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.

Muenster Parental Programme empowers parents in communicating with their infant with hearing loss.

OBJECTIVE: With the implementation of the Universal Newborn Hearing Screening (UNHS), the age of diagnosis of children with hearing loss (HL) has been steadily declining in the past years. Consequently, there is a need for early educational intervention methods that are suitable for infants at the preverbal level. To meet this need we have developed and evaluated the Muenster Parental Programme (MPP), a responsive parenting programme for parents of children with HL aged 3-18 months. It aims at enhancing the parents' communicative skills towards their child. METHODS: The MPP is introduced following confirmation of a HL. Flanked by two individual counselling sessions, the programme comprises six group sessions and two single training sessions with video feedback. The focus of the programme lies in enhancing parents' responsive behaviour and in reducing inappropriate initiative behaviour. The present study involved 29 parents of 24 children aged 6.6 (mean, range: 3-12) months at the outset of the MPP. The children's degree of HL ranged from moderate to profound. Parents of children with unilateral HL and/or risk for an additional developmental delay were included. The prospective study compared parent communication skills of a trained (N = 15) versus a control group (N = 14) before and after the MPP. For this purpose, instances of responsive behaviour to the signals of the child and total time of initiative behaviour within a 4-min video-sample were measured before and after completion of the study in both groups. RESULTS: Trained parents could enhance their responsiveness to vocal and preverbal signals of the child (Wilcoxon test, p = .002) and also their responsiveness to non-verbal signals (Wilcoxon test, p < .001). Moreover, parents reduced their inappropriate initiative behaviour (related t-test, p < .001). Pre-post comparisons in the control group were non-significant. CONCLUSIONS: The increased parental responsiveness to infants with HL is of great importance as these early behaviours underlie later acquisition of speech, language, hearing and social communication skills. The MPP constitutes the first evaluated group concept for parents of infants with HL in the German-speaking countries and equally meets the needs of parents and professionals.

A positive wave at 8 ms (P8) and modified auditory brainstem responses measurement in auditory neuropathy spectrum disorder.

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 (40.5s(-1)), constant rarefaction and condensation stimuli, a reduced click-rate (11.1s(-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.

Progressive hearing loss after completion of cisplatin chemotherapy is common and more pronounced in children without spontaneous otoacoustic emissions before chemotherapy.

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 (≤ 10dB 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.