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Cisplatin (CDDP) is one of the most important chemotherapeutic drugs in modern oncology. However, its use is limited by severe toxicities, which impair life quality after cancer. Here, we investigated the role of organic cation transporters (OCT) in mediating toxicities associated with chronic (twice the week for 4weeks) low-dose (4mg/kg body weight) CDDP treatment (resembling therapeutic protocols in patients) of wild-type (WT) mice and mice with OCT genetic deletion (OCT1/2−/−). Functional and molecular analysis showed that OCT1/2−/− mice are partially protected from CDDP-induced nephrotoxicity and peripheral neurotoxicity, whereas ototoxicity was not detectable. Surprisingly, proteomic analysis of the kidneys demonstrated that genetic deletion of OCT1/2 itself was associated with significant changes in expression of proinflammatory and profibrotic proteins which are part of an OCT-associated protein network. This signature directly regulated by OCT consisted of three classes of proteins, viz., profibrotic proteins, proinflammatory proteins, and nutrient sensing molecules. Consistent with functional protection, CDDP-induced proteome changes were more severe in WT mice than in OCT1/2−/− mice. Laser ablation-inductively coupled plasma-mass spectrometry analysis demonstrated that the presence of OCT was not associated with higher renal platinum concentrations. Taken together, these results redefine the role of OCT from passive membrane transporters to active modulators of cell signaling in the kidney.

Specific history-taking, drawing a family tree and thorough clinical examination are explained in detail. Standards and calibration in audiometry are presented. Pure-tone audiometry (PTA) and principles of masking, loudness tests and dead-region testing are outlined. Different test methods of behavioural measurements in children are provided.

Cochlear implants provide individuals who are deaf with access to speech. Although substantial advancements have been made by novel technologies, there still is high variability in language development during childhood, depending on adaptation and neural plasticity. These factors have often been investigated in the auditory domain, with the mismatch negativity as an index for sensory and phonological processing. Several studies have demonstrated that the MMN is an electrophysiological correlate for hearing improvement with cochlear implants. In this study, two groups of cochlear implant users, both with very good basic hearing abilities but with non-overlapping speech performance (very good or very poor speech performance), were matched according to device experience and age at implantation. We tested the perception of phonemes in the context of specific other phonemes from which they were very hard to discriminate (e.g., the vowels in /bu/ vs. /bo/). The most difficult pair was individually determined for each articipant. Using behavioral measures, both cochlear implants groups performed worse than matched controls, and the good performers performed better than the poor performers. Cochlear implant groups and controls did not differ during time intervals typically used for the mismatch negativity, but earlier: source analyses revealed increased activity in the region of the right supramarginal gyrus (220±260 ms) in good performers. Poor performers showed increased activity in the left occipital cortex (220±290 ms), which may be an index for cross-modal perception. The time course and the neural generators differ from data from our earlier studies, in which the same phonemes were assessed in an easy-to-discriminate context. The results demonstrate that the groups used different language processing strategies, depending on the success of language development and the particular language context. Overall, our data emphasize the role of neural plasticity and use of adaptive strategies for successful language development with cochlear implants.

Objectives The term “nonorganic hearing loss” (NOHL) (pseudohypacusis, functional or psychogenic hearing loss) describes a hearing loss without a detectable corresponding pathology in the auditory system. It is characterized by a discrepancy between elevated pure tone audiometry thresholds and normal speech discrimination. The recommended audiological management of NOHL in children comprises history taking, diagnosis, and counseling. According to the literature, prognosis depends on the severity of the patient's school and/or personal problems. Routine referral to a child psychiatrist is discussed as being controversial. Methods The clinical history of 34 children with NOHL was retrospectively evaluated. In 15 children, follow up audiometry was performed. Results of biographical history, subjective and objective audiometry, additional speech and language assessment, psychological investigations and follow up audiometry are presented and discussed. Results The prevalence of NOHL was 1.8% in children with suspected hearing loss. Mean age at diagnosis was 10.8 years. Girls were twice as often affected as boys. Patient history showed a high prevalence of emotional and school problems. Pre-existing organic hearing loss can be worsened by nonorganic causes. Children with a fast recovery of hearing thresholds (n = 6) showed a high rate (4/6) of family, social and emotional problems. In children with continuous threshold elevation (n = 9), biographical history showed no recognizable or obvious family, social or emotional problems; learning disability (4/9) was the most frequently presented characteristic. Conclusions Due to advances in objective audiometry, the diagnosis of NOHL is less challenging than management and counseling. Considering the high frequency of personal and school problems, a multidisciplinary setting is helpful. On the basis of our results, drawing conclusions from hearing threshold recovery on the severity of underlying psychic problems seems inappropriate. As a consequence, a referral to a child psychiatrist can be generally recommended.

Das universelle Neugeborenenhorscreening (UNHS) fordert die Abklarung auffalliger Horbefunde in den ersten 3 Lebensmonaten. Die Machbarkeit dieser Forderung soll uberpruft, die Horprufmethoden sollen bewertet werden. Ausgewertet wurden 617 Patientenakten (329 m., 288 w.), darunter 246 Kinder mit auffalligem UNHS, 393 mit Risikofaktoren. Bei 459 Kindern (74%) wurde mit Kontrollscreening der AABR („automated auditory brainstem responses“) eine sprachrelevante Schwerhorigkeit ausgeschlossen, bei 129 (21%) eine Schwellen-BERA („brainstem evoked response audiometry“) durchgefuhrt: Davon wiesen 20 (16%) normale, 109 (84%) erhohte Schwellen auf. Horgerate erhielten 91 (83%), eine Ergusstherapie 11 (10%). Schwerhorig waren 18% aller Kinder, 24% der UNHS-Auffalligen und 34% der UNHS-Auffalligen mit Risikofaktoren. Kraniofaziale Dysmorphien, Fruhgeburten

Objective Auditory neuropathy spectrum disorder (ANSD) is characterized by absent or atypical auditory brainstem responses (ABR), recordable otoacoustic emissions and/or cochlear microphonics. Modification of ABR stimuli is discussed to improve wave V synchronization in ANSD patients. Design Ten ANSD children (seven unilateral) underwent ABR measurement with an alternating stimulus (40.5 s −1 ), constant rarefaction and condensation stimuli, a reduced click-rate (11.1 s −1 ) and a chirp-stimulus. Results The results showed no remarkably better synchronization with modified stimuli. Whereas higher levels showed no synchronization, reproducible positive waves at 8 ms (P8) at intensities of 65–85 dB were found in six patients with all stimuli. Conclusions We suggest an ipsilateral auditory origin of the positive potentials at 8 ms. They could be characteristic of synchronization abnormalities in some cases of ANSD.

Hintergrund Neben der Schwerhorigkeit fuhren auch Sprach- und Sprechstorungen zu Einschrankungen der Kommunikationsfahigkeit. Sie sind weit verbreitete Erkrankungen und treten in allen Altersstufen auf, z. B. als Sprachentwicklungsstorungen, Stottern, Dysarthrien oder Aphasien. Unabhangig vom Fachgebiet wird jeder Arzt mit hoher Wahrscheinlichkeit mit kommunikationsgestorten Patienten sprechen, die Storung einordnen und ggf. eine adaquate Therapie einleiten mussen.

Objective High frequency hearing loss following cisplatin chemotherapy is frequent in children and often necessitates the fitting of hearing aids. During therapy, hearing is usually monitored. Post-therapeutic follow-up does not routinely include monitoring of hearing, although there are indications that hearing thresholds can decline after therapy. Methods Pure-tone audiograms taken from 27 children (17 males, 10 females) treated with cisplatin at Muenster university hospital (mean age 9.84 years, standard deviation 3.67 years) including an audiological follow-up at least 6 months after therapy, were analyzed retrospectively. Results In follow-up tests after completion of therapy, 24.1% of all ears showed an increase in mean high frequency hearing thresholds (4–8 kHz). Post-therapeutic hearing deterioration was significant at 4 kHz and significantly more pronounced in children without measurable spontaneous otoacoustic emissions (SOAE) before therapy. Post-therapeutic hearing deterioration did not occur in ears with normal pure tone thresholds (≤10 dB at all frequencies) after cisplatin therapy. No correlation was found between post-therapeutic hearing deterioration and cranial irradiation. Conclusions Cisplatin chemotherapy follow-up should include audiological monitoring in all children with elevated pure tone thresholds after therapy. Routine SOAE measurements taken as part of baseline audiometry before the start of chemotherapy can be taken into consideration.

BACKGROUND The parent questionnaire ELFRA-2 is considered a valid tool for early detection of delayed language development in 2-year-old children. Applicability for children treated with cochlear implants (CI) is to be investigated. METHODS By means of the ELFRA-2 we documented longitudinally for up to 24 months post implantation language development in 27 children treated before 3 years of age. The critical developmental criteria (related to age) were applied to CI children (related to duration of CI use) and gender-related normative data were taken as a reference. RESULTS Only two boys were identified as showing a language delay after 2 years of CI use. However, using normative data 11-44% of the children performed below average. Development in girls was faster than in boys. The influence of preoperative hearing experience declined over time. CONCLUSION The critical developmental criteria of ELFRA-2 have proved to be unreliable for the identification of varying development after CI. Modified and gender-related evaluation is necessary.

The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wild-type and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.

The present study investigated musical imagery in musicians and nonmusicians by means of magnetoencephalography (MEG). We used a new paradigm in which subjects had to continue familiar melodies in their mind and then judged if a further presented tone was a correct continuation of the melody. Incorrect tones elicited an imagery mismatch negativity (iMMN) in musicians but not in nonmusicians. This finding suggests that the MMN component can be based on an imagined instead of a sensory memory trace and that imagery of music is modulated by musical expertise.

Although the influence of long-term musical training on the processing of heard music has been the subject of many studies, the neural basis of music imagery and the effect of musical expertise remain insufficiently understood. By means of magnetoencephalography (MEG) we compared musicians and nonmusicians in a musical imagery task with familiar melodies. Subjects listened to the beginnings of the melodies, continued them in their imagination and then heard a tone which was either a correct or an incorrect further continuation of the melody. Only in musicians was the imagery of these melodies strong enough to elicit an early preattentive brain response to unexpected incorrect continuations of the imagined melodies; this response, the imagery mismatch negativity (iMMN), peaked approximately 175 ms after tone onset and was right-lateralized. In contrast to previous studies the iMMN was not based on a heard but on a purely imagined memory trace. Our results suggest that in trained musicians imagery and perception rely on similar neuronal correlates, and that the musicians' intense musical training has modified this network to achieve a superior ability for imagery and preattentive processing of music.

Female-to-male gender dysphoric individuals rarely access medical services for voice problems arising out of hormonal treatment leading to "voice reassignment". The aim of this study was a close monitoring of voice deepening in the first year following the commencement of testosterone treatment. Voice recordings from nine female-to-male (FTM) were analyzed with Praat software and values for speaking fundamental frequency (SFF) were calculated. Audio recordings were made prior to and within the first year (mean 55.2 weeks) of testosterone treatment at a mean of 35.4 different time points. The values for speaking fundamental frequency were compared with values taken from 21 biological men with healthy voices. The 10th to 90th percentile range of FTM overlapped with those of biological men after about 36 weeks. The mean SFF change was a decrease of 8.78 seminotes at week 52 and at this point in time no significant difference between SSF in FTM and biological men was found. Testosterone treatment led to significant voice deepening within the first year with the degree of change decreasing over time. Mean SFF change in the first year was almost a sixth and thus less than one octave but nonetheless reached an SFF comparable with biological men.

Though brainstem audiometry is one of the most important investigations in pediatric audiology, it often necessitates sedation or general anaesthetics, especially in newborns and infants. Melatonin, inducing natural sleep without the risks of sedation, has been successfully used to induce sleep prior to EEG investigations. 250 children (142 male, 108 female) with suspected hearing loss underwent ABR (auditory brainstem responses) tests in melatonin-induced sleep. Click-induced and notched-noise ABR tests were performed. Click tests were successfully performed in 216 of 249 children or 86.7% (123 male, 93 female), notched-noise tests in 115 of 155 children or 74.2%. Failure rates showed an age dependence increasing from 4% in children1 year to 25%3 years, but no gender difference. In conclusion, melatonin-induced sleep is a good alternative to sedation, especially in children younger than 3 years. This method is widely accepted by parents and permits earlier diagnosis of hearing impairment in a routine clinical setting. The number of children undergoing general anaesthesia for ABR investigation was reduced from over 60 per year in 2000-2002 to 12 in 2005, which means80% less general anaesthesia.

Universal newborn hearing screening (UNHS) has significantly reduced the age of children undergoing audiological examinations. Middle ear function is usually evaluated with tympanometry using a probe tone of 226 Hz, although higher frequencies are recommended in infants. The aim of this study was to compare the feasibility of 226 and 1000 Hz tympanometry for different trace classification systems in relation to age, risk factors for hearing loss and ear canal volume.Data from 577 infants (915 ears)1 year were analyzed. Tympanograms were classified according to the classification systems of Jerger, Marchant et al. and Kei et al. and correlated with ear microscopy as the gold standard. Test quality parameters of tympanometry with probe tones of 226 and 1000 Hz were compared in four different age groups.The trace classification following Kei et al. presented the best correlation to ear microscopy and reduced the number of unclassified tympanograms. The use of probe tones of 226 Hz in infants below the age of nine months showed a poor level of sensitivity.We recommend the use of a 1000 Hz probe tone in infants at least up to the age of nine months. In this age group, 226 Hz tympanometry is inappropriate. In children with craniofacial abnormalities and smaller ear canal volumes, 1000 Hz tympanometry could be taken into consideration, even for older children. High-frequency tympanograms should be evaluated according to the classification system of Kei et al., which differentiates between peaked (normal) and flat (abnormal) curves.

The cortical correlates of speech and music perception are essentially overlapping, and the specific effects of different types of training on these networks remain unknown. We compared two groups of vocally trained professionals for music and speech, singers and actors, using recited and sung rhyme sequences from German art songs with semantic and/ or prosodic/melodic violations (i.e. violations of pitch) of the last word, in order to measure the evoked activation in a magnetoencephalographic (MEG) experiment. MEG data confirmed the existence of intertwined networks for the sung and spoken modality in an early time window after word violation. In essence for this early response, higher activity was measured after melodic/prosodic than semantic violations in predominantly right temporal areas. For singers as well as for actors, modality-specific effects were evident in predominantly left-temporal lateralized activity after semantic expectancy violations in the spoken modality, and right-dominant temporal activity in response to melodic violations in the sung modality. As an indication of a special group-dependent audiation process, higher neuronal activity for singers appeared in a late time window in right temporal and left parietal areas, both after the recited and the sung sequences.

Although the influence of long-term musical training on the processing of heard music has been the subject of many studies, the neural basis of music imagery and the effect of musical expertise remain insufficiently understood. By means of magnetoencephalography (MEG) we compared musicians and nonmusicians in a musical imagery task with familiar melodies. Subjects listened to the beginnings of the melodies, continued them in their imagination and then heard a tone which was either a correct or an incorrect further continuation of the melody. Only in musicians was the imagery of these melodies strong enough to elicit an early preattentive brain response to unexpected incorrect continuations of the imagined melodies; this response, the imagery mismatch negativity (iMMN), peaked approximately 175 ms after tone onset and was right-lateralized. In contrast to previous studies the iMMN was not based on a heard but on a purely imagined memory trace. Our results suggest that in trained musicians imagery and perception rely on similar neuronal correlates, and that the musicians' intense musical training has modified this network to achieve a superior ability for imagery and preattentive processing of music.

Communication disorders are not taught as a self-contained topic in medical education, despite their high incidence and the similarities in the way in which they present clinically.This article describes the development of an elective subject 'Phoniatrics and Pediatric Audiology' covering five topics: hearing, language, and voice as well as psychometric tests and swallowing, with the objective of teaching a basic knowledge of the anatomy, physiology, and pathophysiology of the hearing and language system as well as symptoms, diagnostics, examination, and therapy of communication disorders. It contains theoretical background, practical exercises, and demonstrations of patient examinations.After initial modifications to the course, a statistical evaluation of the last two half-years in 2006 was performed.The majority of students believe that the subject will be useful in their subsequent studies (94.2%) and medical practice (51.9%). All students affirmed that their expectations had been met by the course and they would choose it again.Uniting several communication disorders within a self-contained topic provides the opportunity to understand pathophysiological principles, similarities, and differences between normal and impaired function of the hearing and language system and voice production. In the authors' opinion, it is a reasonable inclusion in medical training recognizing the importance of communication in today's service society.

Bilateral symmetric high frequency hearing loss is regarded as one of the main characteristics of cisplatin-induced ototoxicity. Hair-cell damage because of cisplatin is discussed as the leading cause of hearing loss. Our observations in long-term audiological follow-up of children treated with cisplatin did not always show the anticipated symmetry of hearing loss.Pure-tone audiograms of 55 (34 m, 21 f) children receiving chemotherapy with cisplatin at Muenster university hospital were analyzed. We compared pure tone hearing thresholds, transient evoked otoacoustic emissions levels and distortion product otoacoustic emissions levels before and after chemotherapy with cisplatin.After therapy, the 55 children showed slightly higher average hearing levels in the range 2000 to 8000 Hz in the left ear. The side difference was significant at 4000, 6000, and 8000 Hz. In girls, the effect was less pronounced than in boys.This result, on the one hand, indicates that the auditory system is already responding asymetrically at the cochlear level, on the other hand it underscores the need for further research into the pathophysiology of platinum ototoxicity. There are parallels with stronger effects to the left ear in oiseinduced hearing loss as described in literature. Special attention should be given to possible supracochlear pathways of damage. Clinicians should consider that cisplatin associated hearing loss is not necessarily symmetric.

Reduced speech-in-noise intelligibility is one of the main difficulties experienced by children with auditory processing disorder (APD). Previous studies have established a relationship between the function of the medial olivocochlear system (MOCS) and reduced inhibition of otoacoustic emissions (OAE) in children with APD. This study measured spontaneous OAE (SOAE) in 27 children with reduced speech-in-noise intelligibility, and those of a control group matched by gender and age. A significantly higher prevalence of SOAE was found: 85% of the study group presented SOAE, 44% in the control group. An abnormally functioning MOCS with reduced inhibition could lead to an increase in SOAE. Identifying a higher prevalence and number of SOAE may be a helpful objective mean to include in an APD diagnosis test battery.

Kinder mit auditiver Verarbeitungs- und Wahrnehmungsstörung (AVWS) mit dem Subtyp Selektionsstörung haben Schwierigkeiten, Sprache im Störschall zu erkennen. Dabei wird angenommen, dass die Funktion des medioolivocochleären Bündels (MOCS) eine wichtige Rolle spielt. Wir untersuchten 27 Kinder (9 Mädchen, 18 Jungen im Alter von 5,7 bis 13,1 Jahre) mit Verdacht auf AVWS, die in der verwendeten Testbatterie Auffälligkeiten im Bereich des Sprachverständnisses mit Hintergrundgeräuschen zeigten. Hierzu wurden ein Binaural Intelligibility Level Difference Test (B.I.L.D.-Test) und ein Test zum Sprachverständnis im Störgeräusch ausgewählt. Eine Kontrollgruppe mit unauffälligen Testergebnissen wurde nach Alter und Geschlecht eins zu eins gebildet. Die Frequenzen und Prävalenzen der spontanen otoakustischen Emissionen (SOAE) beider Gruppen wurden verglichen. Die Verteilung der Frequenzen zeigte zwischen den beiden Gruppen keine signifikanten Unterschiede. Bei den Kindern mit Selektionsstörung wurde eine signifikant höhere Prävalenz der SOAE gegenüber der Kontrollgruppe festgestellt: bei 85% der Kinder mit selektiver Hörstörung ließen sich SOAE nachweisen, bei der Kontrollgruppe waren es nur 45%. Dies könnte Ausdruck einer Enthemmung der äußeren Haarzellen bei Störung des MOCS sein. Eine erhöhte Prävalenz der SOAE könnte als Anhaltspunkt für eine AVWS, Subtyp Selektionsstörung, gewertet werden.

We designed a melody perception experiment involving eight harmonic complex tones of missing fundamental frequencies (hidden auditory object) to study the short-term neuronal plasticity of the auditory cortex. In this experiment, the fundamental frequencies of the complex tones followed the beginning of the virtual melody of the tune “Frère Jacques”. The harmonics of the complex tones were chosen so that the spectral melody had an inverse contour when compared with the virtual one. Evoked magnetic fields were recorded contralaterally to the ear of stimulation from both hemispheres. After a base line measurement, the subjects were exposed repeatedly to the experimental stimuli for 1 hour a day. All subjects reported a sudden change in the perceived melody, indicating possible reorganization of the cortical processes involved in the virtual pitch formation. After this switch in perception, a second measurement was performed. Cortical sources of the evoked gamma-band activity were significantly stronger and located more medially after a switch in perception. Independent Component Analysis revealed enhanced synchronization in the gamma-band frequency range. Comparing the gamma-band activation of both hemispheres, no laterality effects were observed. The results indicate that the primary auditory cortices are involved in the process of virtual pitch perception and that their function is modifiable by laboratory manipulation.

Summary Objectives This study investigates differences between the self-assessment and external rating of a person's voice with regard to sex characteristics, age, and attractiveness of the voice and mean fundamental frequency ( F 0 ). Study Design Cross-sectional study. Methods A group of 47 participants with a balanced sex distribution was recruited and the following data were collected: videostroboscopy, voice range profile, F 0 , self-assessment questionnaire (attractiveness, masculinity or femininity of voice, and appearance), Voice Handicap Index, and questionnaires to determine levels of depression and quality of life. External rating was performed by four experts and four laymen. Results In both sexes, fair to moderate significant correlations between the self-assessment of masculinity (men)/femininity (women) of voice and masculinity/femininity of appearance could be found, but not between the self-assessment of attractiveness of voice and appearance. In men, a statistically significant correlation was found between external ratings and self-assessment of attractiveness and, with the exception of the female rating group, of masculinity. In women, self-assessment of femininity and attractiveness of voice did not correlate to a statistically significant extent with the evaluation of the external rater. Additionally, the statistical correlation between estimated and real ages was high. Conclusions Although the objective parameters of age and gender identification could be rated with a high degree of accuracy, subjective parameters showed significant differences between self-assessment and external rating, in particular in rating women's voices. Taking these findings into account in treatments for modifying voice could impede successful interventions. As one consequence, we recommend summarizing target agreements in detail before the treatment.