京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22888号 / 社医博第112号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 川上 浩司, 教授 今中 雄一, 教授 稲垣 暢也 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(人間・環境学) / 甲第23272号 / 人博第987号 / 新制||人||233(附属図書館) / 2020||人博||987(吉田南総合図書館) / 京都大学大学院人間・環境学研究科共生人間学専攻 / (主査)教授 林 達也, 教授 船曳 康子, 教授 久代 恵介, 教授 森谷 敏夫 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DGAM

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.

The study dealt with the influence of exercise on the autonomic nervous system (ANS) and with factors that may influence the results. ANS function was measured in 183 young, healthy participants, before and after a twelve week standardised, medium-to-high volume physical training programme, in a controlled environment. The effects of the training programme were assessed on resting ANS functioning, during standing and on the response to an orthostatic challenge. ANS function was assessed by means of heart rate variability (HRV) determination. HRV was quantified by three different analytical techniques, i.e., time domain analysis (RR, STDRR, RMSSD and pNN50), frequency domain analysis (LF,LFnu, HF, HFnu and LF/HF) and Poincaré plot analysis (SD1 and SD2). The influence of technical variations, such as variations in tachogram length and period of recording, as well as the influence of pre-intervention values of physiological variables, such as blood pressure, BMI, VO2 max and ANS functioning, on the response to the exercise intervention, were assessed. Results on the exercise intervention showed: <ul><li> Increased supine, as well as standing, parasympathetic cardiac control as indicated by time domain, frequency domain and Poincaré analyses. </li><li> Decreased sympathetic control in the supine position and increased sympathetic control during rising and standing. </li><li> Increased vagal withdrawal, as well as increased sympathetic control during the first phase of the orthostatic response to rising from the supine position. </li><li> Only an exercise-induced increase in sympathetic control when the orthostatic response was measured as the difference between standing and supine. </li></ul> Results on exercise-induced changes in sympathetic and parasympathetic ANS control differ, depending on posture. It is suggested that the effects of an exercise intervention on sympathetic and parasympathetic ANS control of the heart should be assessed from measurements in the supine, in the standing, and in response to an orthostatic stressor. It is further suggested that information obtained during rising will give additional information on the response of the ANS. This study showed that technical as well as physiological variations may lead to differences in the outcome of HRV studies. Results from the technique evaluation showed that the length and period of tachogram recordings should be standardised, especially during an orthostatic challenge. Starting the recording too late will miss out on the initial response to a change in body position. Longer recording times will represent the mean of HRV values obtained during the orthostatic response and that obtained after stabilisation in the standing position. Investigations into the influence of pre-intervention physiological status on exercise-induced changes showed: <ul><li> Baseline ANS functioning is a significant contributor to variations in the ANS response to an exercise intervention. </li><li> Pre-intervention values for physiological variables, such as blood pressure, BMI and VO2 max do not have a significant influence on the HRV response to exercise in young, healthy individuals of average fitness</li><li> Regression analyses confirm the correlation results, i.e. that baseline ANS function is a significant predictor of the ANS response to exercise. </li><li> However, regression results indicated that the combination of pre-intervention values for LFms2, HFms2, BMI, VO2 max, gender and blood pressure, contributes only between 12.83% and 29.82%, depending on the HRV variable, to the exercise induced changes in the autonomic nervous system. </li></ul> / Thesis (PhD)--University of Pretoria, 2011. / Physiology / unrestricted

Title: Possibilities of monitoring and evaluation of accompanying non-locomotor manifestacions during reflex locomotion according to Vojta Objectives: The aim of study is to determine suitable conditions for measuring and evaluating non-locomotor manifestations. Furthermore, to clarify whether there are changes in the accompanying non-locomotor manifestations during the stimulation of trigger zones from the concept of Vojta's principle. Accompanying non-locomotor manifestations are mainly manifestations of the autonomic nervous system. Measurement of respiratory rate, heart rate and swallowing rate was chosen to evaluate these parameters. Methods: The research was conducted on 7 adult subject for measuring respiratory and heart rate and 12 adult subject for measuring swallowing frequency. These were healthy women aged 18-30. Data were obtained from a CamNtech Actiheard compact ECG sensor and from a video recording. Each proband was first measured for a resting ECG and then measured during activaton of the thoracic trigger zone from the Vojta concept, twice in a row for fifteen minutes. One measurement was performed with the eyes open, the other with the eyes closed, the order was randomized. The obtained data were processed into a video recording and evaluated for each proband separately. It was...

Background Myocardial infarction (MI) induces remodeling in stellate ganglion neurons (SGNs). Objective We investigated whether infarct site has any impact on the laterality of morphologic changes or neuropeptide expression in stellate ganglia. Methods Yorkshire pigs underwent left circumflex coronary artery (LCX; n = 6) or right coronary artery (RCA; n = 6) occlusion to create left- and right-sided MI, respectively (control: n = 10). At 5 ± 1 weeks after MI, left and right stellate ganglia (LSG and RSG, respectively) were collected to determine neuronal size, as well as tyrosine hydroxylase (TH) and neuropeptide Y immunoreactivity. Results Compared with control, LCX and RCA MIs increased mean neuronal size in the LSG (451 ± 25 vs 650 ± 34 vs 577 ± 55 μm2, respectively; P =.0012) and RSG (433 ± 22 vs 646 ± 42 vs 530 ± 41 μm2, respectively; P =.002). TH immunoreactivity was present in the majority of SGNs. Both LCX and RCA MIs were associated with significant decreases in the percentage of TH-negative SGNs, from 2.58% ± 0.2% in controls to 1.26% ± 0.3% and 0.7% ± 0.3% in animals with LCX and RCA MI, respectively, for LSG (P =.001) and from 3.02% ± 0.4% in controls to 1.36% ± 0.3% and 0.68% ± 0.2% in LCX and RCA MI, respectively, for RSG (P =.002). Both TH-negative and TH-positive neurons increased in size after LCX and RCA MI. Neuropeptide Y immunoreactivity was also increased significantly by LCX and RCA MI in both ganglia. Conclusion Left- and right-sided MIs equally induced morphologic and neurochemical changes in LSG and RSG neurons, independent of infarct site. These data indicate that afferent signals transduced after MI result in bilateral changes and provide a rationale for bilateral interventions targeting the sympathetic chain for arrhythmia modulation.

Using vagus nerve stimulation (VNS), we sought to determine the contribution of vagal afferents to efferent control of cardiac function. In anesthetized dogs, the right and left cervical vagosympathetic trunks were stimulated in the intact state, following ipsilateral or contralateral vagus nerve transection (VNTx), and then following bilateral VNTx. Stimulations were performed at currents from 0.25 to 4.0 mA, frequencies from 2 to 30 Hz, and a 500-μs pulse width. Right or left VNS evoked significantly greater current-and frequency-dependent suppression of chronotropic, inotropic, and lusitropic function subsequent to sequential VNTx. Bradycardia threshold was defined as the current first required for a 5% decrease in heart rate. The threshold for the right vs. left vagus-induced bradycardia in the intact state (2.91 ± 0.18 and 3.47 ± 0.20 mA, respectively) decreased significantly with right VNTx (1.69 ± 0.17 mA for right and 3.04 ± 0.27 mA for left) and decreased further following bilateral VNTx (1.29 ± 0.16 mA for right and 1.74 ± 0.19 mA for left). Similar effects were observed following left VNTx. The thresholds for afferent-mediated effects on cardiac parameters were 0.62 ± 0.04 and 0.65 ± 0.06 mA with right and left VNS, respectively, and were reflected primarily as augmentation. Afferent-mediated tachycardias were maintained following β-blockade but were eliminated by VNTx. The increased effectiveness and decrease in bradycardia threshold with sequential VNTx suggest that 1) vagal afferents inhibit centrally mediated parasympathetic efferent outflow and 2) the ipsilateral and contralateral vagi exert a substantial buffering capacity. The intact threshold reflects the interaction between multiple levels of the cardiac neural hierarchy.

Aims: Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Methods and results: Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 ± 0.004 vs. 0.050 ± 0.011 pmol/μg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 ± 6% vs. 69 ± 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. Conclusion: These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.

The pathological conse-quences of ischemic heart disease involve signaling through the autonomic nervous system. Although early activation may serve to maintain hemodynamic stability, persistent aberrant sympathoexcitation contributes to the development of lethal arrhythmias and heart failure. We hypothesized that as the myocardium reacts and remodels to ischemic injury over time, there is an analogous sequence of gene expression changes in the thoracic spinal cord dorsal horn, the processing center for incoming afferent fibers from the heart to the central nervous system. Acute and chronic myocardial ischemia (MI) was induced in a large animal model of Yorkshire pigs, and the thoracic dorsal horn of treated pigs, along with control nonischemic pigs, was harvested for transcriptome analysis. We identified 32 differentially expressed genes between healthy and acute ischemia cohorts and 46 differentially expressed genes between healthy and chronic ischemia cohorts. The canonical immediate-early gene c-fos was upregulated after acute MI, along with fosB, dual specificity phosphatase 1 and 2 (dusp1 and dusp2), and early growth response 2 (egr2). After chronic MI, there was a persistent yet unique activation of immediate-early genes, including fosB, nuclear receptor subfamily 4 group A members 1±3 (nr4a1, nr4a2, and nr4a3), egr3, and TNF-β-induced protein 3 (tnfaip3). In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and the stress response. These findings support a dynamic progression of gene expression changes in the dorsal horn with maturation of myocardial injury, and they may explain how early adaptive autonomic nervous system responses can maintain hemodynamic stability, whereas prolonged maladaptive signals can predispose patients to arrhythmias and heart failure. NEW & NOTEWORTHY Activation of the autonomic nervous system after myocardial injury can provide early cardiovascular support or prolonged aberrant sympathoexcitation. The later response can lead to lethal arrhythmias and heart failure. This study provides evidence of ongoing changes in the gene expression signature of the spinal cord dorsal horn as myocardial injury progresses over time. These changes could help explain how an adaptive nervous system response can become maladaptive over time.

Purpose: This study will identify that patients with chronic neck pain have an altered autonomic functioning compared to a control group, and that manipulation might directly influence the autonomic nervous system as measured by using a fully automated pupillometry system. Subjects: 100 chronic pain patients and 50 control subjects participated in this study to achieve a power of 0.80, effect size of 0.5, and a type I error rate of 0.05 for two-tailed hypothesis testing. Method: A quasi-experimental design was be used. The ANOVA and Chi square test were used to establish homogeneity of baseline characteristics. The Mann-Whitney U test was performed to compare the pre-intervention pupil diameter amongst the groups. The Friedman's test was used to determine the pupil diameter change during the three measurements. The Wilcoxen Signed-ranks test was used to analyze the difference in pupil size between the pre- and post-intervention measures and to determine if there was a difference in pupil diameter between the two groups undergoing the thoracic manipulation. The Kruskal-Wallis test was used to compare the pupil diameter change to the presence of joint sounds. And the Fisher's Exact test was used to determine the relationship between the number of pops and the VAS change score > 13mm. Results: This study demonstrated that the chronic pain group had a statistically significant smaller pupil diameter than the healthy control group (P=0.022). Manipulation resulted in a relative increase in pupil diameter following the manipulation, however this was not statistical significant. There was a statistical significant decrease in pupil diameter in the placebo group (pConclusions: It appears that a T3-T4 manipulation results in a relative non-specific increase in sympathetic activity. Recommendations: Manipulation may be used by physical therapists to affect the autonomic nervous system. Visual pupil assessment may become part of the evaluation process to identify patients that might present with autonomic dysfunction and to determine the effect of treatment modalities.