The physiological signals of human are very important for the diagnosis of diseases. There are two different applications of physiological signals in this study. One is using oxyhemoglobin saturation to diagnose the obstructive sleep apnea hypopnea syndrome (OSAS); the other is to determine the association between dermatoglyphics and schizophrenia by using fingerprint asymmetry measures. The objective of the first part is to comprehensively evaluate the capablity and reliability of the previously proposed oxyhemoglobin indices derived automatically for predicting the severity of OSAS. Patients with a diagnosis of OSAS by standard polysomnography were recruited from China Medical University Hospital Sleep Center. The result revealed that when AHI cutoff value was set to 30/h, ODI achieves 87.8% sensitivity and 96.6% specificity. Another important finding is that, for both apnea and hypopnea, probability of oxyhemoglobin desaturation increases with increases of body mass index (BMI) and neck circumference (NC). Early detection and intervention strategies for schizophrenia are receiving increasingly more attention. Dermatoglyphic patterns have been hypothesized to be indirect measures for early abnormal developmental processes that can lead to later psychiatric disorders such as schizophrenia. However, previous results have been inconsistent in trying to establish the association between dermatoglyphics and schizophrenia. The goal of second part of this work is to try to resolve this problem by borrowing well developed techniques from the field of fingerprint matching. Fingerprint images were acquired digitally from 40 schizophrenic patients and 51 normal individuals. Based on these images, the sample means of the proposed measures consistently identified the patient group as having a higher degree of asymmetry than the control group.

There is evidence that non-surgical treatment of OSA improves blood pressure (BP) in patients with obstructive sleep apnea (OSA). The objective of this study is to determine the effect of maxillomandibular advancement (MMA) surgery for OSA on BP. 15 patients undergoing MMA surgery for treatment of OSA were enrolled. Ambulatory BP, and BMI were recorded pre- and post-operatively. The average age of the patients was 48.9 years and they had mean preoperative AHI of 40.8 and a mean baseline BMI of 30.8 kg/m2. There were no statistically significant reductions in mean systolic or diastolic BP postoperatively. The BMI was found to decrease on average from 30.8 kg/m2 to 29.3 kg/m2 at follow up (p = 0.01). There were no identifiable relationships between OSA severity and BP. Given the prevalence of OSA and it’s adverse medical consequences, more studies to determine the effect of MMA on BP are warranted.

Techniques ambulatoires de diagnostic et de monitoring des troubles respiratoires liés au sommeil.Le syndrome d’apnées obstructives du sommeil (SAOS) est un trouble du sommeil très fréquent, fortement lié à l’obésité, ce qui explique sa prévalence en pleine expansion. En parallèle, la demande d’examens polysomnographiques (PSG) en laboratoire du sommeil, méthode diagnostique de référence, est en croissance. Comme l’accès à cette technique est peu aisé, de nombreux appareils simplifiés d’enregistrement de sommeil ont été récemment développés, mais restent imparfaits (mauvaise évaluation du temps de sommeil, sous-estimation de la sévérité du SAOS, faux négatifs, taux d’échec élevé) et sont d’un apport limité pour le diagnostic du SAOS. La PSG au domicile (PSG-d) est une alternative bien plus informative, permettant d’éviter nombre des désavantages rencontrés par l’usage d’appareils simplifiés. Nous l’avons dès lors étudiée pour le diagnostic du SAOS, au travers d’une étude randomisée comparant la PSG-d vs la PSG hospitalière. En termes d’efficacité diagnostique, les résultats sont excellents, avec un faible taux d’échec d’examens à domicile (4.7 vs 1.5%). Les patients préfèrent être enregistrés dans leur propre environnement où la qualité de leur sommeil est d’ailleurs meilleure. Nous avons ensuite voulu faire le point sur la littérature récente au travers d’un article de revue, en analysant les études prospectives randomisées comparant la PSG-d et au labo du sommeil. Les résultats de ces études concordent pour démontrer que la PSG-d constitue une excellente alternative aux tests réalisés à l’hôpital. Outre le SAOS, l’outil permet le diagnostic d’autres troubles du sommeil, comme les mouvements périodiques des jambes durant le sommeil, les troubles du rythme circadien, Une question restée jusqu’ici sans réponse était l’influence de la localisation du branchement des PSG-d, à l’hôpital ou à domicile. Une étude prospective randomisée nous a permis d’établir que la localisation du branchement des PSG-d n’influençait pas la qualité globale de l’examen, ce qui simplifiera l’utilisation de cet outil à l’avenir. Enfin, nous avons utilisé des techniques de télé monitoring (TM) pour contrôler, en temps réel, la qualité des PSG-d. Dans une première étude pilote, la faisabilité a été confirmée, malgré quelques difficultés techniques. Nous avons voulu appliquer la technique à une population de patients souffrant d’un syndrome coronarien aigu, incapables d’être enregistrés au labo du sommeil. Nous avons étudié la qualité du screening du SAOS par PSG vs polygraphie (PG). Les résultats se sont révélés surprenants :82% de cette population présentait des troubles respiratoires liés au sommeil, principalement centraux. La PSG était nettement plus sensible que la PG, et le TM améliorait la qualité des PSG. Chez les patients traités pour SAOS, nous avons ensuite utilisé un outil de monitoring, l’actigraphie (Act), afin d’observer, dans la vie de tous les jours, les changements de schémas de sommeil et d’activité physique engendrés par la pression positive continue (PPC). Dans un premier travail, rétrospectif, nous avons observé ces paramètres chez des SAOS avant traitement, puis au travers d’une étude prospective multicentrique, nous avons suivi 150 patients avant et après PPC, et observé chez eux une augmentation de temps de sommeil, mais pas de l’activité physique. En conclusion, nous avons démontré dans cette thèse l’intérêt clinique de deux excellents outils ambulatoires, la PSG-d et l’Act, pour la prise en charge du SAOS. Les implications potentielles sont une meilleure accessibilité diagnostique pour le SAOS, une initiation thérapeutique plus précoce et un suivi plus précis des SAOS traités, dans des conditions ambulatoires, plus confortables et plus adéquates pour les patients. / Ambulatory diagnostic and monitoring techniques for sleep disordered breathingSleep disordered breathing (SDB), including obstructive sleep apnea syndrome (OSAS), is directly related to obesity. Significant morbi-mortality is associated with OSAS, explaining the increasing demand for in-hospital polysomnography (PSG), the reference diagnostic method. As this technique is complex and time-consuming, many simplified portable monitoring (PM) devices for home sleep testing have been developed. However, the ability of PM devices to detect OSA remains limited: sleep time is not correctly assessed, OSA severity is underestimated, false negative results occur and the failure rate of the tests is high, up to 30%. Home-PSG (H-PSG) is an interesting alternative, avoiding many of these drawbacks. In the first part of this work, we studied the tool in an original study comparing H-PSG and in-lab PSG. Diagnostic efficacy was good and the failure rate low (4.7 vs 1.5%). Patients slept in their own environment and thus sleep quality was better. We were then interested by reviewing recent literature data regarding prospective randomised trials comparing H-PSG and in-lab PSG. We concluded that H-PSG is an excellent alternative for in-lab PSG, allowing not only OSA detection but also diagnosis of a large panel of other sleep disorders (periodic leg movements during sleep, circadian disorders,). As the best place to perform set-up for H-PSG remained unknown, we studied, in another prospective randomised study, the recording’s quality obtained in both settings. As no difference was observed, lab set up was found to be the simpler option for performing H-PSG. We then tested, in a prospective pilot study, real-time telemonitoring (TM) of H-PSG in order to enhance recording quality. Results were encouraging but we faced some technical problems. In a second study, we applied TM coupled with PSG to detect SDB in acute coronary syndrome, in patients too unstable to come in the sleep lab. We compared also PSG results to polygraphy (PG). Surprisingly, 82% of patients suffered from SDB. PSG was much more sensitive than PG to screen SDB in this population and TM improves recording quality. In the second part of this work, we have used actigraphy (Act) to assess sleep and physical activity in OSA patients in real-life conditions. Firstly, in a retrospective study, we documented these parameters before treatment. In a second multicentre study, we evaluated the changes in sleep schemes and physical activity under continuous positive airway pressure (CPAP) in 150 OSA patients. We observed that sleep time was increased under CPAP, but physical activity was not improved, contrarily to sleepiness and quality of life. In conclusion, we have shown through these works the clinical interest of two excellent ambulatory tools, H-PSG and Act, for OSA management. Potential clinical implications include enhanced healthcare accessibility, earlier treatment initiation and a closer follow-up of treated patients, through ambulatory tools, in a comfortable environment for the patients. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Background-Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results-We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community-based study of existing ("parent") cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12-lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea-hypopnea index (OAHI). CSA was defined by a central apnea index >= 5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow-up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2-to 3-fold increased odds of developing AF (central apnea index >= 5 odds ratio [OR], 3.00, 1.40-6.44; Cheyne-Stokes respiration OR, 1.83, 0.95-3.54; CSA or Cheyne-Stokes respiration OR, 2.00, 1.16-3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91-1.03; OAHI 5 to <15 OR, 0.84, 0.59-1.17; OAHI 15 to <30 OR, 0.93, 0.60-1.45; OAHI >= 30 OR, 0.76, 0.42-1.36). Conclusions-In a prospective, community-based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors.

Patients undergoing surgery with unrecognized obstructive sleep apnea (OSA) are at greater risk of complications. Ninety percent of those affected in the United States remain undiagnosed. To improve identification, screening tools such as the STOP-Bang questionnaire (Chung et al. 2008), provide anesthesia providers a method of detecting undiagnosed OSA. The purpose of this study is to assess anesthesia providers' practice of preoperative screening for OSA. An email survey was conducted at a Level-III trauma center in Phoenix, Arizona. The survey consisted of a 13 question, 5-point Likert scale questionnaire. It was sent to 29 Certified Registered Nurse Anesthetists (CRNA). A total of 8 CRNA's responded. Respondents were either neutral or disagreed that current methods of OSA screening works well and generally agree that the STOP-Bang tool would provide an advantage over the current methods, accurately detect OSA, and inform their anesthetic plan over current methods. Respondents leaned towards strong agreement that improving the recognition of undiagnosed OSA is needed. However, they were generally neutral on agreement that the STOP-Bang is necessary at their facility. Respondents agreed that the STOP-Bang tool is easy to use and interpret. However, most agreed that integrating the tool would add complexity to the preanesthesia evaluation but they remained neutral on whether it would add significant time to this process. Respondents were neutral on their observations that the STOP-Bang tool would improve early detection of OSA or reduce perianesthesia complications. Just 25% of respondents reported being aware of the existence of the STOP-Bang tool and none reported having used it. In conclusion, this project demonstrates that some providers have not used the STOP-Bang screening tool to detect undiagnosed OSA, but agree this tool is preferred over their current method. Results from the survey brought insight to a potential quality improvement strategy related to improving the perianesthesia care of patients with undiagnosed OSA. Improving knowledge through dissemination of evidence illustrates the value of the STOP-Bang prior to piloting the tool. The rates of perioperative complications justify the implementation of perioperative strategies such as the STOP-Bang as a tool for anesthesia providers.

Background: Obstructive sleep apnea (OSA) consists of repeated, involuntary breathing suspension during sleep. These events induce rapid depletion/repletion of blood/tissue oxygen content, a phenomenon known as intermittent hypoxia. Aside from causing daytime sleepiness, the most important health consequence of OSA is a 2-fold increase in cardiovascular (CVD) risk. Animal studies provide evidence that intermittent hypoxia, a simulating model of OSA, causes important rise in plasma TG, especially in the postprandial state. However, the underpinning mechanisms linking intermittent hypoxia to altered postprandial TG levels remain unknown. As such, the objective of this study was to characterize the effects of acute intermittent hypoxia on postprandial TG levels in 2 distinct lipoprotein subtypes in humans: chylomicrons which are secreted by the intestine and carry dietary lipids, and denser TG carriers (mainly VLDL) which are secreted by the liver and carry endogenous lipids. Methods: The research consisted of a randomized crossover design. In collaboration with the Sleep laboratory at Montfort Hospital, 7 individuals diagnosed with moderate sleep apnea were recruited through phone calls as well as 8 healthy individuals without OSA from the University of Ottawa. While lying on a bed, participants were given a meal after which they were exposed for 6 hours to normoxia or intermittent hypoxia corresponding to moderate OSA, e.g. 15 hypoxic events per hour. Blood lipid levels were measured hourly.  Results: Plasma TG levels increased over time in both experimental conditions and tended to be greater under 6-h exposure to intermittent hypoxia (p=0.093, effect size ηp2= 0.383.). This trend toward higher total plasma TG under intermittent hypoxia was attributable to increased levels in denser TG carrying lipoproteins such as VLDL and CM remnants (p= 0.009, ηp2 = 0.173).  Conclusion: Acute intermittent hypoxia, a simulating model of obstructive sleep apnea, tends to negatively affect postprandial TG levels, which is attributable to an increase in denser TG carrying lipoprotein levels such as VLDL and CM remnants. These results lend support to the increase in blood lipid levels in animal studies observing the effect of acute hypoxia in mice.  Contribution to advancement of knowledge: This proposed research will allow a better understanding of the mechanisms by which obstructive sleep apnea may alter blood lipid profile. This information will be beneficial to the treatment of obstructive sleep apnea related dyslipidemia and contribute to reduce CVD risk in the large proportion of obstructive sleep apnea patients who are reluctant to current treatment avenues.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23097号 / 医博第4724号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 尚己, 教授 稲垣 暢也, 教授 石見 拓 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Obstructive sleep apnea syndrome (OSAS) is a serious disorder that affects an estimated 24% of middle-age males, and 9% of middle-aged females. In addition, a large portion of individuals with OSAS go undiagnosed. OSAS is associated with several adverse health problems, including the metabolic syndrome. Therefore, there is a clear need to identify new methods for assessing OSAS risk. The exercise test has been used effectively as a diagnostic and prognostic tool for those at high risk for cardiovascular disease and hypertension. Research into the cardiopulmonary responses to exercise testing in young adult men with OSAS has not been examined. Objectives: The objectives of this study were to: 1) evaluate whether OSAS is characterized by exaggerated ventilatory responses to ramp exercise testing, with a secondary aim to evaluate if variations in serum leptin concentration might exert a regulatory in ventilatory responses during exercise; 2) To evaluate whether autonomic control of the cardiovascular response during exercise is distorted by OSAS in young overweight men, as manifested by a blunting of heart rate and exaggeration of blood pressure responses.; 3) To explore whether various simple clinical measures and response patterns from graded exercise testing might serve to discriminate between young men with and without OSAS. Methods: For objectives one and two, 14 obese men with OSAS [age = 22.4 ± 2.8; body mass index (BMI) = 32.0 ± 3.7; apnea-hypopnea index (AHI) = 22.7 ± 18.5], 16 obese men without OSAS (age = 21.4 ± 2.6; BMI = 31.4 ± 3.7), and 14 normal weight subjects (objective 2) (age = 21.4 ± 2.1; BMI = 22.0 ± 1.3) were recruited. For objective three, 91 men (age = 21.6 ± 2.8; AHI range = 0.6 – 60.5; BMI range = 19.0 – 43.9) were recruited. Subjects completed a ramp cycle ergometer exercise test, and a fasting blood sample was obtained to measure plasma leptin and blood lipid levels. Repeated measures ANOVA and stepwise linear regression was used to examine objectives 1 and 2. For objective 3, stepwise linear regression and receiver operator curve (ROC) analysis was utilized. Results: Ventilation (VE), the ventilatory equivalents for oxygen (VE/VO₂) and carbon dioxide (VE/VCO₂) were greater in the OSAS subjects vs. the overweight subjects without OSAS (P = 0.05, P < 0.05 and P < 0.005, respectively) at all exercise intensities. Heart rate (HR) recovery was attenuated in the overweight OSAS subjects compared to the No-OSAS and Control groups throughout 5 minutes of active recovery (P = 0.009). Oxygen uptake, HR, and blood pressure did not differ throughout exercise. Leptin was not associated with ventilatory responses at any exercise intensity. Linear regression analysis revealed hip-to-height ratio (HHR), hip circumference (HC), triglyceride levels, and recovery systolic blood pressure ratio (SBPR) at 2 and 4 minutes were independent predictors of AHI (model fit: R² = 0.68, p <0.0001). ROC analysis determined that percent body fat, HHR, and recovery HR at 2 minutes and 4 minutes were the best single predictors of OSAS risk (AUC = 0.77 for each measure, p = 0.003). Conclusions: Unique ventilatory and hemodynamic characteristics to maximal exercise testing are exhibited in young men with OSAS. These characteristics may be related to alterations in the sympathetic nervous system and chemoreceptor activation, and may be early clinical signs in the progression of OSAS. These exercise characteristics, along with anthropometric and body composition measures may provide useful information in identifying young men at risk for OSAS. / Ph. D.

Obstructive sleep apnea syndrome (OSAS) is a complex disorder characterized by repetitive bouts of upper airway collapse during sleep, causing subsequent intermittent hypoxia, hypercapnia, and fragmented sleep and is also associated with significant morbidity including daytime sleepiness, hypertension, and elevated cardiovascular risk. OSAS affects at least 4% of men and 2% of women; unfortunately, it is estimated that 80% to 90% of adults with OSAS remain undiagnosed. Both clinical characteristics and complex genetic and environmental interactions have made it difficult to understand OSAS disease etiology and identifying patients at risk is still elusive. A pattern of gene expression in cells or tissues related to a disease state for OSAS would provide beneficial information to be most effective in screening or diagnosing this disease. Objectives: The objectives of this study were to: 1) map out the study design and bench assay strategies by which to investigate this issue; 2) find out if there are specific differences in the global gene expression profiles of adult females with OSAS compared to those without OSAS, under conditions in which subjects were clinically similar (BMI, diabetes, cardiovascular disease, etc.); and 3) assess the protein expression differences that could potentially be linked via well-established molecular pathways associated with any differences found in global gene expression profiles in the presence and absence of OSAS. Methods: Subjects were overweight premenopausal Caucasian women with untreated OSAS (n=6; age = 40.7 ± 3.4; BMI = 49.04 ± 6.97; apnea-hypopnea index = 27.3 ± 16.02), and control subjects (n=10) (age = 38.2 ± 7.6; BMI = 47.94 ± 6.15; apnea-hypopnea index < 5), and matched for other clinical characteristics (diabetes, cardiovascular disease status, medications, etc.) recruited from either Carilion Clinic Pulmonary/Sleep Medicine or Carilion Clinic Bariatric Surgery practices. Subjects provided a fasting blood sample in which the monocytes were isolated from whole blood. The RNA was extracted from the monocytes, assessed for purity and quantity, frozen and shipped to collaborators at Dana-Farber Cancer Institute and hybridized to Affymetrix whole human genome chips on a gene chip. The initial computational evaluation and interpretation generated the hypothesis. Two-step quantitative real time polymerase chain reaction (qPCR) was performed to verify the results from the microarray analysis. The laminin enzyme immunoassay (EIA), and cellular adhesion assays were performed to determine if genomic changes resulted in proteomic and phenotypic assessments. Results: OSAS subjects had nine aberrantly regulated genes, of which three genes (LAMC-1, CDC42, and TACSTD2) showed a pattern in segregation between OSAS and controls subjects based on expression patterns. In addition, qPCR indicated a 2.1 fold increase in LAMC-1 and a 1.1 fold increase CDC42 expression unique to the tissue samples of patients with OSAS. Though the serum laminin EIA did not differ between groups, a statistically significant increase in peripheral blood mononuclear cells (PBMC) cellular adhesion in OSAS patients versus control subjects was found. The OSAS subjects had a well cell count of 9.27 ± 1.54 cells vs. controls 5.75 ± 0.78 cells (p Ë‚ 0.05), which is relative to the 103 cells/field that were plated. Conclusions: Cells isolated from women with moderate-severe OSAS show an abnormality in cellular adhesion, a process driven in part by the gene LAMC-1, which was also aberrantly expressed in these subjects. This suggests that inflammation may be linked to the pathogenesis of OSAS. This pilot study has provided the framework and preliminary data needed to propose a larger study with extramural research funding. / Ph. D.

Heart Rate Variability (HRV) currently is utilized when assessing the risk of mortality in individuals suffering from coronary heart disease or diabetic neuropathy. Research has shown that patients with Obstructive Sleep Apnea (OSA) also show a decrease in HRV, as well as an increase in sympathetic drive characterized by an increase in the low-frequency component of HRV. HRV, in conjunction with other indicators, may represent a non-invasive, low cost method for the confirmation of severity of OSA in some patients and therefore may represent an additional tool for the assessment of risk in these individuals. This becomes especially true when urinary catecholamines, fitness level, and quality of life (QOL) assessment are included. The purpose of this study was to determine if a correlation exists between severity of OSA as assessed by respiratory distress index (RDI) and the selected measures HRV, fitness, QOL, and catecholamine output. Subjects were 6 men and 5 women who were recently diagnosed with OSA by polysomnographic (PSG) study. HRV and blood pressure was measured during two consecutive trials consisting of 512 heartbeats. Catecholamine levels were determined by HPLC following 24-hour urine collection. Fitness levels were established following cycle ergometer testing and QOL following questionnaire completion. Subjects with lower weight, BMI, and neck circumference had significantly higher parasympathetic influence as analyzed through the amount of high frequency component of HRV (r =.738, .726, .789, respectively; p<0.05). Respiratory distress index (RDI) was negatively related to the average heart rate (HR=RR average, r = -.610, p<0.05), while the amount of total sleep (r = .657, p<0.05) and REM sleep (r = .739, p<0.01) increased as HR increased. The average HR was correlated to the predicted VO2max (r = .677, p<0.05). When the frequency components of HRV, fitness, QOL, and catecholamines were combined, the association to RDI increased dramatically (r = .984, p = .02). The results indicate that as the severity of OSA increases, markers of fitness, QOL, and sleep decrease. There is also an inverse relationship between autonomic function and severity of OSA. It is concluded that HRV and fitness levels are inversely related to the severity of OSA, and that these measures may be developed into a risk assessment tool for use in OSA patient evaluatio / Master of Science