Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder with multiple features caused by hypothalamic deficiency, including infantile failure to thrive, hyperphagia leading to obesity, growth hormone deficiency, hypogonadism, and central adrenal insufficiency. Other features of PWS including global developmental delay, hypotonia, pain insensitivity, gastrointestinal dysfunction, and psychiatric disorders are caused by deficits in other regions of the nervous system. PWS is caused by the loss of a subset of paternally-expressed genes on chromosome 15, which includes NDN and MAGEL2. Necdin and Magel2 are both members of the melanoma antigen (MAGE) family of proteins and are expressed throughout development, particularly in the nervous system. This thesis describes experiments that examine the loss of function of necdin and Magel2 in mice and their potential roles in the pathogenesis of PWS. Targeted inactivation of Ndn and Magel2 in mice has aided in determining how loss of function of these proteins affects the development and function of the nervous system. Loss of necdin causes reduced axonal outgrowth and neuronal differentiation in the central and peripheral sensory nervous systems. I examined the autonomic nervous system in Ndn-null embryos and identified a defect in the migration of the most rostral sympathetic chain ganglion and consequently increased neuronal cell death and reduced innervation of target tissues supplied by this ganglion. Reduced axonal outgrowth was observed throughout the sympathetic nervous system in Ndn-null embryos although no gross deficits in the parasympathetic and enteric nervous systems were identified. Loss of Magel2 causes reduced fertility and abnormal circadian rhythm patterns in mice. I further identified an altered response to stress, a delayed response to insulin-induced hypoglycemia, a reduced stimulated growth hormone response, and lower thyroid hormone levels in Magel2-null mice, indicative of deficits in multiple hypothalamic-pituitary axes. The findings presented in this thesis support a role for necdin and Magel2 in the development and function of the nervous system. The data also indicates that these MAGE proteins play a key role in multiple features of PWS, including endocrine deficiencies and autonomic dysfunction

Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 133-143). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 133-143). Also available on the Internet.

Heart rate is tonically regulated by the two branches of the autonomic nervous system (ANS); parasympathetic activation decreases heart rate while sympathetic activation increases it. Previous studies on the ANS in chickens have focused mainly on embryonic development, but it is largely unknown what happens in the weeks following hatching. The present study focused on the development of the autonomic nervous system in 2 and 5 week old broiler and Red Junglefowl (RJF). Since broilers are less fearful, less stressed and less active than their wild ancestor RJF, a possible domestication effect on the sympathetic nervous system was investigated by evaluating both physiological and behavioural responses during stress. I found that the heart is mainly under control from the sympathetic nervous system in 2 and 5 week old broiler and RJF as propranolol significantly decreased heart rate during baseline and stress conditions while injection of atropine had little or no effect on baseline heart rates. When the adrenergic tone was blocked, heart rate still increased during stress, more so in 5 week old birds than in 2 week old birds. This suggests that some other physiological regulatory mechanism with fast recruitment is involved in the stress response and it matures in the weeks following hatch. No differences in behaviour between broiler and RJF were observed when the sympathetic nervous system was blocked. As both breeds show similar responses, a domestication effect on the ANS from these results cannot be confirmed.

In most adult animals, stress is generally thought to be detrimental to reproductive (sexual) function. However, in humans, there is a limited body of literature that indicates some stress can potentially be beneficial for sexual function. One theory is that there is an inverted U relationship between stress and sexual function with low and high levels of stress (or anxiety) causing an impairment of sexual response, while a moderate level of stress facilitates sexual arousal. This aim of this dissertation is to identify the mechanisms through which both acute and chronic stress may facilitate or impair sexual arousal in women. In particular, I examined the role of adrenal hormones, the autonomic nervous system (ANS), and psychological factors. To test these mechanisms, I measured cortisol, dehydroepiandrosterone sulfate (DHEAS), heart rate, distraction, and misattribution of arousal during stressful and sexual laboratory situations. Two of the studies examined the effects of acute stress, and the final study focused on chronic stress. Results indicated that acute stress is beneficial for genital arousal in women, and that the sympathetic branch of the ANS is the key mechanism involved in that relationship. High levels of chronic stress were found to significantly impair genital arousal compared to average levels of chronic stress. Increased levels of cortisol and distractions contributed to this effect. DHEAS did not appear to play a role in the relationship between stress and sexual arousal, and there was no evidence for misattribution of arousal. Neither acute nor chronic stress affected women’s subjective (psychological) arousal. Acute and chronic stressors affect sexual arousal in different ways and through separate mechanisms. The findings from these studies can inform treatment approaches for women with sexual arousal difficulties. / text

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The first chapter of this thesis consists in a critical review of the literature on cardiac and cardiac-related autonomic activity, and infant development. Empirical findings are presented on mechanisms of interaction between heart rate and the autonomic nervous system; their relationship with infant development; their genetic and environmental influences; their gender effects; and related quantification issues. / This is followed by a study of 322 5-month-old twin pairs that investigated the genetic and environmental influences on sleeping heart rate and cardiac-related autonomic activity, as indexed by spectral analysis of heart rate variability and response to postural change. The postural change elicited only minor changes in cardiovascular activity, perhaps due to immaturity of the baroreflex. As a result, analyses focused on supine cardiovascular activity. Multivariate genetic modeling indicated that individual differences in sleeping HR and high frequency HR variability were determined by unique environmental and distinct additive genetic factors. These variables, along with low frequency HR variability, were also affected by overlapping familial environmental influences. Familial influences on individual differences in high frequency HR variability were more pronounced for baby girls than boys. Estimates of relative low and high frequency HR variability were determined by common (familial) and unique environmental factors; familial influences on these estimates of HR variability did not overlap with familial influences on sleeping HR. / A second study using the same twin sample is then presented. Its objectives were to investigate the indices of genetic and environmental etiology of individual differences in five month-old twins' HR reactivity and to evaluate the possible overlap, if any, between the familial influences on HR in states of sleep and reactivity. Multivariate genetic modeling showed that the total variance of individual differences was decomposed in the following manner: Sleeping and awake HR were under the influence of shared additive genetic factors; sleeping HR also shared common environmental influences with the absolute power spectrum values; and absolute high frequency power additionally had phenotype-specific additive genetic factors influencing its expression. Relative power spectrum values were under the influence of phenotype-specific common environmental factors. / Overall, these results suggest the presence of important familial (genetic and environmental) influences on heart rate and cardiac-related autonomic activity at five months of age: There is an absence of overlap of these (familial) additive genetic influences but the presence of a partial overlap of the (familial) environmental influences.

Introduction Heart rate variability (HRV) is regarded as a useful, non-invasive method for investigating the autonomic nervous system (ANS). Over the past decade there has been an increase in the number of HRV investigations in the disciplines of medical, sport and exercise science. Despite the extensive use of HRV in investigations of ANS functioning, there are questions relating to the reliability of the technique. Therefore, HRV reliability studies for different population groups have been advocated. Furthermore, research on gender differences in HRV is contradictory. This has resulted in the need to investigate gender characteristics in HRV. Objectives The objective of this study was to evaluate the reliability of short-term (5min) recordings of HRV, and to determine the association between HRV and gender. Methods Forty four physically active students (n= 21, age= 21.17 (1.55) males and n=23, age= 19.75 (1.76) females) participated in the study. Heart rate variability parameters were determined from five minute recording of interbeat intervals (IBI) using a Suunto t6 heart rate monitor (HRM). Testing was repeated over 4 consecutive days under the same conditions. The following HRV time and frequency domain measures were calculated using Kubios HRV Software Version 2.0: mean heart rate (HR), standard deviation of normal to normal intervals (SDNN), root mean square of successive differences (RMSSD), percentage of beats that changed more than 50 ms from the previous beat (pNN50), low frequency in normalized units (LFnu), high frequency in normalized units (HFnu) and low frequency to high frequency ratio in normalized units (LF/HFnu ratio). The data was summarized using routine descriptive statistics. Relative reliability was calculated using interclass correlation coefficients (ICC) (ICC of >0.80 indicated good to excellent reliability) and absolute reliability using typical error of measurement (TEM) and TEM as a percentage of the mean score (TEM%). This statistical measures were computed for days 2 vs 3 (REL 1), 3 vs 4 (REL 2). Day 1 was used as a familiarization day. An unpaired T-test was used to determine whether there were any differences between males and females for the above HRV parameters. Significance was set at p .0.05. Results The ICCs for both REL 1 and REL 2 indicated good to excellent (ICC >0.8) reliability for IBIs and pNN50 for the time domain results. In general, the time domain results had a higher relative reliability than the frequency domain results. Males had an overall lower relative reliability than females for frequency domain parameters. Absolute reliability for REL 2 showed a slightly lower TEM value as compared to REL 1.The largest gender differences in TEM were seen in the frequency domain parameters. Specifically, for males, the TEM was higher than females for the LF/HFnu ratio (REL 2: 116%), the HFnu (REL 1: 90%) and the LFnu (REL 1: 68%). Overall the TEM% was relatively high in most HRV parameters specifically for LF/HFnu (REL 1: 31.4% females and 48.1% males; REL 2: 29.7% females and 40.4% males). These findings indicate that males have decreased absolute reliability compared to females and that random error is greater in men for the frequency domain parameters. Gender differences illustrated significant differences for resting HR (16% higher in females (p < 0.0001)), IBIs (21% higher in females (p <0.0001)) and LF/HFnu ratio (41% higher in males (p = 0.003)). The findings indicate that females have higher total HRV. Conclusions Short term recordings of HRV over consecutive days using the Suunto t6 HRM and Kubios custom HRV software are reliable depending on the HRV parameter being analysed. Overall, the relative reliability results suggest that HRV using the Suunto t6 and Kubios is good. However, the absolute reliability results suggest low reliability. In particular, males demonstrated a poorer absolute reliability (high TEM and TEM%) than females, suggesting a larger day to day random error in males. Furthermore, specific HRV measures differed between males and females demonstrating that females have higher parasympathetic modulation compared to men. The overall higher HRV in females could explain the possible cardio-protective mechanism observed in premenopausal women. Key words: Heart rate variability, Parasympathetic, Reliability, Interbeat Intervals / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2011.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Eine Dysregulation neuro-immunologischer Interaktionen und eine veränderte Stressantwort werden als Teil der Pathogenese der Rheumatoiden Arthrtitis (RA) diskutiert. Dabei könnte eine autonome Dysfunktion eine wichtige Rolle spielen. Um dem nachzugehen, wurde an Patienten mit unterschiedlicher Krankheitsaktivität die Aktivität des autonomen Nervensystems in Ruhe und in Reaktion auf minor Stress sowie erstmals deren Assoziation zu Gen-Polymorphismen β2- adrenerger Rezeptoren (β2ARs), welche sich u.a. auf Immunzellen befinden, untersucht. Zur Bestimmung autonomer Aktivität wurde an 112 RA- und 48 Osteoarthrose-Patienten die sympathische Hautantwort (SSR) sowie die Herzratenvariabilität (HRV) getestet. Standardisierte Stresstests kamen zur Anwendung. Eine Allel-spezifische Polymerase-Ketten-Reaktion diente zur Ermittlung der Varianten des β2ARs an Aminosäureposition 16, 27 und 164. Es konnte gezeigt werden, dass die autonome Aktivität bei RA in Ruhe durch eine signifikant erhöhte Herzfrequenz, ein Überwiegen des Sympathikus im Verhältnis zum Parasympathikus sowie eine signifikant erniedrigte Parasympathikusaktivität gekennzeichnet ist. Die Stressantwort bei RA war signifikant häufiger pathologisch als bei der Kontrollgruppe und durch signifikante Hypoaktivität und Hyporeaktivität des Parasympathikus sowie eine signifikant erniedrigte HRV charakterisiert. Das Zusammenspiel beider Schenkel des ANS erschien gestört. Die SSR-Werte befanden sich im Normbereich. Schlechtere Werte waren jedoch signifikant mit hohem CRP assoziiert. Desweiteren war Heterozygotie an allen Gen-Positionen der β2ARs signifikant mit RA assoziiert. Gln27Gln (signifikant häufiger für Gesunde) ging mit signifikant niedrigerer Krankheitsaktivität einher. Starkes Überwiegen des SNS in Ruhe sowie niedrige parasympathische Aktivität (HRV-Daten) waren signifikant mit hoher Krankheitsaktivität assoziiert. Zusammenfassend weist die vorliegende Arbeit auf eine autonome Dysregulation bei Patienten mit RA hin, was mit klinischen Parametern der RA assoziiert war. Weiterhin unterstreicht die Studie die Assoziation von β2AR Polymorphismen mit einer RA und liefert einen weiteren Beitrag zum Verständnis der Pathogenese dieser Erkrankung.