Development of a genotyping microarray for Usher syndrome

BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

[The model project "newborn auditory screening" in the Upper Palatinate: high process and result quality of an interdisciplinary concept]

BACKGROUND: In May 2003, a newborn auditory screening program was initiated in the Upper Palatinate. METHODS: Sequential OAE- and BERA-screening was conducted in all hospitals with obstetric facilities. The Screening Center at the Public Health Authority was responsible for the coordination of the screening process, completeness of participation, the follow-up of all subjects with a positive screening test and the quality of instrumental screening. RESULTS: A total of 96% of 17,469 newborns were screened. The referral rate at discharge was 1.6% (0.4% for bilateral positive findings). For 97% of the positive screening results, a definite diagnosis to confirm or exclude hearing loss was achieved; for 43% only after intervention by the Screening Center. Fifteen children with profound bilateral hearing impairment were identified of whom eight were only detected by the intervention of the Screening Center. CONCLUSION: The effective structures established in the Upper Palatinate provide a standard for the quality of neonatal auditory screening achievable in Germany.

Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae.

To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.05) in 5 patients who developed hearing impairment or secondary epilepsy than in those who recovered without neurological deficits. Levels of MMP-9 correlated with concentrations of TIMP-1 (P<.001) and tumor necrosis factor-alpha (P=.03). Repeated lumbar punctures showed that levels of MMP-8 and MMP-9 were regulated independently and did not correlate with the CSF cell count. Therefore, MMPs may derive not only from granulocytes infiltrating the CSF space but also from parenchymal cells of the meninges and brain. High concentrations of MMP-9 are a risk factor for the development of postmeningitidal neurological sequelae.

Einschluss oder Ausschluss von Gleichaltrigen mit Hörschädigung? Entscheidungen von hörenden Kindern und Jugendlichen aus integrativen Klassen

Nicht selten werden Mitschülerinnen und Mitschüler von schulisch integrierten Kindern mit Hörschädigung mit Situationen konfrontiert, in denen der Integrationsgedanke in Konflikt zu den eigenen Interessen steht. In der vorliegenden Studie wurde untersucht, inwiefern sich Urteile und Handlungsentscheidungen zum Einschluss von Gleichaltrigen mit Hörschädigung in Abhängigkeit von Situation, Jahrgangsstufe und Kontaktbereitschaft unterscheiden. Hierfür wurden 212 Schülerinnen und Schüler aus Regelklassen (Klasse 3, 5, 7) mit einem einzelintegrierten Kind mit Hörschädigung zu Geschichten befragt, in denen sich eine Protagonistin bzw. ein Protagonist zwischen dem Einschluss eines Kindes mit oder ohne Hörschädigung entscheiden muss. Die Mehrheit beurteilte den Einschluss des Kindes mit Hörschädigung in Situationen als richtig, in denen nur das Kind mit Behinderung zur Auswahl stand. Konnte sich die Protagonistin bzw. der Protagonist hingegen zwischen einem Kind mit oder ohne Hörschädigung entscheiden, erwartete nur noch die Hälfte den Einschluss des Kindes mit Hörschädigung. Zudem unterschieden sich die Einschlussentscheidungen in Abhängigkeit des Kontextes, der Jahrgangsstufe und der Kontaktbereitschaft.

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

Mild cognitive impairment in medical inpatients: the mini-mental state examination is a promising screening tool

AIM: To assess the prevalence of mild cognitive impairment (MCI) in medical inpatients aged 55-85 years without known cognitive deficits, and how often ward physicians mentioned MCI in their discharge notes. Moreover, we aimed to identify variables associated with MCI and to assess the sensitivity and specificity of the Mini-Mental State Examination (MMSE) for MCI. METHODS: Two neuropsychologists administered a 60-min battery of validated tests to evaluate different cognitive domains. The diagnosis of MCI was based on a prespecified algorithm. The sensitivity and specificity of the MMSE for MCI were calculated. RESULTS: Fifteen patients showed a normal cognitive profile (21.4%), while 55 patients (78.6%) showed MCI. Ward physicians, blinded to the results of the neuropsychological evaluation, did not mention MCI in their discharge notes of any of the evaluated patients. The only variable independently associated with MCI was the MMSE. A MMSE score of < or =28 showed a sensitivity of 85.5% and a specificity of 66.7% for MCI. CONCLUSION: MCI is frequent albeit overlooked in elderly medical inpatients without previously known cognitive deficits. In view of therapies preventing the progression of MCI to dementia, MCI screening will be crucial. The MMSE represents a promising screening tool for MCI in medical inpatients.

Bilateral impairment of concurrent saccade programming in hemispatial neglect

When healthy observers make a saccade that is erroneously directed toward a distracter stimulus, they often produce a corrective saccade within 100ms after the end of the primary saccade. Such short inter-saccadic intervals indicate that programming of the secondary saccade has been initiated prior to the execution of the primary saccade and hence that the two saccades have been programmed concurrently. Here we show that concurrent saccade programming is bilaterally impaired in left spatial neglect, a strongly lateralized disorder of visual attention resulting from extensive right cerebral damage. Neglect patients were asked to make saccades to targets presented left or right of fixation while disregarding a distracter presented in the opposite hemifield. We examined those experimental trials on which participants first made a saccade to the distracter, followed by a secondary (corrective) saccade to the target. Compared to healthy and right-hemisphere damaged control participants the proportion of secondary saccades directing gaze to the target instead of bringing it even closer to the distracter was bilaterally reduced in neglect patients. In addition, the characteristic reduction of secondary saccade latency observed in both control groups was absent in neglect patients, whether the secondary saccade was directed to the left or right hemifield. This pattern is consistent with a severe, bilateral impairment of concurrent saccade programming in left spatial neglect.

Incidence and predictors of atrioventricular conduction impairment after transcatheter aortic valve implantation

Atrioventricular (AV) conduction impairment is well described after surgical aortic valve replacement, but little is known in patients undergoing transcatheter aortic valve implantation (TAVI). We assessed AV conduction and need for a permanent pacemaker in patients undergoing TAVI with the Medtronic CoreValve Revalving System (MCRS) or the Edwards Sapien Valve (ESV). Sixty-seven patients without pre-existing permanent pacemaker were included in the study. Forty-one patients (61%) and 26 patients (39%) underwent successful TAVI with the MCRS and ESV, respectively. Complete AV block occurred in 15 patients (22%), second-degree AV block in 4 (6%), and new left bundle branch block in 15 (22%), respectively. A permanent pacemaker was implanted in 23 patients (34%). Overall PR interval and QRS width increased significantly after the procedure (p <0.001 for the 2 comparisons). Implantation of the MCRS compared to the ESV resulted in a trend toward a higher rate of new left bundle branch block and complete AV block (29% vs 12%, p = 0.09 for the 2 comparisons). During follow-up, complete AV block resolved in 64% of patients. In multivariable regression analysis pre-existing right bundle branch block was the only independent predictor of complete AV block after TAVI (relative risk 7.3, 95% confidence interval 2.4 to 22.2). In conclusion, TAVI is associated with impairment of AV conduction in a considerable portion of patients, patients with pre-existing right bundle branch block are at increased risk of complete AV block, and complete AV block resolves over time in most patients.

Development of an auditory implant manipulator for minimally invasive surgical insertion of implantable hearing devices

To present the auditory implant manipulator, a navigation-controlled mechanical and electronic system which enables minimally invasive ('keyhole') transmastoid access to the tympanic cavity.

Design of a semi-implantable hearing device for direct acoustic cochlear stimulation

A new hearing therapy based on direct acoustic cochlear stimulation was developed for the treatment of severe to profound mixed hearing loss. The device efficacy was validated in an initial clinical trial with four patients. This semi-implantable investigational device consists of an externally worn audio processor, a percutaneous connector, and an implantable microactuator. The actuator is placed in the mastoid bone, right behind the external auditory canal. It generates vibrations that are directly coupled to the inner ear fluids and that, therefore, bypass the external and the middle ear. The system is able to provide an equivalent sound pressure level of 125 dB over the frequency range between 125 and 8000 Hz. The hermetically sealed actuator is designed to provide maximal output power by keeping its dimensions small enough to enable implantation. A network model is used to simulate the dynamic characteristics of the actuator to adjust its transfer function to the characteristics of the middle ear. The geometry of the different actuator components is optimized using finite-element modeling.

How internet telephony could improve communication for hearing-impaired individuals

To test, whether modern Internet telephony with a broadband transmission (0.1-8 kHz) of speech improves speech perception in comparison to conventional telephony (0.3-3.5 kHz) in hearing-impaired and normal-hearing adults.

Non-organic hearing loss: new and confirmed findings

Although non-organic hearing losses are relatively rare, it is important to identify suspicious findings early to be able to administer specific tests, such as objective measurements and specific counseling. In this retrospective study, we searched for findings that were specific ti or typical for non-organic hearing losses. Patient records from a 6 year period (2003-2008) from the University ENT Department of Bern, Switzerland, were reviewed. In this period, 40 subjects were diagnosed with a non-organic hearing loss (22 children, ages 7-16, mean 10.6 years; 18 adults, ages 19-57, mean 39.7 years; 25 females and 15 males). Pure tone audiograms in children and adults showed predominantly sensorineural and frequency-independent hearing losses, mostly in the range of 40-60 dB. In all cases, objective measurements (otoacoustic emissions and/or auditory-evoked potentials) indicated normal or substantially better hearing thresholds than those found in pure tone audiometry. In nine subjects (22.5%; 2 children, 7 adults), hearing aids had been fitted before the first presentation at our center. Six children (27%) had a history of middle ear problems with a transient hearing loss and 11 (50%) knew a person with a hearing loss. Two new and hitherto unreported findings emerged from the analysis: it was observed that a small air-bone gap of 5-20 dB was typical for non-organic hearing losses and that speech audiometry might show considerably poorer results than expected from pure tone audiometry.

Audiological results with Baha in conductive and mixed hearing loss

The level of improvement in the audiological results of Baha(®) users mainly depends on the patient's preoperative hearing thresholds and the type of Baha sound processor used. This investigation shows correlations between the preoperative hearing threshold and postoperative aided thresholds and audiological results in speech understanding in quiet of 84 Baha users with unilateral conductive hearing loss, bilateral conductive hearing loss and bilateral mixed hearing loss. Secondly, speech understanding in noise of 26 Baha users with different Baha sound processors (Compact, Divino, and BP100) is investigated. Linear regression between aided sound field thresholds and bone conduction (BC) thresholds of the better ear shows highest correlation coefficients and the steepest slope. Differences between better BC thresholds and aided sound field thresholds are smallest for mid-frequencies (1 and 2 kHz) and become larger at 0.5 and 4 kHz. For Baha users, the gain in speech recognition in quiet can be expected to lie in the order of magnitude of the gain in their hearing threshold. Compared to its predecessor sound processors Baha(®) Compact and Baha(®) Divino, Baha(®) BP100 improves speech understanding in noise significantly by +0.9 to +4.6 dB signal-to-noise ratio, depending on the setting and the use of directional microphone. For Baha users with unilateral and bilateral conductive hearing loss and bilateral mixed hearing loss, audiological results in aided sound field thresholds can be estimated with the better BC hearing threshold. The benefit in speech understanding in quiet can be expected to be similar to the gain in their sound field hearing threshold. The most recent technology of Baha sound processor improves speech understanding in noise by an order of magnitude that is well perceived by users and which can be very useful in everyday life.

Petrous bone cholesteatoma removal with hearing preservation

Clinical and radiologic outcome analysis after petrous bone cholesteatoma (PBC) removal with simultaneous functional reconstruction.