Meniere's disease is a common inner ear disorder that affects balance and hearing. Electrovestibulography (EVestG) is a relatively new vestibular driven test that measures spontaneous and driven field potential activity recorded in the external ear canal in response to various vestibular stimuli. The main objectives of this thesis were to record and analyze EVestG signals in order to 1) testify whether the EVestG technology is capable of classifying individuals with Meniere’s from healthy ones, and if it is, then 2) identify the EVestG tilt stimulus providing the most informative response in relation to identifying Meniere’s symptoms; thus, optimizing the EVestG experimental protocol as a Meniere’s disease diagnostic aid. EVestG signals of two groups of Meniere’s and control individuals during seven different EVestG tilt stimuli were recorded and analyzed by linear and nonlinear signal processing techniques. Data of 14 with Meniere’s disease and 16 healthy individuals were used as the training set, while additional data of 21 individuals with vertiginous disorders (and suspected of Meniere’s disease) and 10 controls were used as the test set. An ad-hoc voting classifier built upon single-feature linear classifiers was designed, and used for classification of the two groups of both training and test datasets. The results showed an overall accuracy of 87% and 84% for training and test datasets, respectively. Among the seven different tilts that each evokes a specific part of the inner ear organ, the side tilt which stimulates most of the labyrinth and particularly the utricle, was found to generate the best characteristic features for identifying Meniere’s disease from controls. Thus, one may simplify the EVestG protocol to only the side tilt stimulus for a quick screening of Meniere’s disease. The proposed method encourages the use of EVestG technology as a non-invasive and potentially reliable diagnostic/screening tool to aid clinical diagnosis of Meniere’s diseases. / October 2016

Ménière's disease (MD) is a complex disorder of the inner ear characterized by the symptoms of hearing loss, tinnitus, and vertigo, with an incidence in Caucasians of one in 1000. The hallmark histopathologic feature of MD is endolymphatic hydrops. Symptoms of MD typically present in the fourth decade of life, and the vertigo attacks experienced by patients with MD can be debilitating. Treatments aimed at alleviating the symptoms of MD are ineffective in approximately 30% of patients. Several studies have attempted to identify genetic factors important in MD through the use of families segregating the disease, but causative genes have not been identified. Many of these studies have been unsuccessful due to the fact that families of sufficient size to generate meaningful linkage results are extremely rare. Attempts to identify a genetic component to MD through the use of candidate gene association studies have been underpowered or poorly designed and therefore also unsuccessful. We hypothesize Ménière's disease is a complex disorder that is due to the interplay of genetic and environmental factors. We tested this hypothesis using linkage and association studies. Initially, we focused on candidate gene replication association studies (KCNE1, KCNE3, iNOS), as well as testing a novel candidate gene (AQP4). We were unable to replicate the previous associations and although we could not identify an association between MD and AQP4 we did discover rare variants of AQP4 in our MD patient population. These variants segregate with a `syndromic' MD phenotype. We also performed a genome-wide linkage study on a large Chilean family segregating MD over three generations and identified a novel MD locus on 1q32.1-1q32.3. Targeted exon capture and pyrosequencing of the region identified two potential disease-causing variants in two genes of unknown function. We next screened a cohort of singleton patients with MD for variants in these same genes. Surprisingly, in both genes, we identified common and rare variants supporting a possible role for either gene in the development of MD. The function of these two genes is unknown. Our results imply that additional studies must be undertaken to determine whether one or both genes has a role in the pathogenesis of MD. Identification of a causative gene will aid in the understanding of disease pathophysiology and lead to improved treatments.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Diss. Stockholm : Karol. inst., 2002. / S. [1] -53: sammanfattning. s. 57-117: 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Cartilage Tissue Engineering. Joint pain and functional impairment due to cartilage damage from osteoarthritis and other means is a major source of disability for adults the world over. Cartilage is an avascular tissue with a very limited capacity for self repair. Current medical and surgical approaches to cartilage repair also have limited efficacy, and in all cases fail to completely restore a normal, healthy cartilage phenotype. Tissue engineering is a relatively new approach to cartilage repair that seeks to fabricate a replacement tissue, indistinguishable from healthy, native tissue. The basic idea of the tissue engineering approach is to seed tissue synthesizing cells into a shapeable, biocompatible/bioabsorbable scaffold that serves as a temporary extracellular matrix with a localized source of bioactive molecules to direct the development of new tissue. The challenge of tissue engineering is to identify cells, scaffolds, and growth conditions that will be optimal for tissue regeneration. The goal of the current studies was to evaluate one aspect of all three of the major components of cartilage tissue engineering: cell source, scaffolding material and preparation, and controlled growth factor delivery. We evaluated the chondrogenic potential of human nasal chondrocytes grown in calcium alginate in an in vivo culture system, the potential of computer-aided design and injection molding with calcium alginate to reliably reproduce complex geometries with high dimensional tolerances, and the potential for the controlled release of TGF-β1 from calcium alginate modified by the covalent addition of a recently discovered TGF-β binding peptide. We found that adult human nasal chondrocytes show significant chondrogenic potential when grown within an alginate scaffold. We also found that alginate is readily amenable to an injection molding process that utilizes precision made molds from computer-aided design and solid free form fabrication, allowing for the fabrication of tissue engineered constructs with very precise shape fidelity. Additionally, we found that calcium alginate could be reliably modified by the covalent addition of peptides, and that the addition of a newly discovered TGF-β binding peptide delayed the release of pre-loaded TGF-β1. Together these results show some of the encouraging prospects for cartilage tissue engineering. `Menière’s Syndrome.Menière’s syndrome is an inner ear disorder characterized by idiopathic endolymphatic hydrops with associated periodic tinnitus, vertigo, and progressive sensorineural hearing loss. It affects approximately 0.2% of the population, for whom it can be quite devastating. In addition to progressive hearing loss people with Menière’s syndrome are prone to sudden attacks of vertigo and tinnitus that are severe enough that they can lead to falls and potentially serious injury. People subject to frequent attacks are unable to drive, with obvious consequences on standard of living. In the current studies we evaluated the standard animal model of Menière’s syndrome by comparing cochlear turn specific hearing thresholds and the degree of hydrops in that turn. A positive correlation between these had previously been established in the study of human temporal bones from people with Menière’s syndrome, but had not been reported in the animal model. We also evaluated the potential of aminoguanidine, a relatively specific inhibitor of the inducible isoform of nitric oxide synthase, as a neuroprotective therapeutic agent for preservation of hearing in animals with surgically induced endolymphatic hydrops. We found, for the first time, a partial correlation between cochlear turn specific hydrops and hearing thresholds in the most commonly used animal model of Menière’s syndrome, helping to validate the utility of this animal model for future studies. We also found that aminoguanidine did indeed partially preserve hearing in animals with surgically induced Menière’s syndrome. This encouraging result appears to be the first report of a medical intervention protective against hearing loss in an animal model of Menière’s syndrome, and may help us to understand the etiology pathology seen in Menière’s syndrome.

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