39 research outputs found
Novel clinical and etiopathogenetic findings in Pseudoxanthoma elasticum
Soft tissue calcification in the human body can be considered part of a process of continuous degeneration which we tend to designate as “aging”. Being an example of technological wit and superb bio-engineering second to none, even the decay of this corpus can
hardly be considered a random or passive event. On the contrary, calcium precipitation is regulated quite tightly by an intruiging interplay between stimulatory proteins and inhibitory factors. Thus, it has been foreseen man not to be turned into a chalk pillar in his prime years, but
rather to endure a much slower process of gradual mineralization. But when this brilliant regulatory opus starts failing, the reign of human pathology is entered, confronting the body with ectopic mineralization disorders.
One of the archetypes of such disease is pseudoxanthoma elasticum or PXE, in which ectopic mineralization of elastic fibres causes skin, ocular and cardiovascular complications. Despite its identification more than two centuries ago, PXE has – as many genetic disorders – always been surrounded by a haze of mystery. It is the aim of this thesis to contribute to the clinical, molecular and histopathological
characterization of this fascinating disease.
Through careful characterization of the PXE patient cohort followed at the Ghent Center for Medical Genetics, we were able to emphasize important clinical features, such as stroke and peripheral artery disease, as well as identifying novel phenotypical features in patients and carriers, among which were abdominal calcifications and testicular microlithiasis. Also the question of a limited or subclinical phenotype in PXE carriers was addressed and we showed them to be more prone to cardiovascular disease, next to limited ophthalmological symptoms
represented by comets and comet tails.
In an exploratory pilot study among over 200 consecutive ischemic stroke patients, ABCC6 hotspot analysis yielded a significant increase in ABCC6 mutations compared to a healthy reference population. This signified another example of heterozygous carriers being prone to cardiovascular and/or cerebrovascular disease and introduced the ABCC6 gene in stroke research.
In single and multi-center studies, this thesis contributed to the characterization and expansion of the ABCC6 mutation spectrum, as well as the exclusion of genotype-phenotype correlations. The applied molecular strategy for mutation analysis of the ABCC6 gene proved to
be an efficient and cost-effective method, yielding the highest mutation detection rate so far. Also, the continuous discussion on the mode of inheritance and in particular the existence of an autosomal dominant form of PXE could be addressed constructively.
Throughout the clinical follow-up of PXE patients, we applied novel fundus imaging techniques, such as autofluorescence and infrared imaging, with substantial improvement of the diagnostic capacities of limited or subtle lesions in fundo. Through collaborative efforts, the
importance of electrophysiological abnormalities – subdivided in three retinopathy phenotypes – was brought to attention.
Within the span of this PhD thesis, a novel phenotype was identified and characterized both clinically and molecularly. This novel autosomal recessive disorder was coined the PXE-like syndrome, because of its resemblance with classic PXE, and was proven to be caused by
mutations in the GGCX gene. Encoding the gamma-carboxylase, an enzyme important in the vitamin K (VK)-cycle, this observation implicated VK and proteins depending on this vitamin – among which are several inhibitors of mineralization – in the pathogenesis of the PXE-like syndrome and hence PXE.
Through various immunohistochemical and ELISA methods, VK-dependent inhibitors of calcification were shown to be inactive or defective in these syndromes, leading to ectopic mineralization in the PXE-like syndrome but also in PXE patients. These observations could be attributed to the GGCX mutations in the PXE-like syndrome. The observation of extremely low VK serum levels – an essential co-factor for protein carboxylation in the VK-cycle – in PXE patients explained why the VK-cycle is defective in PXE. The exact link with the impaired ABCC6 transporter remains unclear, although it is tempting to think of VK or one of its associated molecules as the substrate of ABCC6. Also, these findings hold out the prospect of VK suppletion as a treatment for PXE.
As such, the findings summarized in this thesis have elaborated the clinical and molecular knowledge of PXE and related disorders, and have opened novel avenues for further fundamental and applied research in the field of ectopic mineralization. Above all, they have
benefitted patients and their family though a more efficient molecular diagnosis, a more to-the- point follow-up and the prospect of a treatment for their burdensome disease
Revolutionary Intoxications: Theory of the Avant-garde in the Aesthetics of Nietzsche and Benjamin
This thesis considers the relation between concepts of intoxication and of the avant-garde in some nineteenth and twentieth-century aesthetics. It argues that intoxication serves as a formulation of revolt alternative to those strategies of the avant-garde which result in increasingly rigidified cycles of antagonism and recuperation and the failure to effect social or institutional change. The ultimate interdependency of avant-garde and establishment makes it necessary to formulate alternative assessments of the way in which cultural agency may operate.
The argument takes the origin of the artistic avant-garde in the 1830s as intensifying opposition to bourgeois political conservatism insofar as it considers social progress as determined by scientific rationalism and manifested by the proliferation of commodities. Coinciding with the first socialist appeals to an artistic avant-garde, the claim of art's diminishing significance made by G.W.E Hegel in his Aesthetics is here held to be the symptom of a crisis in a sense of purpose that leads artists and writers towards new formulations of relevance along political lines. The extremes of aesthetic detachment and militant ecstasy in Charles Baudelaire's poetry and the acclamation of differing concepts of intoxication in Friedrich Nietzsche's aesthetics redefine this purpose as subversive thought intended to conclusively uproot delusory humanist prejudices which are stalling radical change in the nineteenth century.
Walter Benjamin's writing on Baudelaire, hashish, Surrealism, and the conditions for culture in the Soviet Union are pivotal in this thesis for discussing intoxication as it functions in cultural revolt, historically considered indispensable for the success of organised revolution. It is argued here that an alternative approach to assessing revolt lies in the subversiveness of ecstatic language and thought whose delicacy and indeterminacy persistently open up possibilities that conventional formulations of progress or revolution occlude
Broadcast speech and the effect of voice quality on the listener : a study of the various components which categorise listener perception by vocal characteristics.
Voice quality is crucial to the art of the broadcast speaker. Acceptable voice
quality is a necessity for an acceptable microphone voice and essential therefore for
employment as a broadcaster. This thesis investigates the characteristics of the
voice which provide that acceptability; and categorises the features which lead the
listener to make judgements about their vocal likes and dislikes. These subjective
judgements are explored by investigating the psychological, medical, and innate
features contributing to the vocal perceptions of the listener. Voice quality is
related to the efficiency of the larynx and its importance to voice production; and
to the various vocal disorders which can affect the broadcaster.
It becomes evident throughout the thesis that each listener receives a clear
impression of the personality of the speaker through the features present in the
voice. Many of these impressions however are based on stereotypes. The thesis
relates these stereotypical judgements to accents, investigating their relationship to
the 'BBC' voice, the 'World Service' voice, the 'ILR' voice and the 'reporter's
voice' . It is shown that the listener's subjective impression of the voice and the
broadcaster personality is formed by the presentational and physical aspects of voice
quality.
Listener perceptions of voice acceptability are tested and discussed. The data is
analysed to provide a set of dominant characteristics from which are drawn voice
histograms and frequency polygons.
The result is a set of preferred voice characteristics which apply specifically to the
broadcast speaker and which can be sought during the selection process
Listening to Distances and Hearing Shapes:Inverse Problems in Room Acoustics and Beyond
A central theme of this thesis is using echoes to achieve useful, interesting, and sometimes surprising results. One should have no doubts about the echoes' constructive potential; it is, after all, demonstrated masterfully by Nature. Just think about the bat's intriguing ability to navigate in unknown spaces and hunt for insects by listening to echoes of its calls, or about similar (albeit less well-known) abilities of toothed whales, some birds, shrews, and ultimately people. We show that, perhaps contrary to conventional wisdom, multipath propagation resulting from echoes is our friend. When we think about it the right way, it reveals essential geometric information about the sources--channel--receivers system. The key idea is to think of echoes as being more than just delayed and attenuated peaks in 1D impulse responses; they are actually additional sources with their corresponding 3D locations. This transformation allows us to forget about the abstract \emph{room}, and to replace it by more familiar \emph{point sets}. We can then engage the powerful machinery of Euclidean distance geometry. A problem that always arises is that we do not know \emph{a priori} the matching between the peaks and the points in space, and solving the inverse problem is achieved by \emph{echo sorting}---a tool we developed for learning correct labelings of echoes. This has applications beyond acoustics, whenever one deals with waves and reflections, or more generally, time-of-flight measurements. Equipped with this perspective, we first address the ``Can one hear the shape of a room?'' question, and we answer it with a qualified ``yes''. Even a single impulse response uniquely describes a convex polyhedral room, whereas a more practical algorithm to reconstruct the room's geometry uses only first-order echoes and a few microphones. Next, we show how different problems of localization benefit from echoes. The first one is multiple indoor sound source localization. Assuming the room is known, we show that discretizing the Helmholtz equation yields a system of sparse reconstruction problems linked by the common sparsity pattern. By exploiting the full bandwidth of the sources, we show that it is possible to localize multiple unknown sound sources using only a single microphone. We then look at indoor localization with known pulses from the geometric echo perspective introduced previously. Echo sorting enables localization in non-convex rooms without a line-of-sight path, and localization with a single omni-directional sensor, which is impossible without echoes. A closely related problem is microphone position calibration; we show that echoes can help even without assuming that the room is known. Using echoes, we can localize arbitrary numbers of microphones at unknown locations in an unknown room using only one source at an unknown location---for example a finger snap---and get the room's geometry as a byproduct. Our study of source localization outgrew the initial form factor when we looked at source localization with spherical microphone arrays. Spherical signals appear well beyond spherical microphone arrays; for example, any signal defined on Earth's surface lives on a sphere. This resulted in the first slight departure from the main theme: We develop the theory and algorithms for sampling sparse signals on the sphere using finite rate-of-innovation principles and apply it to various signal processing problems on the sphere