Through a series of original research articles, this thesis explores the characteristics of autonomic cardiac regulation and respiratory function during sleep in association with depression and antidepressant medication use and validates a novel diagnostic biomarker of depression. Cardiorespiratory dysfunction during sleep may contribute to the increased risk of developing cardiovascular disease amongst individuals with depression. Sleep represents a unique physiological state shielded from many external confounding factors and may be a more relevant window to observe the effects of depression on cardiorespiratory function. In a first study, we found that depression was associated with abnormal autonomic modulation of cardiac activity during sleep. Specifically, depression was associated with reduced heart rate variability compared to healthy controls, and this difference was most prominent during sleep as compared to wake, which may indicate impairments in the parasympathetic modulation of the cardiac sinoatrial node. Secondly, we validated a machine-learning algorithm that uses patterns of heart rate during sleep to identify depression. This algorithm was found to have 79.9% classification accuracy, based on the differences in autonomic modulation associated with distinct mental states. The algorithm was highly generalizable across different depression subgroups and thus may be useful as an adjunct diagnostic tool. Finally, we found that the use of antidepressants, particularly serotonergic agents, was associated with worse sleep-related respiratory disturbances compared to non-medicated individuals with depression and those using non-serotonergic antidepressants. We proposed that depression-related alterations in serotonin receptor expression and binding may shape the response of the respiratory system to the use of serotonergic agents. Considering the high comorbidity between depression and sleep-related breathing disturbances and their impact on cardiovascular health, this has great clinical implications for the management of depression. Taken together, these results show that depression is associated with several sleep-related abnormalities in terms of cardiorespiratory function, which may represent a valid biomarker of depression.

by Phillip Y.P. Jen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 97-110). / Abstract --- p.iii / Acknowledgements --- p.x / Chapter 1. --- Review of literature --- p.1 / Chapter 2. --- Materials and Methods --- p.8 / Chapter 2.1 --- Collection and preparation of tissues --- p.8 / Chapter 2.2 --- Immunofluorescence --- p.9 / Chapter 3. --- Results --- p.15 / Chapter 3.1 --- Urinary bladder --- p.15 / Chapter 3.1.1 --- Bladder detrusor muscle --- p.15 / Chapter 3.1.2 --- Intramural ureters and superficial trigone --- p.17 / Chapter 3.1.3 --- Bladder mucosa --- p.19 / Chapter 3.1.4 --- The bladder neck --- p.20 / Chapter 3.2 --- Vas deferens and seminal vesicle --- p.22 / Chapter 3.2.1 --- The smooth muscle coat --- p.30 / Chapter 3.2.2 --- The mucosa --- p.24 / Chapter 3.3 --- Prostate --- p.26 / Chapter 3.4 --- Urethra --- p.30 / Chapter 3.4.1 --- Rhabdosphincter --- p.31 / Chapter 3.4.2 --- Smooth muscle coat and lamina propria --- p.32 / Chapter 3.5 --- Autonomic ganglia and paraganglia --- p.34 / Chapter 4. --- Discussion --- p.70 / Chapter 4.1 --- Urinary bladder --- p.70 / Chapter 4.2 --- Vas deferens & seminal vesicle --- p.81 / Chapter 4.3 --- Prostate --- p.84 / Chapter 4.4 --- Autonomic ganglia --- p.87 / Chapter 5. --- Suggestions for further study --- p.93 / Chapter 6. --- References --- p.101

Chow Tsun Cheung, Louis. / "May 2000." / Thesis (M.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Philip Y.P. Jen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (p. 94-111). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-09-05T17:40:12Z No. of bitstreams: 1 BrunaMagalhaes.pdf: 1619365 bytes, checksum: 8e85fa3f4e5169afc1c5134549e5f9ed (MD5) / Made available in DSpace on 2017-09-05T17:40:12Z (GMT). No. of bitstreams: 1 BrunaMagalhaes.pdf: 1619365 bytes, checksum: 8e85fa3f4e5169afc1c5134549e5f9ed (MD5) Previous issue date: 2017-05-10 / Introduction: PPAR-γ 2 is a nuclear receptor that differentiates adipocytes, adequately stores lipids and attenuates hypertension. The PPAR - γ 2 Pro 12 Ala gene polymorphism reduces the activity of this receptor by up to 50%. Therefore, this polymorphism has been associated with obesity, arterial hypertension and other cardiovascular diseases. Since hypertension and obesity provide autonomic imbalance, it is not yet known if this genetic mutation can be associated with an increase in sympathetic nervous expression in obesity and Other autonomic modular changes. Objective: To analyze the influence of PPAR-γ 2 Pro12 Ala gene polymorphism on the anthropometric, hemodynamic and autonomic parameters of obese adolescents. Materials and methods: A cross-sectional study was carried out in São Luís, Brazil, with 95 adolescents between 11 and 19 years of age, divided into groups of eutrophic (GE), obese (GO) and obese with polymorphism (GOP). The measurements of height, weight, BMI,% of fat, BP and sexual maturation were obtained. Heart rate data were also collected through the ECG for the autoregressive analysis of heart rate variability, considering the variables SDNN, RMSSD, LF and HF (ms and n.u), in addition to the LF / HF index. The identification of the polymorphism was examined By genotyping for Pro12Ala using the Restriction Fragment Polymorphism - Polymerase Chain Reaction (PCR - RFLP). ANOVA was used to compare the groups. Results: The genotype frequency corresponded to Pro / Pro 81%, Pro / Ala 16%. Pro allelic frequency was 90% and Ala was 9%. Variables that were significantly increased in GOP compared to GE (p <0.05 ) Were: body weight (61.3 kg vs.47.5 kg), waist circumference (74.4 cm vs.63.7 cm) and fat mass% (25.6% vs.18.6%) . Significantly higher values of GO were compared with SBP (113.7 mmHg vs.104.5 mmHg), DBP (66.0 mmHg vs.60.2 mmHg), LF n.u (50.56 n.u vs. .38.71 n.u), HF% (49.46 n.u vs..61.29 n.u) and LF / HF index (1.13 vs.0.68). Conclusion: Obesity is an independent condition for autonomic modulation alterations, since the polymorphism of the Pro 12 Ala gene did not influence the anthropometric, hemodynamic and autonomic alterations of obese adolescents. / Introdução: O PPAR-γ 2 é um receptor nuclear que diferencia os adipócitos, armazena adequadamente os lipídios e atenua da hipertensão. O polimorfismo do gene Pro 12 Ala do PPAR - γ 2 reduz a atividade deste receptor em até 50%. Por isso, este polimorfismo tem sido associado a obesidade, hipertensão arterial e demais doenças cardiovasculares.Uma vez que a hipertensão e a obesidade proporcionam o desequilíbrio autonômico ainda não se sabe se esta mutação genética pode está associada ao aumento da expressão nervosa simpática na obesidade e demais alterações modulares autonômicas. Objetivo: Analisar a influência do polimorfismo do gene Pro12 Ala do PPAR- γ 2 sobre os parâmetros antropométricos, hemodinâmicos e autonômicos de adolescentes obesos. Materiais e métodos: É um estudo transversal, realizado em São Luís, com 95 adolescentes entre 11 e 19 anos de ambos os sexos divididos em grupos de adolescentes eutróficos (GE), obesos(GO) e obesos com polimorfismo(GOP), em que foram obtidas as medidas de altura, peso, IMC, % de gordura, PA e maturação sexual. Foi também coletado dado da frequência cardíaca através do ECG para análise auto-regressiva da variabilidade da frequência cardíaca, considerando as variáveis SDNN, RMSSD, LF e HF (ms e n.u), além do índice LF/HF.A identificação do polimorfismo foi examinada por genotipagem para Pro12Ala usando o Fragmento de Restrição Polimorfismo - Polimerase Reação em Cadeia (PCR – RFLP). Para comparação dos grupos adotou-se o teste ANOVA. Resultados: A frequência genotípica correspondeu a Pro/Pro 81%,Pro/Ala 16%.Frequência alélica de Pro foi de 90% e Ala de 9%.As variáveis que estavam significativamente aumentadas no GOP comparado ao GE (p< 0,05) foram: peso corporal (61,3 kg vs.47,5 kg),circunferência da cintura (74,4 cm vs.63,7 cm) e % de massa gorda (25,6% vs.18,6%).Os valores significativamente maiores de GO em comparação ao GE foram em: PAS (113,7 mmHg vs.104,5 mmHg), PAD (66,0 mmHg vs.60,2 mmHg), LF n.u (50,56 n.u vs.38,71 n.u), HF n.u (49,46 n.u vs.61,29 n.u) e índice LF/HF (1,13 vs.0,68). Conclusão: a obesidade é uma condição independente para alterações da modulação autonômica, pois o polimorfismo do gene Pro 12 Ala não influenciou nas alterações antropométricas, hemodinâmicas e autonômicas de adolescentes obesos.

Doctor of Philosophy (PhD) / Little is known about the role that tachykinins, such as substance P and its receptor, the neurokinin-1 receptor, play in the generation of sympathetic nerve activity and the integration within the ventrolateral medulla (VLM) of many vital autonomic reflexes such as the baroreflex, chemoreflex, somato-sympathetic reflex, and the regulation of cerebral blood flow. The studies described in this thesis investigate these autonomic functions and the role of tachykinins through physiological (response to hypercapnoea, chapter 3), anatomical (neurokinin-1 receptor immunohistochemistry, chapter 4) and microinjection (neurokinin-1 receptor activation and blockade, chapters 5 and 6) experiments. In the first series of experiments (chapter 3) the effects of chemoreceptor activation with hyperoxic hypercapnoea (5%, 10% or 15% CO2 in O2) on splanchnic sympathetic nerve activity and sympathetic reflexes such as the baroreflex and somato-sympathetic reflex were examined in anaesthetized rats. Hypercapnoea resulted in sympatho-excitation in all groups and a small increase in arterial blood pressure in the 10 % CO2 group. Phrenic nerve amplitude and phrenic frequency were also increased, with the frequency adapting back to baseline during the CO2 exposure. Hypercapnoea selectively attenuated (5% CO2) or abolished (10% and 15% CO2) the somato-sympathetic reflex while leaving the baroreflex unaffected. This selective inhibition of the somato-sympathetic reflex while leaving the baroreflex unaffected was also seen following neurokinin-1 receptor activation in the rostral ventrolateral medulla (RVLM) (see below). Microinjection of substance P analogues into the RVLM results in a pressor response, however the anatomical basis for this response is unknown. In the second series of experiments (chapter 4), the distribution of the neurokinin-1 receptor in the RVLM was investigated in relation to catecholaminergic (putative sympatho-excitatory “C1”) and bulbospinal neurons. The neurokinin-1 receptor was demonstrated on a small percentage (5.3%) of C1 neurons, and a small percentage (4.7%) of RVLM C1 neurons also receive close appositions from neurokinin-1 receptor immunoreactive terminals. This provides a mechanism for the pressor response seen with RVLM microinjection of substance P analogues. Neurokinin-1 receptor immunoreactivity was also seen a region overlapping the preBötzinger complex (the putative respiratory rhythm generation region), however at this level a large percentage of these neurons are bulbospinal, contradicting previous work suggesting that the neurokinin-1 receptor is an exclusive anatomical marker for the propriobulbar rhythm generating neurons of the preBötzinger complex. The third series of experiments (chapter 5) investigated the effects of neurokinin-1 receptor activation and blockade in the RVLM on splanchnic sympathetic nerve activity, arterial blood pressure, and autonomic reflexes such as the baroreflex, somato-sympathetic reflex, and sympathetic chemoreflex. Activation of RVLM neurokinin-1 receptors resulted in sympatho-excitation, a pressor response, and abolition of phrenic nerve activity, all of which were blocked by RVLM pre-treatment with a neurokinin-1 receptor antagonist. As seen with hypercapnoea, RVLM neurokinin-1 receptor activation significantly attenuated the somato-sympathetic reflex but did not affect the sympathetic baroreflex. Further, blockade of RVLM neurokinin-1 receptors significantly attenuated the sympathetic chemoreflex, suggesting a role for RVLM substance P release in this pathway. The fourth series of experiments (chapter 6) investigated the role of neurokinin-1 receptors in the RVLM, caudal ventrolateral medulla (CVLM), and nucleus tractus solitarius (NTS) on regional cerebral blood flow (rCBF) and tail blood flow (TBF). Activation of RVLM neurokinin-1 receptors increased rCBF associated with a decrease in cerebral vascular resistance (CVR). Activation of CVLM neurokinin-1 receptors decreased rCBF, however no change in CVR was seen. In the NTS, activation of neurokinin-1 receptors resulted in a biphasic response in both arterial blood pressure and rCBF, but no significant change in CVR. These findings suggest that in the RVLM substance P and the neurokinin-1 receptor play a role in the regulation of cerebral blood flow, and that changes in rCBF evoked in the CVLM and NTS are most likely secondary to changes in arterial blood pressure. Substance P and neurokinin-1 receptors in the RVLM, CVLM and NTS do not appear to play a role in the brainstem regulation of tail blood flow. In the final chapter (chapter 7), a model is proposed for the role of tachykinins in the brainstem integration of the sympathetic baroreflex, sympathetic chemoreflex, cerebral vascular tone, and the sympatho-excitation seen following hypercapnoea. A further model for the somato-sympathetic reflex is proposed, providing a mechanism for the selective inhibition of this reflex seen with hypercapnoea (chapter 3) and RVLM neurokinin-1 receptor activation (chapter 5). In summary, the ventral medulla is essential for the generation of basal sympathetic tone and the integration of many vital autonomic reflexes such as the baroreflex, chemoreflex, somato-sympathetic reflex, and the regulation of cerebral blood flow. The tachykinin substance P, and its receptor, the neurokinin-1 receptor, have a role to play in many of these vital autonomic functions. This role is predominantly neuromodulatory.

Persons with chronic fatigue syndrome (CFS) often complain of an inability to maintain activity levels and experience a variety of orthostatic symptoms such as dizziness, trembling, nausea, postural hypotension with bradycardia or tachycardia, sweating, palpitations, paleness, and syncope. Orthostatic intolerance (OI) may be defined as an inability to maintain systolic blood pressure (SBP) within 20 mmHg of resting level upon moving from a supine to upright posture. The primary objective of this study is to determine whether men and women with CFS are more susceptible to OI during a 3-stage head-up tilt (HUT) than non CFS, sedentary subjects matched by age, sex, and ethnicity. The secondary objective is to examine whether possible underlying mechanisms may be predictively associated with OI susceptibility in CFS. Possible causes of OI include autonomic nervous system (ANS) dysfunction and altered hematological profile. Thus, specific aims included within this objective are: 1) to determine whether there are differences in resting cardiovascular function {i.e., blood pressure [BP], heart rate [HR], stroke volume [SV], cardiac output [CO], total peripheral resistance [TPR], and contractility [i.e., ejection fraction (EF), fractional shortening (FS), and the velocity of circumferential shortening corrected by HR (VCFc)]}, ANS function {i.e., beta1-, beta2-, and alpha-receptor sensitivities, baroreceptor sensitivity [BRS], and vagal function [i.e., respiratory sinus arrhythmia (RSA), RSA envelope (RSAE), high frequency (HF) spectral component, and HR range]}, and hematological profile [i.e., red blood cell volume (RBCV), plasma volume (PBV), and total blood volume (TBV)] between CFS and non-CFS groups; and 2) to determine whether cardiovascular, ANS, and hematological measures differentially predicted OI during HUT. The results indicate that OI susceptibility does not occur with greater prevalence in persons with CFS than non-CFS sedentary persons. However, power analyses revealed that with a much larger sample size group differences in OI susceptibility would be found. The CFS group was distinguished from the control group only by differences in blood volume measures. There appears to be no substantive group differences in a range of cardiovascular and ANS measures; moreover, none of these measures, including the blood volume measures, accounted for differences in OI susceptibility. Compensatory mechanisms may be present in CFS for the diminished blood volume that could explain the lack of group differences in OI susceptibility. In addition, future research may find some clues relevant to CFS pathophysiology in the assessment of hemodynamic responses during orthostatic challenge in the present subjects.

Background: Clinical findings indicate that touch massage has the ability to induce positive emotions and influence stress responses. However, little is known about mechanisms that can explain observed responses. Aim: To understand mechanisms behind observed emotional and physiological responses during and after touch massage. Methods: This thesis is based upon healthy volunteers in Studies I, II, IV and patients undergone aortic surgery in Study III. Study I had a crossover design, participants served as their own controls. After randomization they received TM on one occasion and the other occasion served as control. Heart rate variability (HRV), heart rate (HR) saliva cortisol concentration, glucose, insulin in serum and extracellular (ECV) levels of glucose, lactate, glycerol and pyruvat were measured before, during and after TM/control. In study II, functional magnetic resonance imaging (fMRI) was used in order to measure brain activity during TM movement. The study design included four different touch stimulations, human touch with movement (TM movement) human stationary touch and rubber glove with or without movement. Force (2.5 N) and velocity (1.5 cm/s) were held constant across conditions. The pleasantness of the four different touch stimulations was rated on a visual analog scale (VAS-scale). Study III had a randomized controlled design. The intervention group received TM and the control group rested. HRV, cortisol, glucose, insulin in serum, blood pressure, oxygen saturation, respiratory frequency and anxiety levels were measured before, during and after TM/control. In study IV participants were interviewed about experiences after TM and the text was analyzed in by qualitative content analyze. Results: Study I. TM reduced the stress response as indicated by decreased heart rate and decreased activity in the sympathetic nervous system, followed by a compensatory decrease in parasympathetic nervous activity in order to maintain balance. Cortisol and insulin levels decreased significantly after intervention, while serum glucose levels remained stable. A similar, though less prominent, pattern was seen during the control session. There were no significant differences in ECV concentrations of analyzed substances. Study II. Human moving touch (TM movement) was significantly rated as the most pleasant touch stimulation. The fMRI results revealed that human moving touch (TM movement) most strongly activated the pregenual anterior cingulate cortex (pgACC). Study III. Selfrated anxiety levels significantly decreased in the patient group that received TM compared with control group. There were no significant differences in physiological stress-related outcome parameters between patients who received touch massage and controls. Study IV. In this study participants talked about the experience of TM in terms of rewards. Expressions like need, desire, pleasure and conditioning could be linked with a theoretical model of reward. Four different categories were identified as wanting, liking, learning and responding. In conclusion: Results from these studies indicate that receiving TM is experienced as rewarding. Touch massage movement activates a brain area involved in coding of rewarding pleasant stimulations. TM decreases anxiety and dampens the stress response by a decreased activation of the sympathetic nervous activity. Our results indicate that TM is a caring intervention that can be used to induce pleasure, decrease anxiety and stress in the receiver.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous, often familial disease, characterized by cardiac hypertrophy, predominantly affecting the interventricular septum. To date, no study has systematically analysed the genetic and phenotypic aspects of the disease in a Swedish population. The aim of this thesis was to identify the genotypes causing HCM in northern Sweden, to characterize the disease phenotypes and correlate these findings. Forty-six patients were recruited for the genetic studies (21 women), 11 familial and 35 sporadic cases. Eight sarcomeric protein genes were screened for mutations. A total of 11 different disease causing mutations were found in four genes. Six of the mutations were previously not described. A novel mutation (a 33 base pair deletion) in the troponin I gene was found in one HCM family. Despite the severe genetic defect, the associated phenotype displayed only mild cardiac hypertrophy and few symptoms. Most mutations (64%) were identified in the myosin binding protein C gene, a gene considered to have a low penetrance. Mutations were identified in 10 of 11 familial HCM cases, but only in three of the 35 sporadic cases. It was found that cardiac amyloidosis can sometimes present itself as HCM. Three HCM patients (7%) carried the ATTR Val30Met mutation, also found in Swedish patients with familial amyloid polyneuropathy (FAP). The patients had no symptoms of polyneuropathy, but cardiac amyloidosis as the cause of hypertrophy was verified by myocardial biopsy in an index case. Amyloid heart disease should therefore be considered as a differential diagnosis in patients with HCM. By studying heart rate variability (HRV), it was found that young patients with HCM had signs of autonomic dysfunction, expressed as a reduced HRV. Treatment with beta-blockade attenuated these effects. Abnormal autonomic function might be a substrate for lethal arrhythmias, most often encountered in younger patients with HCM. The results suggest a possible protective effect of beta-blockade, remaining to be studied further. Ventricular function is frequently abnormal in HCM. In particular, diastolic dysfunction has been demonstrated. The recently described myocardial performance index allows the assessment of cardiac function by combining systolic and diastolic performance. We found that patients with hypertrophic cardiomyopathy had evidence of global and regional right ventricular dysfunction, besides left ventricular dysfunction. Hypertrophic cardiomyopathy is traditionally considered to be a disease of the left ventricle. The results show that hypertrophic cardiomyopathy should more be regarded as a biventricular disease. In conclusion, the myosin binding protein C gene is the most common gene causing familial HCM in northern Sweden. This disease gene is considered to be associated with a mild, late-onset disease with ≈50% penetrance at 30 years of age. The low disease penetrance emphasizes the importance of adequate family screening when evaluating patients with HCM, since the familial nature of the disease might easily be overlooked. These particular disease features in northern Sweden contrast to most previous reports, which indicate another disease gene as the most frequent in HCM, associated with a much higher penetrance. Amyloid heart disease, requiring different treatment than HCM, should be kept in mind as a differential diagnosis in the management of patients with HCM. Key words: Hypertrophic cardiomyopathy, genetics, autonomic nervous system, familial amyloid polyneuropathy, echocardiography.

The constant growth in network communications technologies and the emergence of Service Specific Overlay Networks (SSONs), coupled with the rapid development of multimedia applications make the management of such technologies a major challenge. This thesis investigates the SSONs management problem and proposes an autonomic architecture, a self-organizing and self-adapting algorithm, and a utility function for monitoring the Quality of Experience (QoE) of IPTV streams in SSONs. First, we examine the different issues stemming from the autonomic management of SSONs and identify the limitations of existing approaches. We then propose an architecture to ease the management of SSONs by incorporating autonomic computing principles to make SSONs acquire self-management capabilities. The proposed architecture introduces autonomic control loops that continuously monitor network components and analyze the gathered data. An Autonomic System (AS) is comprised of one or more Autonomic Managers (AM) which take control of managing other elements in the network. The proposed architecture highlights the different components of an AM and identifies its purpose. The distributed nature of the proposed architecture avoids limitations of centralized management solutions. We then propose a scheme to allow AMs to emerge among the set of nodes in the network as the most powerful ones in terms of different factors, including processing capabilities and stability. Using a self-organizing and self-adapting distributed protocol, each node in the overlay selects an appropriate AM to report to so that sensed data is delivered error-free, and in a timely manner, while the load is distributed over the AMs. Finally, we propose a utility function to monitor the quality of IPTV streams by predicting QoE based on statistical Quality of Service (QoS) information. The proposed function is simple and does not require high processing power. It allows the QoE of IPTV users to be monitored in real-time by the AMs, so that quality degradations are accurately identified and adaptation mechanisms are triggered at the right moment to correct issues causing degradations. Theoretical analysis and simulations studies are presented to demonstrate the performance of the proposed schemes.