Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

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.

Two-Way Radio Modem Data Transfer for Newborn Hearing Screening Devices.

INTRODUCTION: The success of a newborn hearing screening program depends on successful tracking and follow-up to ensure that children who have had positive screening results in the first few days of life receive appropriate and timely diagnostic and intervention services. The easy availability, through a suitable infrastructure, of the data necessary for the tracking, diagnosis, and care of children concerned is a major key to enhancing the quality and efficiency of newborn hearing screening programs. MATERIALS AND METHODS: Two systems for the automated two-way transmission of newborn hearing screening and configuration data, based on mobile communication technology, for the screening devices MADSEN AccuScreen® and Natus Echo-Screen® were developed and tested in a field study. Radio modem connections were compared with conventional analogue modem transmissions from Natus Echo-Screen devices for duration, transmission rate, number of lost connections, and frequency of use. RESULTS: The average session duration was significantly lower with the MADSEN AccuScreen (12 s) and Natus Echo-Screen both with radio modem (15 s) than the Natus Echo-Screen with analogue modem (108 s). The transmission rate was significantly higher (898 and 1,758 vs. 181 bytes/s) for the devices with radio modems. Both radio modem devices had significantly lower rates of broken connections after initial connection (2.1 and 0.9 vs. 5.5%). An increase in the frequency of data transmission from the clinics with mobile radio devices was found. CONCLUSIONS: The use of mobile communication technology in newborn hearing screening devices offers improvements in the average session duration, transmission rate, and reliability of the connection over analogue solutions. We observed a behavioral change in clinical staff using the new technology: the data exchange with the tracking center is more often used. The requirements for on-site support were reduced. These savings outweigh the small increase in costs for the Internet service provider.

Change of speech fundamental frequency explains the satisfaction with voice in response to testosterone therapy in female-to-male gender dysphoric individuals.

Previous studies demonstrated that there is a significant change in speaking fundamental frequency after testosterone therapy in female-to-male gender dysphoric individuals. It is yet an open question how the satisfaction with voice alteration can be predicted because until now it is not clear whether a testosterone therapy is sufficiently effective. The aim of the current study was not only to measure satisfaction with voice, but additionally to detect factors that predict or explain satisfaction with voice after testosterone therapy. Therefore, nine female-to-male gender dysphoric individuals were examined during the first year of testosterone treatment at different points of time. The patients underwent several voice analyses within 1 year and had to fill out several questionnaires concerning their voice, depressive symptoms, quality of life and voice handicap index. Multiple regression analyses were performed to find the factors that explained satisfaction with altered voice after 1 year. The difference of voice frequency in semitones before the treatment and after 1 year is the only significant predictor for satisfaction after 1 year (B = 0.442; SE = 0.049) and more important than the absolute fundamental frequency.

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.

Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation.

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.

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.

The Influence of Age, Gender, Health-Related Behaviors, and Other Factors on Occupationally Relevant Health Complaints of Singers.

OBJECTIVES: Professional singers' careers are usually associated with health-relevant factors that they themselves may or may not be able to influence. We have therefore investigated the effect of modifiable health-related behaviors and non-modifiable factors on singers' occupational health. METHODS: In an explorative, questionnaire-based study, self-reported, occupationally relevant health complaints and behaviors, along with singer-specific characteristics, were surveyed from 349 professional singers and voice teachers (116 men, 233 women; age 18-73 years) and the influence of age, gender, duration of daily and lifelong singing, voice category, and health-related behaviors (smoking, alcohol consumption, physical activity) on occupationally relevant health complaints were analyzed using bi- and multivariate statistical methods. RESULTS: Singers reported less risky alcohol consumption (5.4% versus ≈15%) and smoking (15.5% versus 29.7%) than the general population, and too little physical activity was described in two thirds of both populations. After controlling for multiple testing, no effect was found for these behaviors, the time spent singing daily, gender, or voice categories on singers' complaints. Health complaints were significantly fewer for males (P < .001) and older women and were reported more frequently for higher-pitched male voices, a trend not found in females. CONCLUSION: Singers seem to smoke and drink less than members of the general population. These factors did not affect their complaints. Female singers described more work-related health complaints than males, a finding that corresponds to women in the general population. Older singers reported fewer complaints than younger singers, possibly because of selection effects or older singers acquiring strategies to avoid health-damaging behavior.

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Spasmodic dysphonia, perceptual and acoustic analysis: presenting new diagnostic tools.

In this article, we investigate whether (1) the IINFVo (Impression, Intelligibility, Noise, Fluency and Voicing) perceptual rating scale and (2) the AMPEX (Auditory Model Based Pitch Extractor) acoustical analysis are suitable for evaluating adductor spasmodic dysphonia (AdSD). Voice recordings of 12 patients were analysed. The inter-rater and intra-rater consistency showed highly significant correlations for the IINFVo rating scale, with the exception of the parameter Noise. AMPEX reliably analyses vowels (correlation between PUVF (percentage of frames with unreliable F0/voicing 0.748), running speech (correlation between PVF (percentage of voiced frames)/voicing 0.699) and syllables. Correlations between IINFVo and AMPEX range from 0.608 to 0.818, except for noise. This study indicates that IINFVo and AMPEX could be robust and complementary assessment tools for the evaluation of AdSD. Both the tools provide us with the valuable information about voice quality, stability of F0 (fundamental frequency) and specific dimensions controlling the transitions between voiced and unvoiced segments.

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.

PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents.

AIMS: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. METHODS: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. RESULTS: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. CONCLUSIONS: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.

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.

Intrafamilial phenotypic variability of Specific Language Impairment.

We investigated language functions in 32 members of a four generation family with several members affected by Specific Language Impairment with an extensive language test battery in order to determine the prevalence, overlap, and homogeneity of linguistic deficits within one pedigree. In sum, one fourth of all family members tested fulfilled the criteria of Specific Language Impairment. Despite of some similarities in language abilities, different combinations of language deficits were observed, and individual language profiles varied substantially. Thus, though there is a high prevalence of language deficits in this family which raises the likelihood of a genetic origin of these deficits, and though all affected study participants displayed selective linguistic deficits with normal non-verbal functioning, language testing showed considerable variance in overlap and homogeneity of linguistic deficits. Thus, even in one genetic population, an underlying linguistic disorder manifests itself in different language abilities to a variant degree.

A systematic review of the mismatch negativity as an index for auditory sensory memory: From basic research to clinical and developmental perspectives.

Auditory sensory memory is an important ability for successful language acquisition and processing. The mismatch negativity (MMN) in response to auditory stimuli has been proposed as an objective tool to measure the existence of auditory sensory memory traces. By increasing interstimulus intervals, attenuation of MMN peak amplitude and increased MMN peak latency have been suggested to reflect duration and decay of sensory memory traces. The aim of the present study is to conduct a systematic review of studies investigating sensory memory duration with MMN. Searches of electronic databases yielded 743 articles. Of these, 37 studies met final eligibility criteria. Results point to maturational changes in the time span of auditory sensory memory from birth on with a peak in young adulthood, as well as to a decrease of sensory memory duration in healthy aging. Furthermore, this review suggests that sensory memory decline is related to diverse neurological, psychiatric, and pediatric diseases, including Alzheimer's disease, alcohol abuse, schizophrenia, and language disorders. This review underlines that the MMN provides a unique window to the cognitive processes of auditory sensory memory. However, further studies combining electrophysiological and behavioral data, and further studies in clinical populations are needed, also on individual levels, to validate the MMN as a clinical tool for the assessment of sensory memory duration.

Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity.

AIM: Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity. PATIENTS & METHODS: Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults. RESULTS: The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02). CONCLUSION: These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014.

Differences between self-assessment and external rating of voice with regard to sex characteristics, age, and attractiveness.

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 (F0). 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, F0, 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.