Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 13/19 Archiv

In this thesis, three aspects of downbeat nystagmus (DBN) were examined. First, changes of its intensity during daytime; second, an analysis of the underlying mechanisms, in particular, the modulation of otolith input; and third, the effects of a pharmacotherapy with potassium channel blockers 4-aminopyridine in comparison with 3,4-diaminopyridine. Downbeat nystagmus consists of ocular drifts upwards. These upward drifts cannot be deliberately controlled. As a correcting mechanism, the upward drifts are followed by downward saccades. Downbeat nystagmus is either due to lesions in the cerebellum, due to lesions to the brainstem or due to cryptogenic/idiopathic causes. In order to reduce symptoms effectively, it is of particular importance to increase our knowledge about DBN. In chapter 1 of this thesis it is shown that the intensity of DBN decreases during daytime. In chapter 2, it is demonstrated that resting positions have an influence on the extent of DBN. During daytime, where people are generally in upright body position, DBN decreases effectively when people remain upright during their resting periods, i.e. when people sit instead of lying down to rest. There is a possible reason why DBN in upright position significantly decreases when people rest upright. This could have been due to otoliths exerting a stabilizing influence on the central vestibular neurons of the patients while remaining upright for a continuous period. Moreover, it does not make a difference whether patients with DBN rest with the light switched on or with the light switched off. Chapters 1 and 2 also have implications for symptomatic treatment. It can be suggested to patients to rest in an upright position during the day, and to engage in activities such as reading or screen-related work in the afternoon rather than in the morning. In chapter 3, another way of symptom reduction is presented, where the aminopyridines 4-AP and 3,4-DAP are compared against each other. The efficacy of reducing DBN had previously been demonstrated individually for both aminopyridines. In this thesis, the efficacy of both aminopyridines was examined in a double-blind study with cross-over design. The major finding was that 4-AP is more effective than 3,4-DAP in terms of reducing the intensity of DBN. Moreover, 4-AP revealed a tentative trend towards a particular efficacy for cerebellar patients, which is in line with experimental evidence, where it had been reported to better cross the blood-brain barrier and to have at least the same (probably even a longer) half-life than 3,4-DAP. In conclusion, no causative treatment is in sight for DBN, but clinical studies can lead to a better understanding of DBN and may contribute to symptom alleviation.

Obwohl sich gleichermaßen für gerade und schräge VOIs eine erhebliche kraniokaudale Abnahme der vBMD nachweisen ließ, zeigten die geraden Implantatlager beider Geschlechter erheblich höhere absolute Dichtewerte. Wie zu erwarten war, fielen die vBMDs der männlichen VOIs höher aus, als die der weiblichen. Eine intraindividuelle Seitendifferenz ergab sich nicht. Vielmehr zeigte sich eine hohe bis sehr hohe Korrelation der Seiten, insbesondere für die geraden, männlichen Subzylinder. In der Analyse des Altersverlaufes zeigte sich für die Gesamtstichprobe und mehr noch für die männliche Untergruppe eine deutliche Abnahme der Knochendichte für beide VOIs. Es wurden auf dem Alter basierende Regressionsgleichungen generiert, die für die Gesamtstichprobe gute und für die männlichen Proben exzellente Bestimmtheitsmaße erreichten. Wider Erwarten ergab sich keine signifikante Altersabhängigkeit für die weiblichen Proben. In Zusammenschau der gewonnenen Erkenntnisse muss, bei isolierter Betrachtung des proximalen Implantatlagers, eine deutliche biomechanische Überlegenheit der geraden gegenüber den kranial gebogenen humeralen Marknägeln postuliert werden. Hinsichtlich des bekannten Einflusses der dreidimensionalen morphometrischen Struktur auf die mechanischen Eigenschaften des spongiösen Knochens empfiehlt sich die Untersuchung dieser und Korrelation mit den Daten aus der vorliegenden Studie. Ebenso erscheint eine ergänzende Untersuchung der Schraubenlager als Gegenstand zukünftiger Studien sinnvoll.

Epidemiological studies have shown that elevated air pollution levels and day-to-day variations in air temperature are associated with increases in cardiovascular events such as arrhythmias, myocardial infarctions, and sudden cardiac death. Precursors of these events might be acute changes in heart rate, a reduced heart rate variability (HRV), and changes in the repolarization of the heart, such as QTc-prolongation as well as changes in T-wave amplitude. Furthermore, elevated levels of blood markers of inflammation and coagulation might also lead to the observed adverse cardiac health outcomes. There is already a large body of literature with regard to air pollution effects on HRV parameters and blood markers but the exact biological pathways are still unclear. Little is known about the association between temperature and HRV as well as blood markers. Moreover, potential mechanisms how air pollutants and temperature affect repolarization have received less attention. Researchers have reported that individuals with genetic predispositions or underlying diseases such as diabetes mellitus type 2 might be more susceptible to air pollution exposure. Therefore, more comprehensive investigations in these groups of individuals are necessary in order to gain a better insight in the biological mechanisms. In the first publication of this thesis, I examined the effects of air temperature on markers of inflammation and coagulation in men with coronary or pulmonary disease. A temperature decrease was associated with changes in several blood biomarkers such as platelet counts, factor VII, fibrinogen, and C-reactive protein. However, the direction and timing of the relationship differed between patients with coronary and pulmonary disease. In a second publication, I observed a prolongation of the QT-interval in association with elevated levels of particulate matter (PM) in myocardial infarction survivors. This association was more pronounced in participants with at least one minor allele of the NFE2L2 single nucleotide polymorphism (SNP) rs2364725 which is believed to be involved in the defense against oxidative stress. Furthermore, I detected immediate T-wave flattening and delayed increases in T-wave amplitude associated with elevated air pollution levels. The association between temperature and the T-wave amplitude was inversely U-shaped with highest values at 5C. In a third study among participants with diabetes or impaired glucose tolerance (IGT), I detected reduced HRV, predominantly the standard deviation of normal-to-normal intervals, in association with increases in PM and ultrafine particles. These effects were more pronounced in participants with IGT. I also observed air pollution effect modifications by SNPs supposed to influence cardiac rhythm. In conclusion, this thesis confirms and extends published results on short-term air pollution effects on intermediate markers of cardiovascular system. Furthermore, it is among the first to examine air temperature effects on blood and ECG parameters. Certain medical conditions as well as certain genetic profiles seem to make some subpopulations more susceptible to environmental stressors. The observed changes in HRV and blood markers might partly explain the reported associations between environmental conditions and cardiovascular events.