[On the interdisciplinary S3 guidelines for the treatment of chronic idiopathic tinnitus]. / Zur interdisziplinären S3-Leitlinie für die Therapie des chronisch-idiopathischen Tinnitus.

INTRODUCTION: Tinnitus is a frequent symptom, which, particularly in combination with comorbidities, can result in a severe disease-related burden. Chronic idiopathic tinnitus (CIT) is the most frequent type of tinnitus. A considerable number of treatment strategies are used to treat CIT-for many of which there is no evidence of efficacy. In order to enable scientific evidence-based treatment of CIT, German interdisciplinary S3 guidelines have recently been constructed for the first time. Here we present a short form of these S3 guidelines. MATERIALS AND METHODS: The guidelines were constructed based on a meta-analysis of the treatment of chronic tinnitus performed by the authors. Additionally, a systematic literature search was performed in the PubMed and Cochrane Library databases. Furthermore, a systematic search for international guidelines was performed in Google, as well as in the Guidelines International Network and National Guideline Clearinghouse (USA) database. Evidence was classified according to the Oxford Centre for Evidence-Based Medicine system. RESULTS: According to the guidelines, alongside counselling, manualized structured tinnitus-specific cognitive behavioral therapy (tCBT) with a validated treatment manual is available as evidence-based therapy. In addition, the guidelines recommend concurrent treatment of comorbidities, including drug-based treatment, where appropriate. Particularly important is treatment of anxiety and depression. Where a psychic or psychiatric comorbidity is suspected, further diagnosis and treatment should be performed by an appropriately qualified specialist (psychiatrist, neurologist, psychosomatic medicine consultant) or psychological psychotherapist. In cases accompanied by deafness or hearing loss bordering on deafness, cochlear implants may be indicated. CONCLUSION: No recommendations can be made for drug-based treatment of CIT, audiotherapy, transcranial magnetic or electrical stimulation, specific forms of acoustic stimulation or music therapy; or such recommendations must remain open due to the lack of available evidence. Polypragmatic tinnitus treatment with therapeutic strategies for which there is no evidence of efficacy from controlled studies is to be refused.

Olivocochlear reflex effect on human distortion product otoacoustic emissions is largest at frequencies with distinct fine structure dips.

Activity of the medial olivocochlear efferents can be inferred by measuring the change of the level of distortion product otoacoustic emissions (DPOAE) during ipsilateral or contralateral acoustic stimulation, the so-called medial olivocochlear reflex (MOCR). A limitation of this measurement strategy, however, is the distinct variability of MOCR values depending on DPOAE primary tone levels and frequency, which makes selection of the stimulus parameters difficult. The objective of this study was to evaluate the dependence of MOCR values on DPOAE fine structure in humans. MOCR during contralateral acoustic stimulation was measured at frequencies with distinct non-monotonicity ("dip") in the DPOAE fine structure, and in frequencies with flat fine structure. One hundred and twenty one different primary tone level combinations were used (L(1)=50-60dB SPL, L(2)=35-45dB SPL, 1dB steps). The measurement was repeated on another day. The major findings were: (1) Largest MOCR effects can be found in frequencies which exhibit a distinct dip in DPOAE fine structure. (2) Primary tone levels have a critical influence on the magnitude of the MOCR effect. MOCR changes of up to 23dB following a L(1) change of only 1dB were observed. Averages of the maximum MOCR change per 1dB step were in the 3-5dB-range. Both findings can be interpreted in the light of the DPOAE two-generator model [Heitmann, J., Waldmann, B., Schnitzler, H.U., Plinkert, P.K., Zenner, H.P. 1998. Suppression of distortion product otoacoustic emissions (DPOAE) near 2f1-f2 removes DP-gram fine structure - evidence for a secondary generator. Journal of the Acoustical Society of America 103, 1527-1531]. According to the present results we propose, that assessing MOCR specifically at frequencies with a distinct dip in the DPOAE fine structure, in combination with fine variation of the stimulus tone levels, allows for a more targeted search for maximum MOCR effects. Future studies must show if this approach can contribute to the further clarification of the physiological roles of the olivocochlear efferents.

Olivocochlear activity and temporary threshold shift-susceptibility in humans.

STUDY OBJECTIVES: Animal studies (guinea pig, cat, chinchilla) have shown that activity of the medial olivocochlear efferents can exert noise-protective effects on the cochlea. It is not yet known whether such effects are also existent in humans. Olivocochlear activity can be estimated indirectly by contralateral suppression (CS) of otoacoustic emissions (OAE). MATERIAL AND METHODS: We measured Input/Output functions of distortion products of OAE (DPOAE), with and without contralateral acoustic stimulation by white noise, in 94 normal hearing young male subjects. Seven stimuli with L2 between 20 and 60 dB SPL and L1 = 39 dB + 0.4 L2 ("scissor paradigm") were used at f2 = 2, 3, 4, 5, and 6 kHz. The measurement was repeated 2 weeks later. In 83 subjects of the same group, pure tone audiometry was registered before and 6 minutes after shooting exercises to evaluate individual susceptibility to develop a temporary threshold shift (TTS). RESULTS: Test-retest repeatability of CS was generally good. CS averaged 0.98 dB SPL (SD 1.19 dB, median 0.56 dB). As expected, CS was greatest at low stimulus levels (median 1.06 dB at L2 = 20 dB, as compared with 0.33 dB at L2 = 60 dB). The smallest average CS was found at 4 kHz, and the greatest CS appeared at 2 kHz. A TTS occurred in 7 of 83 (8.5%) subjects. Statistical analysis did not reveal any correlation between the amount of CS and individual TTS susceptibility. CONCLUSIONS AND OUTLOOK: 1) Measurement of CS of DPOAE using an extensive measurement paradigm revealed good test-retest repeatability, confirming the reliability of this audiologic tool. 2) CS of DPOAE does not predict individual susceptibility to mild TTS induced by impulse noise in humans. Possible explanations for the missing association are discussed. Future perspectives include longitudinal studies to further elucidate the association between medial olivocochlear bundle-activity and permanent threshold shift in humans. The goal is to develop a diagnostic tool for the prediction of individual noise vulnerability in humans, thereby preventing noise-induced hearing loss.

Open Tübingen titanium prostheses for ossiculoplasty: a prospective clinical trial.

OBJECTIVE: The overall purpose of the study was the evaluation of the efficacy of Tübingen titanium prostheses (TTPs) for ossiculoplasty. STUDY DESIGN: A two-part clinical study of 216 patients undergoing ossiculoplasty was performed. The first part was a prospective study using TTPs (n = 114). The second part involved study of historical control patients (n = 102) with gold and ceramic prostheses. INTERVENTIONS: All patients underwent ossiculoplasty. MAIN OUTCOME MEASURES: Measures included median air conduction thresholds and air-bone gaps. RESULTS: All patients were per-protocol patients. When the air-bone gap "gold standard" (i.e., < or =10 dB) was investigated in the main speech spectrum, partial TTPs reached this level at 2 kHz in 44% (n = 22) and at 3 kHz in 38% (n = 19). Gold and ceramics revealed significantly lower values. Similar results were obtained for total prostheses. Differences for TTPs and ceramics were statistically significant (Mann-Whitney U test, alpha = 5%). CONCLUSION: The use of TTPs for ossiculoplasty is an efficient treatment method.

In vivo experiments in the cat with an implantable piezoelectric hearing aid transducer.

We have recently developed an implantable piezoelectric hearing aid transducer that is suitable for implantation in patients with sensorineural hearing loss. The transducer does not transmit sound but conducts micromechanical vibrations to the cochlea. In ten cat ears we investigated the efficiency of the implantable transducer with respect to the direct transfer of vibrations within the audible frequency range via the ossicles to the cochlea or directly into the vestibule. The acoustically evoked brainstem potential (ABR) threshold was determined prior to implantation, and the middle ear was then opened and the piezoelectric transducer coupled to the ossicles or to the perilymph. Acoustically evoked brainstem potentials were recorded following stimulation at the umbo, long process of the incus, stapes head, stapes foot plate, and in the vestibulum. Comparisons of the acoustically and mechanically evoked thresholds revealed a good correlation of the two stimulation levels. An electrical transducer voltage of 1 V(RMS) produced equivalent sound pressure levels (SPL) of 100-128 dB at the tympanic membrane. To assess the hearing we compared stimulus-dependent latencies of the early potentials (peaks P1-P5) and thresholds. This evaluation was based on four ears with normal hearing in which the piezoelectric transducer was coupled to the long process of the incus. The mean values of the latencies and their scattering range correlated extremely well in the two stimulation modes. They were nearly identical when the equivalent SPL of 100 dB was assigned to the maximally applied electrical level of 0 dB. These in vitro and in vivo findings demonstrate that the characteristics of the transducer warrant its development further from the prototype stage to become a component of an implantable hearing device for patients with sensorineural hearing loss.

Dynamics of middle ear prostheses - simulations and measurements.

The efficient and systematic development of a middle ear prosthesis necessitates the use of computer models for the prosthesis itself and the reconstructed middle ear. The structure and parameters of the computer model have to be verified by specific measurements of the implant and the reconstructed ear. To obtain a realistic model of a reconstructed ear, three steps of modeling and measurements have been carried out. To get a first approach of the coupling elements a mechanical test rig representing a simplified reconstructed middle ear was built. The velocity of the stapedial footplate was measured with a laser Doppler vibrometer. The corresponding computer model was formulated, and the respective parameters were determined using the measured dynamical transfer functions. In the second step, a prosthesis was implanted into a human temporal bone without inner ear. Exciting this system with noise, the velocity of the stapes footplate was measured with the laser Doppler vibrometer. Based on the multibody system approach, a mechanical computer model was generated to describe the spatial motions of the reconstructed ossicular chain. Varying some significant parameters, simulations have been carried out. To describe the dynamical behavior of the system consisting of middle and inner ear, the computer model used in the second step has been enlarged by adding a simplified structure of the inner ear. The results were compared with in situ measurements taken from living humans.

Short-term immunotherapy: a prospective, randomized, double-blind, placebo-controlled multicenter study of molecular standardized grass and rye allergens in patients with grass pollen-induced allergic rhinitis.

BACKGROUND: Short-term immunotherapy (STI) can be beneficial for patients who are noncompliant with long-term specific immunotherapy. OBJECTIVE: The efficacy and tolerance of STI with seven preseasonal injections of molecular standardized allergens from grass and rye pollen has been investigated in a double-blind, placebo-controlled multicenter study with 87 patients at 12 German University hospitals. METHODS: Symptoms of the eyes, nose, and bronchi and use of symptomatic drugs were documented daily in diaries by patients with allergic rhinitis to grass and/or rye pollen and without bronchial asthma. Patients were monitored by skin prick test titration and measurement of levels of specific IgE and IgG4. RESULTS: The median nasal score for the 10 weeks with the strongest symptoms during the grass pollen season was significantly lower (p = 0.014) with 35.0 for STI (n = 41) versus 69.0 for placebo (n = 40); the overall symptom score was 54.0 for STI versus 97.5 for placebo (p = 0.020). Only STI-treated patients exposed to less than 40 pollen grains per cubic meter per week showed a significantly lower nasal symptom score of 39.0 versus 75.0 for placebo (p = 0.006); these patients also had fewer nasal symptoms and less use of topical nasal drugs (p < 0.001). The threshold dose in skin prick tests was significantly higher, being 9.06 histamine equivalent for skin prick test (HEP) for STI-treated patients who received the maximum dose (n = 22) versus 4.33 HEP for placebo (p = 0.005). Specific IgE levels were significantly higher, being 55.9 SU/ml for STI versus 39.2 SU/ml for placebo after seven injections (p = 0.006) and level of specific IgG4 was 5.36% for STI versus 1.28% for placebo (p < 0.001). No severe systemic reactions were observed. CONCLUSION: STI with seven preseasonal injections with molecular standardized allergens is effective and well tolerated.

Extracellular K+ and intracellular pH allosterically regulate renal Kir1.1 channels.

The channels that control K+ homeostasis by mediating K+ secretion across the apical membrane of renal tubular cells have recently been cloned and designated ROMK1, -2, and -3. Native apical K+ channels are indirectly regulated by the K+ concentration at the basolateral membrane through a cascade of intracellular second messengers. It is shown here that ROMK1 (Kir1.1) channels are also directly regulated by the extracellular (apical) K+ concentration, and that this K+ regulation is coupled to intracellular pH. The K+ regulation and its coupling to pH were assigned to different structural parts of the channel protein. K+ regulation is determined by the core region, which comprises the two hydrophobic segments M1 and M2 and the P region. Decoupling from pH was achieved by exchanging the N terminus of ROMK1 by that of the pH-insensitive channel IRK1 (Kir2.1). These results suggest an allosteric regulation of ROMK1 channels by extracellular K+ and intracellular pH, which may represent a novel link between K+ homeostasis and pH control.

Sound-induced displacement responses in the plane of the organ of Corti in the isolated guinea-pig cochlea.

Sound-induced displacement responses in the plane of the organ of Corti were studied in the apical turn in the isolated temporal-bone preparation of the guinea-pig cochlea. Swept sinusoidal sound stimuli (100-500 Hz) were delivered closed-field to the external auditory meatus. The surface of the organ of Corti was continuously monitored using a CCD video camera. Displacement responses in the plane of the organ of Corti were determined by analyzing the change of the location of the cells (pixel-by-pixel) within the visual field of the microscope. Displacement responses followed the stimulus amplitude and were observable at Hensen's cells, three rows of outer hair cells and inner hair cells. The most prominent displacement responses were over the outer hair cells; the maximum amplitude was 0.6-1.7 microns at 100 dB SPL. Tuned displacement responses were found; the Q10 dB was 1.3 +/- 0.6. The best frequency was tonotopically organized, decreasing toward the apex with a space constant of 0.4-0.9 mm/oct. The motion was directed either strial-apically or strial-basally in a frequency dependent manner. With the aid of laser interferometric measurements of the transverse displacement, it was concluded that sound stimulation does not induce slow DC motion in the organ of Corti for the isolated temporal-bone preparation.

[Retrospect and perspective in rhinologic allergology]. / Rückblick und Perspektiven in der rhinologischen Allergologie.

The first classical description of allergic rhinitis was given by John Bostock in 1819, and Blackley demonstrated the etiology in 1873. In 1906 Clemens von Pirquet discussed a relationship between hypersensitivity and immunity: he called it allergy. In 1922 Prausnitz and Kustner described the transfer of the immediate type hypersensitivity by serum. Coca and Cooke called the factor atopic reagin. The breakthrough in 1967 was due to Ishizaka and Ishizaka who discovered the IgE-antibodies, and proved that these are identical with the postulated reaginic antibodies. The knowledge of the new IgE-antibody class allowed the incorporation of nasal allergy in clinical immunology.

K+-induced motility and depolarization of cochlear hair cells. Direct evidence for a new pathophysiological mechanism in Ménière's disease.

In addition to an endolymphatic hydrops in various models of Ménière's disease, ruptures of the membranes lining the endolymphatic spaces or massive changes in their biochemical permeability are believed to allow large amounts of potassium-rich endolymph to deluge the normally low [K+] perilymphatic fluid. Our clinic has shown that exposure of the lateral and basal membrane parts of living isolated outer hair cells to increasing concentrations of potassium ions resulted in a sustained reversible cellular depolarization. Furthermore, potassium intoxication was accompanied by a strictly longitudinal contraction of the hair cells present. This was followed by hair cell relaxation in the presence of artificial perilymph. These findings suggest a supplementary hypothesis for the clinical manifestations of Ménière's disease: the reversible hair cell depolarization can explain the sudden tinnitus and parts of the hearing loss incurred as well as presumably the vertigo experienced; the reversible longitudinal hair cell contraction induces an abnormal change of cochlear micromechanics, resulting in concomitant attacks of deafness and also possibly contributing to the tinnitus perceived.

Tumor cells carried through autotransfusion. Are these cells still malignant?

A suspension of 3 X 10(7) cells of longterm carcinoma cell lines--HLaC 78 and 79 from human laryngeal carcinoma, CaKi 1 derived from renal cell carcinoma and PC 3 from prostatic carcinoma,--was pumped with maximum pressure up to 5 times through the filters of the Bentley autotransfusion device. Following filter passage after centrifugation the untrapped cells were recovered, counted and brought in culture under appropriate conditions. As soon as monolayers were obtained 3 X 10(6) cells were transferred subcutaneously into athymic mice. The time intervals of growth in culture and of developing tumor nodules in nude mice were measured. The histological pattern of the daughter tumors in nude mice was compared with the genuine tumor. After the first filter passage 12.3% respectively 18.2% untrapped cells were found. This number dropped to 3% after the 5th passage. After the 5th passage in only 3 out of 5 experiments there were enough cells to start a culture. After the first passage cell proliferation in the culture as well as yielding tumor nodules in nude mice was markedly reduced. HLaC78 died. After the 5th passage cell growth in the culture as well as tumor growth in nude mice was reduced the more while using HLaC79. Taking CaKi 1 and PC 3 both parameters showed identical growth behaviour as compared with the original not-filter-passaged cells. The histological findings were identical with the pattern of the genuine tumors.