nos2, Tf, Gsta3 and Mt1a increased in a tissue-specific manner. In the SV + SL, Mt1a expression decreased after normoxic and hypoxic conditions. Taken together, using real time RT-PCR, our results imply that oxidative stress may be an important component of cochlear injury during the developing period. In spite of the immaturity of the tissue, a differential response of antioxidant enzymes/proteins with respect to the pathway, the expression levels and regions was observed.

Impact of laser eustachian tuboplasty on middle ear ventilation, hearing, and tinnitus in chronic tube dysfunction.

OBJECTIVES: Long-term Eustachian tube dysfunction (ETD) predisposes to various secondary middle ear diseases. Most surgical and prosthetical interventions on the Eustachian tube itself have proven to be ineffective, whereas middle ear surgeries treat the sequelae of ETD without major influence on the underlying tubal pathology. The purpose of our study was to evaluate the outcome of laser Eustachian tuboplasty (LETP) on tubal function and associated otological symptoms in topically anesthetized ETD patients with intact or perforated eardrums. DESIGN: In a prospective clinical investigation, outpatient LETP was carried out in 31 subjects with therapy-refractory chronic ETD. The study population comprised two groups: 16 patients with mesotympanic eardrum perforations diagnosed with noninflammatory chronic otitis media (COM) and 15 patients with intact eardrums including otitis media with effusion, adhesion processes, and dysfunctional pressure equalization. Clinical examination and data acquisition were performed 2 wks before LETP as well as 8 wks and 1 yr postoperatively. On COM patients, LETP was done at 10-wk intervals before the scheduled tympanoplasty. Assessment of clinical effectiveness was based on transnasal videoendoscopy, ear microscopy, tubal function tests (Valsalva maneuver and passive tubal opening), audio- and tympanometric measurements, and visual analog scales. Tansnasal, fiber-guided laser surgery was performed in contact mode using a semiconductor diode laser (λ = 830 nm, 4 W). We hypothesized that regulated laser ablation of hyperplastic mucosa at the epipharyngeal dorsal circumference of the tubal ostium could be effective in improving the associated symptoms such as dysfunctional pressure equalization, aural fullness, conductive hearing loss, and tinnitus. RESULTS: LETP resulted in persistent volume reduction of the posterior tubal circumference in all patients. Objective parameters revealed significant improvement of tubal function tests and middle ear ventilation in 62% of subjects after 8 wks (66% after 1 yr). Significant long-term reduction of conductive hearing loss was achieved in both patient groups. Besides, tinnitus loudness was significantly reduced in COM subjects after tympanoplasty. Visual analog scales showed very low values for intraoperative pain and discomfort and high scores for long-term overall patient satisfaction as well as improvement of the symptoms such as dysfunctional pressure equalization and aural fullness. Subjects with post-LETP Valsalva feasibility marked higher values for satisfaction and symptom improvement than patients without successful Valsalva maneuver. COM subjects scored higher in hearing improvement and satisfaction after LETP and successful tympanoplasty than patients with intact eardrums. CONCLUSIONS: Outpatient LETP seems to be a suitable, safe, easily applicable, and well-tolerated treatment option before (revision) tympanoplasties and in all investigated diseases developing from long-lasting pathologic middle ear ventilation. Minimally invasive shaping of the hyperplastic nasopharyngeal Eustachian tube under topical anesthesia seems to be effective in improving tubal function as well as the associated symptoms such as dysfunctional pressure equalization, aural fullness, and conductive hearing loss in otherwise therapy-refractory chronic ETD.

The more the worse: the grade of noise-induced hearing loss associates with the severity of tinnitus.

Tinnitus disturbs lives and negatively affects the quality of life of about 2% of the adult world population. Research has shown that the main cause of tinnitus is hearing loss. To analyze a possible association of the degree of hearing loss with the severity of tinnitus, we have performed a retrospective study using admission data on 531 patients suffering from chronic tinnitus. We have found that 83% of our tinnitus patients had a high frequency hearing loss corresponding to a noise-induced hearing loss (NIHL). There was a significant correlation between the mean hearing loss and the tinnitus loudness (p < 0.0001). Interestingly, patients suffering from decompensated chronic tinnitus had a greater degree of hearing loss than the patients with compensated form of tinnitus. In addition, we demonstrate that the degree of hearing loss positively correlates with the two subscales ("intrusiveness" and "auditory perceptional difficulties") of the Tinnitus Questionnaire. Our retrospective study provides indirect evidence supporting the hypothesis that the degree of noise-induced hearing loss influences the severity of tinnitus.

Expression of the proinflammatory cytokines in cochlear explant cultures: influence of normoxia and hypoxia.

Hearing loss can be induced by a variety of factors including hypoxia and inflammation. Here, we investigated in vitro the effect of hypoxia on the expression of proinflammatory cytokines in the explanted cochlear tissues. Using RT-PCR, we determined the expression of genes encoding IL-1beta, IL-6 and TNF in the organ of Corti (OC), modiolus (MOD) and stria vascularis together with spiral ligament (SV+SL). In addition, using ELISA, we determined the concentration of IL-1beta and IL-6 in the supernatants of explant cultures. We found that the dissection, explanting and consecutive 24-h normoxic culture results in highly increased expression of IL-1beta and IL-6, as compared to the freshly isolated tissues. TNFalpha was upregulated only in the MOD. Interestingly, 24h of hypoxia decreased the number of mRNA encoding IL-1beta and IL-6 and increased the number of mRNA encoding TNFalpha in the SV+SL as compared to normoxia. The concentration of IL-6 measured in the explant tissue culture supernatants was significantly lower in hypoxic than in the normoxic cultures. Our results show that tissue dissection and explanting as well as hypoxia can influence the expression and secretion of proinflammatory cytokines. This implies the presence of tissue-specific regulatory pathways between hypoxia and inflammation in the inner ear.

Long-term improvement in tinnitus after modified tinnitus retraining therapy enhanced by a variety of psychological approaches.

This work evaluates an enhanced tinnitus retraining therapy (TRT) for patients with chronic tinnitus based on different group therapeutic interventions in a day hospital setting. Therapy for chronic tinnitus is intended to improve the way patients cope with tinnitus by learning how to reduce tinnitus-induced impairments. Short-term and long-term changes in stress variables and tinnitus-related distress were investigated using 3 psychometric instruments. Patients received 7 consecutive days of a multidisciplinary therapy at the Charité University Hospital in Berlin. The data were assessed before and after therapy, either immediately or after 3, 6 or 12 months. As a control, we used scores of tinnitus patients from the waiting list, and compared these to the scores of the therapy group 3 months after the end of treatment. The main factors of the modified TRT were Jacobson's progressive muscle relaxation, physiotherapy, education via lectures and training of selective attention, as well as changes of appraisal, mental attitude and behavior towards tinnitus. The therapy resulted in a significant reduction in both short-term and long-term tinnitus-related distress and psychometric stress variables, with the latter being more reduced in patients with higher initial scores. Moreover, our study revealed differences in psychometric parameters concerning duration of tinnitus, age and gender, which may explain the different outcomes of therapy. The outpatient setting enables the patients to test, practice and transfer strategies into their everyday life.

Stress induces transient auditory hypersensitivity in rats.

Exposure to harsh environment induces stress reactions that increase probability of survival. Stress influences the endocrine, nervous and immune systems and affects the functioning of a variety of organs. Numerous researchers demonstrated that a 24-h exposure to an acoustic rodent repellent provokes stress reaction in exposed animals. In addition to the activated hypothalamic-pituitary-adrenal (HPA) axis, exposed animals had pathological reactions in the reproductive organs, bronchia and skin. Here, we examined the effect of above stress model on the auditory system of Wistar rats. We found that 24-h stress decreases the thresholds and increases the amplitudes of auditory brainstem responses and distortion product otoacoustic emissions. Resultant auditory hypersensitivity was transient and most pronounced between 3 and 6h post-stress, returning to control levels one week later. The concentration of corticosterone and tumor necrosis factor alpha was systemically elevated in stressed animals between 3 and 6h post-stress, confirming the activation of the HPA axis. In addition, expression of the HPA-axis-associated genes: glucocorticoid receptor (GR) and hypoxia-inducible factor 1 alpha (Hif1a) was modulated in the auditory tissues. In detail, in the inferior colliculus, we found an up-regulation of GR mRNA 3h post-stress and continuous up-regulation of Hif1a up to 24h post-stress. In the spiral ganglion, we found no differences in gene expression between stressed and control animals. In the organ of Corti, expression of GR mRNA remained stable, whereas that of Hif1a was significantly down-regulated one week after stress. In addition, the expression of an outer hair cell marker prestin was significantly up-regulated 6h post-stress. We conclude that 24-h stress induces transient hypersensitivity of the auditory system and modulates gene expression in a tissue-specific manner. Stress-induced auditory hypersensitivity could have evolutionary consequence by giving animals an advantage of hearing better under stress conditions.

Geldanamycin induces production of heat shock protein 70 and partially attenuates ototoxicity caused by gentamicin in the organ of Corti explants.

BACKGROUND: Heat shock protein 70 (HSP70) protects inner ear cells from damage and death induced by e.g. heat or toxins. Benzoquinone ansamycin antibiotic geldanamycin (GA) was demonstrated to induce the expression of HSP70 in various animal cell types. The aim of our study was to investigate whether GA induces HSP70 in the organ of Corti (OC), which contains the auditory sensory cells, and whether GA can protect these cells from toxicity caused by a common aminoglycoside antibiotic gentamicin. METHODS: To address these questions, we used the OC explants isolated from p3-p5 rats. As a read-out, we used RT-PCR, ELISA and immunofluorescence. RESULTS: We found that GA at the concentration of 2 microM efficiently induced HSP70 expression on mRNA and protein level in the OC explants. Confocal microscopy revealed that HSP70 induced by GA is expressed by hair cells and interdental cells of spiral limbus. Preincubation of explants with 2 muM GA prior to adding gentamicin (500 microM) significantly reduced the loss of outer but not inner hair cells, suggesting different mechanisms of otoprotection needed for these two cell types. CONCLUSION: GA induced HSP70 in the auditory sensory cells and partially protected them from toxicity of gentamicin. Understanding the molecular mechanisms of GA otoprotection may provide insights for preventative therapy of the hearing loss caused by aminoglycoside antibiotics.

Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study.

BACKGROUND: Vardenafil (Levitra(R)) represents a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor, which is established for treatment of various diseases. There are several unpublished reports from patients stating that vardenafil has a considerable therapeutic effect on their concomitant tinnitus. This pilot study was conducted to specifically assess the effect of vardenafil in patients with chronic tinnitus. METHODS: This trial was based on a prospective, randomized, double-blind, placebo-controlled, parallel group design. Fourty-two consecutive subjects with mon- or binaural chronic tinnitus received 10 mg vardenafil (N = 21) or matching placebo tablets (N = 21) administered orally twice a day over a period of 12 weeks. Clinical examination and data acquisition took place at each visit: at baseline, after 4 weeks, after 12 weeks (end of treatment with study medication), and at non-medicated follow-up after 16 weeks. Assessment of clinical effectiveness was based on a standardized tinnitus questionnaire (TQ), the Short Form 36 health survey (SF-36), audiometric measurements (mode, pitch and loudness of tinnitus; auditory thresholds) and biomarkers of oxidative stress in patients' blood (malondialdehyde, protein carbonyl, homocysteine and total antioxidative status). Therapeutic efficacy was evaluated by comparison of subjective and objective parameters with baseline data between both treatment groups (ANCOVA). RESULTS: Vardenafil had no superior efficacy over placebo in the treatment of chronic tinnitus during this study. The primary efficacy criterion 'TQ total score' failed to demonstrate significant improvement compared to placebo. Subjective reports of TQ subscales and general quality of life areas (SF-36), objective audiometric examinations as well as investigated biomarkers for oxidative stress did not reveal any significant treatment effects. The safety profile was favorable and consistent with that in other vardenafil studies. CONCLUSION: Although hypoxia and ischemia play a special role in the pathogenesis of tinnitus, the PDE5-inhibitor-induced increase of nitric oxide-mediated vasodilatation exerted no specific influence on tinnitus symptomatology. Considering the unclear risk of rarely associated hearing impairment, systemic application of vardenafil or other PDE5 inhibitors prove to be not appropriate for therapy of chronic tinnitus.

MRNA expression of members of the IGF system in the organ of Corti, the modiolus and the stria vascularis of newborn rats.

We analyzed the mRNA expression of the insulin-like growth factor (IGF) family genes and of selected downstream pathway genes using the Affymetrix microarray system and confirmatory RT-PCR in the freshly prepared organ of Corti (OC), modiolus (MOD) and stria vascularis (SV) from neonatal rats (3-5 days old) and after 24h in culture. Among the seven members of the IGF family analyzed in this paper, IGF1, IGF2 and IGF-binding protein (IGFBP2) had the highest basal expression in all regions. Preparatory stress and culture increased the expression of IGF2, IGFBP2, IGFBP3, IGFBP5, glucose transporterl (GLUT1), signal transducer, and activator of transcription3 (STAT3), phosphoinositide-3-kinase regulatory subunit (Pik3r1), Jun oncogene (c-jun) and decreased that of mitogen-activated protein kinases MAPK3 and MAPK14 in all regions. Region-specific changes were observed in OC (GLUT1), MOD (IGFBP3 and c-jun) and SV (IGF2 and IGFBP2).