An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection.

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 4 weeks) low-dose (4 mg/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.

Voice deepening under testosterone treatment in female-to-male gender dysphoric individuals.

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.

Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions.

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.

Neural basis of music imagery and the effect of 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.

Spontaneous otoacoustic emission enhancement in children with reduced speech-in-noise intelligibility.

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.

Left-right asymmetry in hearing loss following cisplatin therapy in children--the left ear is slightly but significantly more affected.

OBJECTIVES: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Development and evaluation of the new module 'communication disorders' in medical education.

BACKGROUND: 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. AIMS: 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. METHODS: After initial modifications to the course, a statistical evaluation of the last two half-years in 2006 was performed. RESULTS: 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. CONCLUSIONS: 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.

When Hearing Is Tricky: Speech Processing Strategies in Prelingually Deafened Children and Adolescents with Cochlear Implants Having Good and Poor Speech Performance.

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 participant. 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.

Song Perception by Professional Singers and Actors: An MEG Study.

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.