Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model.

Hermansky-Pudlak Syndrome (HPS) is a rare disease caused by mutations in the genes coding for various HPS proteins. HPS proteins are part of multi-subunit complexes involved in the biogenesis of organelles from the lysosomal-endosomal-system. In humans, this syndrome is characterized by the presence of albinism, platelet dysfunction and pulmonary fibrosis. The renal component to the disease remains unstudied and untreated in patients with HPS. Here we demonstrate that in humans, HPS proteins have a high renal expression with active transcription of HPS1, 3, 4 and 5 in human podocyte cell culture, suggesting that impaired function of HPS proteins could directly impact renal function. Therefore, we developed a zebrafish model to study the renal involvement of HPS proteins in proteinuric kidney disease. Remarkably, knockdown of HPS genes in zebrafish causes glomerular injury with edema, proteinuria and structural changes of the glomerular filtration barrier. Moreover, reduced expression of HPS proteins in zebrafish recapitulates other important disease hallmarks, like hypopigmentation and accumulation of intracellular debris characteristic of lysosomal disorders. In conclusion, we present a valid zebrafish model that highlights the previously underestimated relevance of renal disease in HPS. This draws attention to the therapeutic options available to manage this component of the syndrome.

Circulating factors cause proteinuria in parabiotic zebrafish.

Proteinuria can be induced by impairment of any component of the glomerular filtration barrier (GFB). To determine the role of circulating permeability factors on glomerular damage, we developed a parabiosis-based zebrafish model to generate a common circulation between zebrafish larvae. A morpholino-mediated knockdown of a podocyte specific gene (nephronectin) was induced in one zebrafish larva which was then fused to an un-manipulated fish. Notably, proteinuria and glomerular damage were present in the manipulated fish and in the parabiotically-fused partner. Thus, circulating permeability factors may be induced by proteinuria even when an induced podocyte gene dysregulation is the initiating cause.

[Minimal change disease and focal segmental glomerulosclerosis]. / Minimal-change-Glomerulonephritis und fokal-segmentale Glomerulosklerose.

Minimal change disease (MCD) or minimal change glomerulonephritis and focal segmental glomerulosclerosis (FSGS) are the two major causes of nephrotic syndrome in children and young adults. Both disease entities resemble each other and can sometimes only be discriminated on the basis of their clinical courses. MCD and FSGS display two classical examples that share a common pathophysiology in which the glomerular podocyte and the cytoskeleton of its foot processes play important roles. Therefore, the term "podocytopathy" was introduced for both diseases. In this article, we compare their differences and similarities, and summarized new data on pathophysiology and treatment. In adults, only a renal biopsy including electron microscopy allows for the discrimination of MCD and FSGS and other differential diagnoses. The identification of a primary or secondary form of the disease is based on the clinical course. Data from studies on the treatment are sparse; hence, treatment is still based on high-dose steroids followed by additional immunosuppressive agents. In secondary forms, treatment of the underlying disease is elementary.

[Audiologic rehabilitation of patients with cochlear implants]. / Audiologische Rehabilitation von Kochleaimplantat-Trägern.

The outcome and success of rehabilitation of patients with cochlear implants (CIs) is determined to a large extent by the preoperative diagnostics and individual fitting of the speech processor and is assessed by the auditory performance of the CI recipient. Due to the wide spectrum of auditory abilities of recipients and to the large variability with respect to their age and experience, the postoperative audiologic assessment is based on a large battery of subjective tests and objective measures. The results of these functional tests are used for documenting the level of rehabilitation, and they determine the actions taken for fine-tuning the fitting of the speech processor.

[Speech intelligibility tests in cochlear implant patients]. / Sprachverständlichkeitsuntersuchungen bei Kochleaimplantatpatienten.

The investigation of speech intelligibility under quiet and noisy conditions is essential to evaluate the auditory and verbal rehabilitation of cochlear implant patients. A set of audiological tests is introduced that has been validated and optimized by empirical investigations in adult cochlear implant users. The Kiel logatom test, the Freiburg speech intelligibility test and the adaptive measurement of speech perception threshold in noise with the Oldenburg sentence test are methods suggested for clinical use, which are also applicable for scientific investigations. The test battery provides results that can be interpreted by every professional involved in the rehabilitation process of cochlear implant patients.

[Improving speech comprehension using a new cochlear implant speech processor]. / Verbesserung der Sprachverständlichkeit durch neuen Cochlear-Implant-Sprachprozessor.

The aim of this multicenter clinical field study was to assess the benefits of the new Freedom 24 sound processor for cochlear implant (CI) users implanted with the Nucleus 24 cochlear implant system. The study included 48 postlingually profoundly deaf experienced CI users who demonstrated speech comprehension performance with their current speech processor on the Oldenburg sentence test (OLSA) in quiet conditions of at least 80% correct scores and who were able to perform adaptive speech threshold testing using the OLSA in noisy conditions. Following baseline measures of speech comprehension performance with their current speech processor, subjects were upgraded to the Freedom 24 speech processor. After a take-home trial period of at least 2 weeks, subject performance was evaluated by measuring the speech reception threshold with the Freiburg multisyllabic word test and speech intelligibility with the Freiburg monosyllabic word test at 50 dB and 70 dB in the sound field. The results demonstrated highly significant benefits for speech comprehension with the new speech processor. Significant benefits for speech comprehension were also demonstrated with the new speech processor when tested in competing background noise.In contrast, use of the Abbreviated Profile of Hearing Aid Benefit (APHAB) did not prove to be a suitably sensitive assessment tool for comparative subjective self-assessment of hearing benefits with each processor. Use of the preprocessing algorithm known as adaptive dynamic range optimization (ADRO) in the Freedom 24 led to additional improvements over the standard upgrade map for speech comprehension in quiet and showed equivalent performance in noise. Through use of the preprocessing beam-forming algorithm BEAM, subjects demonstrated a highly significant improved signal-to-noise ratio for speech comprehension thresholds (i.e., signal-to-noise ratio for 50% speech comprehension scores) when tested with an adaptive procedure using the Oldenburg sentences in the clinical setting S(0)N(CI), with speech signal at 0 degrees and noise lateral to the CI at 90 degrees . With the convincing findings from our evaluations of this multicenter study cohort, a trial with the Freedom 24 sound processor for all suitable CI users is recommended. For evaluating the benefits of a new processor, the comparative assessment paradigm used in our study design would be considered ideal for use with individual patients.

[Refractory behaviour of the electrically stimulated auditory nerve]. / Das Refraktärverhalten des elektrisch stimulierten Hörnervs.

INTRODUCTION: Electrically evoked compound action potentials (TECAP) of the auditory nerve can be recorded in cochlear implants. TECAP thresholds are used to predict threshold levels for speech processor maps. The auditory nerve's refractory properties can influence these levels. METHODS: Recovery functions were investigated at 84 stimulation sites in 14 patients who had Nucleus CI24 implants; neural response telemetry (NRT) and a modified forward-masking technique were used for these investigations, introducing the reference masker-probe interval (MPI). RESULTS AND CONCLUSION: An interval between 300 and 375 micros was found to be suitable as the reference MPI in our study. The median of the absolute refractory period was determined as 390 s and the median time constant of the recovery function, at 425 s. In practice, a reference MPI of 300 s is suggested for measurement of recovery and amplitude growth functions. As up to now the amplitude growth function has been measured at 500 s and thus mostly in a relatively refractory condition, the refractory behaviour should influence the TNRT. In addition, it was possible to explain the shape of standard forward-masking recovery functions with reference to the latency shift of the neural response.

Performance benefits for adults using a cochlear implant with adaptive dynamic range optimization (ADRO): a comparative study.

The aim of this study was to assess the qualitative and quantitative benefits for speech-recognition ability of a preprocessing strategy known as adaptive dynamic range optimization (ADRO), used in conjunction with the subject's standard MAP, in comparison with the subject's standard MAP alone, for a group of experienced German-speaking adults using the Nucleus 24 Cochlear implant. In a prospective, single-subject, comparative study design, experienced adult CI-users were asked to trial and compare both their standard MAP and the newly fitted ADRO MAP (ADRO MAP fitting - week 0) following a take-home trial period of 5 weeks. Assessment of speech recognition ability performed in quiet (at 50, 60 and 70 dB SPL) and adaptively in noise was carried out repeatedly in two test sessions in weeks 5 and 7 (ADRO MAP postfitting) using both MAPs. The order of speech tests and MAPs tested was counterbalanced across the test sessions to control for potential learning effects during the study. Subjective assessments were performed at week 0 to assess details of current usage. Comparative subjective assessments were carried out at weeks 5 and 7 to obtain impressions of loudness of environmental sounds and speech understanding in a variety of conversational situations with both MAPs and finally MAP preference judgements. Fifteen adult, German-speaking, experienced implant users wearing their body-worn SPrint processor for a minimum of six hours and up to 16 hours per day were enrolled in the study across three university clinic hospitals in Germany. On average, speech-reception thresholds (SRT) were significantly improved with the ADRO MAP compared to using the standard MAP for all speech materials in quiet. The mean advantage for SRT values with the ADRO MAP was 2.9 dB, sigma +/- 2.8 dB (p = 0.002) for the Freiburger Numbers test and 3.3 dB, sigma +/- 3.2 dB (p = 0.008) for the Freiburger Monosyllabic Words test. In noise, the ADRO MAP led to a significant improvement for the group for the mean signal-to-noise ratio required for a 50% speech recognition score (SNR 50) for the Oldenburger sentences of 1.74 dB, sigma +/- 3.2 dB (p = 0.048). Comparison of subjective impressions of loudness of environmental sounds revealed no significant difference in the ratings observed with either MAP. For speech understanding in a variety of listening situations, 35% of subjects preferred the ADRO MAP, 29% preferred the standard MAP whereas 36% reported no difference. Statistically the MAP preferences for the groups were not significant, however a significant MAP preference was noted in four subjects for the ADRO MAP and in two subjects for the standard MAP. Our study results demonstrate significant benefits of ADRO for speech recognition ability in quiet and in noise for both soft and conversational levels of speech. For the majority of subjects, both the ADRO and standard MAPs were found to be useful on a daily basis. No reductions in performance were noted for speech recognition or loudness scaling judgements of environmental sounds when using the newly fitted ADRO MAP, suggesting a smooth transition to the use of the preprocessing algorithm. It is recommended that an ADRO MAP be provided for all CI users as an additional program option to offer potential added benefit in select environments.

Normative findings of electrically evoked compound action potential measurements using the neural response telemetry of the Nucleus CI24M cochlear implant system.

One hundred and forty-seven adult recipients of the Nucleus 24 cochlear implant system, from 13 different European countries, were tested using neural response telemetry to measure the electrically evoked compound action potential (ECAP), according to a standardised postoperative measurement procedure. Recordings were obtained in 96% of these subjects with this standardised procedure. The group results are presented in terms of peak amplitude and latency, slope of the amplitude growth function and ECAP threshold. The effects of aetiological factors and the duration of deafness on the ECAP were also studied. While large intersubject variability and intrasubject variability (across electrodes) were found, results fell within a consistent pattern and a normative range of peak amplitudes and latencies was established. The aetiological factors had little effect on the ECAP characteristics. However, age affected ECAP amplitude and slope of the amplitude growth function significantly; i.e., the amplitude is higher in the lowest age category (15-30 years). Principal component analysis of the ECAP thresholds shows that the thresholds across 5 electrodes can be described by two factors accounting for 92% of the total variance. The two factors represent the overall level of the threshold profiles ('shift') and their slopes across the electrode array ('tilt'). Correlation between these two factors and the same factors describing the T- and C-levels appeared to be moderate, in the range of 0.5-0.6.

[Test set for the evaluation of hearing and speech development after cochlear implantation in children]. / Evaluationsset zur Hör-/Sprachentwicklung nach Cochlea-Implantation bei Kindern.

BACKGROUND: Since autumn 1998 the multicenter interdisciplinary study group "Test Materials for CI Children" has been compiling a uniform examination tool for evaluation of speech and hearing development after cochlear implantation in childhood. METHODS USED: After studying the relevant literature, suitable materials were checked for practical applicability, modified and provided with criteria for execution and break-off. For data acquisition, observation forms for preparation of a PC-version were developed. RESULTS: The evaluation set contains forms for master data with supplements relating to postoperative processes. The hearing tests check supra-threshold hearing with loudness scaling for children, speech comprehension in silence (Mainz and Göttingen Test for Speech Comprehension in Childhood) and phonemic differentiation (Oldenburg Rhyme Test for Children), the central auditory processes of detection, discrimination, identification and recognition (modification of the "Frankfurt Functional Hearing Test for Children") and audiovisual speech perception (Open Paragraph Tracking, Kiel Speech Track Program). The materials for speech and language development comprise phonetics-phonology, lexicon and semantics (LOGO Pronunciation Test), syntax and morphology (analysis of spontaneous speech), language comprehension (Reynell Scales), communication and pragmatics (observation forms). The MAIS and MUSS modified questionnaires are integrated. CONCLUSIONS: The evaluation set serves quality assurance and permits factor analysis as well as controls for regularity through the multicenter comparison of long-term developmental trends after cochlear implantation.

Cochlear implants for adults obtaining marginal benefit from acoustic amplification: a European study.

OBJECTIVE: This study aimed to examine the application of a speech recognition score of 30% on open-set word materials as the upper limit for preoperative performance in determining cochlear implant (CI) candidacy for European non-English-speaking hearing-impaired persons. This study also aimed to determine the effect of implantation on residual pure-tone hearing thresholds and to determine the incidence and benefit of a contralateral hearing aid postimplant. STUDY DESIGN: The single-subject design study, involving 20 postlinguistically deafened subjects, compares preoperative performance with hearing aids to postoperative performance with a CI at 6 months after surgery. Subjects were implanted with either the Nucleus Mini 22 or the Nucleus 24 CI systems implementing the MPEAK and SPEAK coding strategies. Fourteen subjects meeting the selection criteria were accrued consecutively specifically for inclusion in the study, whereas the remaining 6 retrospectively implanted subjects were identified for inclusion via patient records. PATIENTS: The investigation included 8 clinics over 3 countries (France, Germany, and Spain) and involved 20 postlinguistically deafened subjects who obtained marginal benefit from acoustic amplification before surgery. Nineteen subjects were older than 18 years of age with 1 subject being 14 years old included in the data report as well. MAIN OUTCOME MEASURES: Open-set speech recognition was evaluated before and after surgery using recorded word lists and sentence lists in the subject's native language to determine benefit from the treatment. Baseline audiograms were obtained before surgery for frequencies of 0.25-8.0 kHz for both ears and compared to pure-tone hearing thresholds measured at 1 month after surgery to determine the effect of the implantation on residual hearing. Additionally, a questionnaire was administered to determine the incidence and benefit of continued hearing aid use in the contralateral ear postimplant. RESULTS: Nineteen of the 20 study subjects displayed a significant benefit after surgery at 6 months after switch-on for open-set speech recognition. The remaining subject displayed no significant change in performance on objective testing. The implantation resulted in a significant downward shift in hearing thresholds for the implant ear in the majority of subjects. However, 50% of subjects displayed conservation of some residual hearing. For the majority of subjects, hearing aid use in the contralateral ear was discontinued because of lack of perceived benefit after surgery. CONCLUSIONS: The Nucleus Multichannel CI provides a significant benefit for postlinguistically deafened adults who display marginal benefit from acoustic amplification. Therefore, in French-, German-, and Spanish-speaking clinics, a speech recognition score of 30% on open-set word materials is considered an appropriate upper limit for preoperative performance in determining CI candidacy. In view of a significant downward shift in pure-tone thresholds in the implant ear for the majority of subjects, in cases of asymmetry, it is recommended that the poorer ear be implanted. After surgery, the majority of subjects did not perceive an added benefit from continued use of their contralateral hearing aid.

[Cochlear implant for non-deaf patients?]. / Cochlear-Implant-Versorgung bei nicht tauben Patienten?

BACKGROUND: Cochlear implants have proven to be the method of choice for postlingually deafened adults. The great success of this application requires discussion of the degree in which the indication for cochlear implantation should be expanded to include patients with residual hearing. METHOD AND PATIENTS: Following an initial discussion of the term deafness, we present the preoperative and postoperative results in five patients with residual hearing. These patients achieve a certain degree of speech recognition with their well fitted hearing aids. However, their aided speech intelligibility did not exceed 30% with the standardized Freiburg monosyllabic word test at 70 dB. In each case the worse hearing ear was treated with a cochlear implant. Speech discrimination in silence and noise are compared with the results of a group of postlingually deafened cochlear implant patients. RESULTS: The five patients are very satisfied with the cochlear implant and use the telephone to communicate with unknown partners. They score 100% in the standardized four-syllable number test above 55 dB and they document a loss of speech discrimination between 0 and 25% within the open-set monosyllabic word test. The mean increase of best monosyllable intelligibility by the cochlear implant over the hearing aids is 65%. Using the innsbruck sentence test the patients score 100% at 70 dB; with the Göttingen sentence test, the mean result is 75%. Their mean results in noise are also very good, 76% at 10 dBS/N and 57% at 5 dBS/N respectively. None of these patients use the hearing aid on the untreated, better hearing ear. CONCLUSION: A multichannel cochlear implant lead to a significant improvement of speech comprehension in these patients with residual hearing. We can successfully implant patients with minimal benefit of their well fitted hearing aids. Our group is too small to be able to define general selection criteria. For the time being we use as an audiological indication a open-set monosyllabic word intelligibility of not more than 30% at 70 dB with well fitted hearing aids.

Which sensitivity setting should a child use?

The influence of the sensitivity setting of the cochlear implant speech processor on speech recognition is investigated with 15 experienced postlinguistically deafened adult cochlear implant users. We describe the use of loudness scaling in the course of speech processor fine tuning and checkup of the speech processor map to demonstrate how their speech processors are programmed. The Freiburg monosyllabic word test, a standardized German open set speech intelligibility test, is used in silence and the very difficult Göttingen sentence test is used in silence and noise to measure speech recognition scores as a function of sensitivity setting. The median of the optimal sensitivity setting was four steps higher than the value recommended by the manufacturer. In noisy everyday hearing situations patients generally use a sensitivity setting one step lower than the one we found to be optimal for openset word understanding under test room conditions. With children who cannot select optimal speech processor settings by themselves, we do not recommend the use of noise reduction and set the sensitivity three steps higher than the one recommended by the manufacturer.

[Noise signal reduction in cochlear implant speech processors]. / Zur Störsignalreduktion bei Cochlear Implant Sprachprozessoren.

Cochlear implant wearers suffer from an additional impairment of auditory-verbal communication due to environmental noise, similar to that experienced by many users of conventional hearing aids. To reduce this problem the mini-22 cochlear implant system has implemented a noise suppression function in the Mini Speech Processor (MSP) decreasing background noise-induced stimulation. The efficacy of this algorithm was investigated in 18 experienced postlingually-deafened adult cochlear implant users. By means of a computer-assisted speech intelligibility measurement unit, speech understanding was compared with and without the noise suppression function. Paired observations were conducted in noise as well as in silence. The recording of complete performance-intensity functions in terms of speech discrimination tested with the standardized Freiburg speech intelligibility test and a newly developed sentence test demonstrated the benefit of the noise reduction mechanism. Better understanding was achieved in silence in the normal speech processing mode of the MSP, whereas a significant improvement in noise resulted from the noise suppression. Considerable interindividual differences were found in the gain patients derived from using the noise suppression algorithm. The more often the S-position was used, the better the individual result with activated noise suppression. However, providing the cochlear implant patients with more information, as in the spectral peak ("SPEAK") stimulation strategy recently developed by Cochlear Corporation, could lead to higher speech discrimination scores in interfering noise. Paired comparison studies revealed that the new strategy added significantly to results of speech understanding. Average intelligibility rose 40% when using the new coding method instead of the MSP with activated noise suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Multicentric field evaluation of a new speech coding strategy for cochlear implants.

In a multicentric study involving 4 European cochlear implant centers, the speech perception abilities of 20 native German-speaking individuals implanted with the Nucleus 22 Channel Cochlear Implant System when using a new spectral peak (SPEAK) speech coding strategy were investigated. This strategy continuously analyzes the speech signal using 20 digital programmable bandpass filters and presents up to 10 spectral maxima to the 22 implanted electrodes. Each subject's performance on a variety of auditory perceptual tasks was evaluated with the experimental encoder (SPEAK), relative to his or her performance in a reference condition. An ABAB experimental design was used whereby each strategy was reversed and replicated. The reference levels of auditory performance were established using the multipeak (MPEAK) speech-processing strategy of the Nucleus speech processor. Only subjects who achieved open-set monosyllable word recognition in the reference condition were included in this study. Significant differences in group mean scores for most speech recognition subtests were obtained for the SPEAK versus the MPEAK strategy. The largest overall improvements were observed for the sentence tests under noisy conditions.

[Experiences in Kiel with the cochlear implant]. / Kieler Erfahrungen mit der Cochlear Implant-Versorgung.

Since 1988 22 deaf patients were provided with a 22-channel cochlear implant at the Kiel University Hospital. No surgical or postoperative complications were seen in any of the patients. Side effects like facial stimulation and pain sensation during electrode activation do not reduce the utility. Tinnitus may initially be severe but usually subsides to preop levels after a few days. A tinnitus masking effect is pronounced during stimulation but hardly lasts long after switch off. Besides an individually arranged hearing training the accurate speech processor fitting to the needs of the patient remains the cornerstone of successful rehabilitation. Objective intraoperative measurements such as the electrically evoked brain stem potentials and the middle ear reflexes yield estimates of the threshold values relevant for initial processor programming. Further information needed for the following extensive fine adjustment is obtained by subjective evaluation of loudness growth during electrical stimulation with variable parameters, by loudness scaling of narrow band noises with different middle frequencies and intensities presented under free field conditions and by speech audiometric procedures. The latter include a monosyllabic rhyme test and a logatom test developed at this institution. More speech testing is applied to document the degree of auditive rehabilitation. The results of speech tracking and the Freiburg tests as well as a new sentence test in silence and noise are discussed. In the multisyllable Freiburg test all but two of the adults understand the complete presented material, in the open set monosyllable test an average of 55% correct is achieved. Speech discrimination-oriented ranking showed 95% of all postlingually deaf patients in the highest performance category.

The value of fentanyl/diazepam anesthesia for experimental operations and recordings of compound action potentials in the guinea pig cochlea.

Fentanyl/diazepam anesthesia is an appropriate combination for surgical operations on the guinea pig, since it ensures definitive anesthesia and analgesia without respiratory depression. Comparative investigations with pentobarbital and urethane were carried out to check their applicability for electrocochleographic recordings. We found that fentanyl/diazepam combination anesthesia is more suitable for electrocochleographic investigations than pentobarbital. We were thereby able to prove that pentobarbital has an attenuating effect on electrocochleographic recordings in contrast to the findings reported in the available literature. For this reason, and because the lowest rates of animal morbidity occurred with fentanyl/diazepam, this combination anesthesia should be used preferentially for electrophysiological experiments in guinea pigs.

Time constants of the vestibular thermal reaction.

For the thermal test, adaptation time constants of about 100 s are described in the literature. By automatically alternating hot-cold irrigation, as designed by us, precision of stimulus application of different temperatures was considerably improved. Furthermore, temperature was registered with a thermocouple device. The actually effective thermal stimulus on the horizontal canal was calculated by a mathematical model. Nystagmus analysis was carried out automatically with the Kiel-program. With 15 radical cavities (where stimulus intensity is very strong) non-linearities were especially distinct. After switching to the 44 degrees C stimulus, there was an extremely steep rise in the reaction in the form of a so-called "on-effect" or "post-inhibitory overshoot". After reaching maxima of up to 150 degrees/s, the reaction decreased quickly with time constants of 22-45 s.