Julia Dlugaiczyk

Lack of brain-derived neurotrophic factor hampers inner hair cell synapse physiology, but protects against noise-induced hearing loss

The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNFPax2 KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNFPax2 KO IHCs showed a normal maturation. Likewise, in BDNFPax2 KO membrane capacitance (ΔCm) as a function of inward calcium current (ICa) follows the linear relationship typical for normal adult IHCs. In contrast the maximal ΔCm, but not the maximal size of the calcium current, was significantly reduced by 45% in basal but not in apical cochlear turns in BDNFPax2 KO IHCs. Maximal ΔCm correlated with a loss of IHC ribbons in these cochlear turns and a reduced activity of the auditory nerve (auditory brainstem response wave I). Remarkably, a noise-induced loss of IHC ribbons, followed by reduced activity of the auditory nerve and reduced centrally generated wave II and III observed in control mice, was prevented in equally noise-exposed BDNFPax2 KO mice. Data suggest that BDNF expressed in the cochlea is essential for maintenance of adult IHC transmitter release sites and that BDNF upholds opposing afferents in high-frequency turns and scales them down following noise exposure.

Accompanying Symptoms Overlap during Attacks in Menière’s Disease and Vestibular Migraine

Menière’s disease and vestibular migraine (VM) are the most common causes of spontaneous recurrent vertigo. The current diagnostic criteria for the two disorders are mainly based on patients’ symptoms, and no biological marker is available. When applying these criteria, an overlap of the two disorders is occasionally observed in clinical practice. Therefore, the present prospective multicenter study aimed to identify accompanying symptoms that may help to differentiate between MD, VM, and probable vestibular migraine (pVM). Two hundred and sixty-eight patients were included in the study (MD: n = 119, VM: n = 84, pVM: n = 65). Patients with MD suffered mainly from accompanying auditory symptoms (tinnitus, fullness of ear, and hearing loss), while accompanying migraine symptoms (migraine-type headache, photo-/phonophobia, visual aura), anxiety, and palpitations were more common during attacks of VM. However, it has to be noted that a subset of MD patients also experienced (migraine-type) headache during the attacks. On the other hand, some VM/pVM patients reported accompanying auditory symptoms. The female/male ratio was statistically higher in VM/pVM as compared to MD, while the age of onset was significantly lower in the former two. The frequency of migraine-type headache was significantly higher in VM as compared to both pVM and MD. Accompanying headache of any type was observed in declining order in VM, pVM, and MD. In conclusion, the present study confirms a considerable overlap of symptoms in MD, VM, and pVM. In particular, we could not identify any highly specific symptom for one of the three entities. It is rather the combination of symptoms that should guide diagnostic reasoning. The identification of common symptom patterns in VM and MD may help to refine future diagnostic criteria for the two disorders.

Expression of glycine receptors and gephyrin in the rat cochlea

The cochlear efferent feedback system exerts direct impact on cochlear nerve activity and balances interaural sensitivity. So far, acetylcholine, GABA and dopamine are known to be transmitters of the inhibitory efferent system. Despite the wealth of information about glycinergic neurotransmission in the central auditory system, the inhibitory glycine receptor (GlyR) has not yet been regarded as a target molecule of efferent transmission in the cochlea. Using RT-PCR, in situ hybridization and immunohistochemistry, we show that GlyRα3, GlyRβ and gephyrin are expressed in the organ of Corti and spiral ganglion neurons. Furthermore, two alternative splice variants of GlyRα3, corresponding to the long (α3_L) and short (α3_K) human isoforms, could be distinguished. The localization of glycine receptors below inner hair cells and in outer hair cells of the adult cochlea suggests that these inhibitory receptors may serve as target molecules of the efferent olivocochlear bundle.

Oropharyngeal tularemia – a differential diagnosis of tonsillopharyngitis and cervical lymphadenitis

ZusammenfassungFrancisella tularensis, der Auslöser der Tularämie, ist seit fast 100 Jahren als Krankheitserreger bei Mensch und Tier bekannt. Durch die steigende Zahl von Krankheitsausbrüchen in verschiedenen Regionen Europas außerhalb klassischer Endemiegebiete hat das Interesse an dieser seltenen Infektionskrankheit in den letzten Jahren wieder stark zugenommen. Wir berichten über einen Fall von oropharyngealer Tularämie bei einem 18-jährigen Mädchen aus Bayern (Deutschland) mit Tonsillopharyngitis und zervikaler Lymphknotenschwellung. Die Diagnose einer Tularämie wurde durch hochpositive Serologie und den Nachweis von F. tularensis subspecies holarctica in Lymphknotengewebe mittels PCR gestellt. Nach einer Langzeitbehandlung mit Doxycyclin, vorübergehend auch in Kombination mit Ciprofloxacin, erholte sich die Patientin vollständig. Anhand des vorgestellten Falles und einer Literaturübersicht werden klinisches Bild, Diagnostik, Therapie und aktuelle epidemiologische Entwicklungen der Tularämie in Europa diskutiert.SummaryFrancisella tularensis, the causative agent of tularemia, has been recognized as a human and zoonotic pathogen for almost 100 years. The increasing number of tularemia outbreaks in regions of Europe outside the classic endemic areas in recent years has prompted renewed interest in this rare infectious disease. We report on a case of oropharyngeal tularemia in an 18-year-old girl from Bavaria (Germany) who presented with tonsillopharyngitis and cervical lymphadenitis. Strongly positive serological tests and PCR detection of F. tularensis subsp. holarctica in lymph node tissue led to the diagnosis of tularemia. After long-term treatment with doxycycline, partly in combination with ciprofloxacin, the patient recovered completely. Clinical presentation, diagnostics, treatment and recent epidemiological aspects of tularemia in Europe are discussed in this case report and review of the literature.

Involvement of the anterior semicircular canal in posttraumatic benign paroxysmal positioning vertigo.

Objective: To study the involvement of the different semicircular canals in posttraumatic benign paroxysmal positioning vertigo (BPPV) with special reference to the anterior canal (AC). Study Design: Retrospective review. Setting: Tertiary referral center. Patients: Seventy-four BPPV patients. Interventions: Neurotologic assessment with video-oculography; treatment of BPPV with the canalith repositioning procedure appropriate for the affected semicircular canal. Main Outcome Measures: Number of patients with AC, posterior canal (PC), horizontal canal (HC), and multiple-canal involvement in posttraumatic versus idiopathic BPPV. Results: 85.1% of patients were classified as idiopathic BPPV, whereas 14.9% had a history of posttraumatic BPPV. The prevalence of AC BPPV was significantly higher in the posttraumatic group (27.3%) compared with that in the idiopathic group (3.2%; Fishers exact test: p = 0.021). Multiple-canal (combined) BPPV was observed more frequently after head trauma (27.3%) compared with the idiopathic form of the disorder (1.6%; p = 0.009). In particular, the risk for combined AC/PC BPPV was greater in posttraumatic than idiopathic cases (odds ratio, 13.78; 95% confidence interval, 1.13-167.8). No significant differences were observed for the involvement of the PC and HC between the two groups. Two cases of combined AC/PC BPPV are presented with particular respect to the underlying trauma mechanism. Conclusion: Head trauma is a risk factor for AC and combined BPPV, in particular AC/PC BPPV. Involvement of the AC should especially be considered in patients who experienced head trauma resulting in a nonupright position of the body.

Genome-wide copy number profiling using a 100K SNP array reveals novel disease-related genes BORIS and TSHZ1 in juvenile angiofibroma

Juvenile angiofibroma (JA) is a unique fibrovascular tumor, which is almost exclusively found in the posterior nasal cavity of adolescent males. Although histologically classified as benign, the tumor often shows an aggressive growth pattern and has been associated with chromosomal imbalances, amplification of oncogenes and epigenetic dysregulation. We present the first genome-wide profiling of JAs (n=14) with a 100K single nucleotide polymorphism (SNP) microarray. Among the 30 novel JA-specific amplifications detected on autosomal chromosomes with this technique, the genes encoding the cancer-testis antigen BORIS (brother of the regulator of imprinted sites) and the developmental regulator protein TSHZ1 (teashirt zinc finger homeobox 1) were selected for further analysis. Gains for both BORIS (20q13.3) and TSHZ1 (18q22.3) were confirmed by quantitative genomic PCR. Furthermore, quantitative RT-PCR revealed a significant up-regulation of BORIS (p<0.001) and TSHZ1 transcripts (p<0.05) for JAs compared to nasal mucosa. Following detection of BORIS and TSHZ1 proteins in western blots of JAs, subcellular localization was determined for both proteins in immunostaining of JA cryosections. In conclusion, genomic copy number profiling using an SNP microarray has been proven to be a suitable and reliable tool for identifying novel disease-related genes in JAs and newly implicates BORIS and TSHZ1 overexpression in the pathogenesis of JAs. Detection of BORIS in JAs is described with special regard to tumor proliferation and epigenetic dysregulation, and the finding of TSHZ1 amplifications is discussed with special respect to the hypothesis of JAs as malformations of the first branchial arch artery.

Expression of sex hormone receptors in juvenile angiofibromas and antiproliferative effects of receptor modulators.

Predilection of juvenile angiofibromas in adolescent boys has prompted the hypothesis of hormone‐dependent tumor growth. However, knowledge on expression and function of sex hormone receptors in juvenile angiofibromas is still sparse and inconsistent.

Anti-proliferative effect of glucocorticoids on mesenchymal cells in juvenile angiofibromas

Glucocorticoids (GCs) not only regulate metabolic and inflammatory mechanisms, but also are known to suppress tumor growth. Despite previous detection of glucocorticoid receptors (GRs) in juvenile angiofibromas, their distribution and function have not further been studied.

A New Method to Analyze Distortion Product Otoacoustic Emissions (DPOAEs) in the High-Frequency Range Up to 18 kHz Using Windowed Periodograms

Distortion product otoacoustic emissions (DPOAEs) are widely used as an objective examination procedure to determine cochlear function. In a clinical routine setting, the amplitude of the DPOAE signal at 2f1-f2 is applied as an indicator for a potential hearing loss up to 8 kHz. Due to their poor signal-to-noise ratio, meatal nodes from standing waves and calibration issues, high-frequency DPOAEs >; 8 kHz have hardly been addressed in experimental and clinical audiology so far. Here, we present a new method of measuring DPOAE signal levels based on optimal maximum likelihood estimation with windowed power spectral density estimation of stochastic signals and filtering theory. Analysis of simulated data showed that the proposed method effectively reduces the disturbing noise floor compared to conventional averaging techniques. Robust DPOAE signals were measured in 20 ears from ten normally hearing young adults (21-27 years) from 0.5 to 18 kHz . Repeated DPOAE recordings in one individual yielded a good to very good test-retest reliability of the proposed method. These observations are discussed in the context of DPOAE signal processing and possible clinical applications of high-frequency DPOAE measurements.

Electromotive Triggering and Single Sweep Analysis of Vestibular Evoked Myogenic Potentials (VEMPs)

Cervical (c) and ocular (o) vestibular evoked myogenic potentials (VEMPs) provide important tools for measuring otolith function. However, two major drawbacks of this method are encountered in clinical practice. First, recording of oVEMPs is compromised by small n10 amplitudes. Second, VEMP analysis is currently based on the averaging technique, resulting in a loss of information compared to single sweep analysis. Here, we: 1) developed a novel electromotive trigger mechanism for evoking VEMPs by bone-conducted vibration to the forehead and 2) established maximum entropy extraction of complex wavelet transforms for calculation of phase synchronization between VEMP single sweeps. Both c- and oVEMPs were recorded for n=10 healthy individuals. The oVEMP n10 amplitude was consistently higher (right: 24.84±9.71 μV; left: 27.40±14.55 μV) than previously described. Stable VEMP signals were reached after a smaller number of head taps (oVEMPs 6; cVEMPs 11) compared to current recommendations. Phase synchronization vectors and phase shift values were successfully determined for simulated and clinically recorded VEMPs, providing information about the impact of noise and phase jitter on the VEMP signal. Thus, the proposed method constitutes an easy-to-use approach for the fast detection and analysis of VEMPs in clinical practice.