Background and Purpose: Little is known about influences of obstructive sleep apnea syndrome (OSAS) on dietary intake and body composition. The purpose of this study was to evaluate dietary status, body fat distribution and leptin in overweight young men with and without OSAS in comparison to published values for normal weight counterparts. Methods: Groups were comprised of 24 sedentary overweight young men with and without OSAS, who had a body mass index (BMI) greater than 25 kg/m². Serum leptin concentration was measured in the 24 subjects using radioimmunoassay, while OSAS assessment was done using nighttime home somnography. Analysis of 4-day diet recalls was performed using Nutritionist Pro (First DataBank, Inc., San Bruno, CA). A Healthy Eating Index (HEI) score was calculated for the 24 overweight subjects. Results: There were no differences between the two overweight groups for total fat mass, central abdominal fat, BMI, waist circumference, leptin, or the HEI. The HEI was not predictive of overall OSAS severity; however, BMI was moderately related to OSAS severity (r = 0.39; p=0.05). The normal weight group did have a 50% higher report of carbohydrate intake, and consumed on average, 500 more kilocalories per day. The normal weight group consumed 50% less sodium, and 50% more Vitamin's C and E including a 13% increase in the HEI. Conclusions: Regulation of eating behavior and related influences on diet composition may be affected by a number of neurohormonal disturbances associated with OSAS and/or obesity, itself. Further research is needed to quantify these possible differences on dietary status and the underlying mechanism involved. / Master of Science

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

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.

An electronically-controlled positive-displacement bellows-type air pump has been developed in the Bio-medical Engineering Laboratory for the treatment of adult Sleep Apnea Syndrome (SAS). An electronically-controlled positive-displacement pump has been employed in order to eliminate the pressure regulator and accompanying noise of present therapeutic devices. The positive-displacement pump is found to quietly and effectively provide the required airway pressures for the treatment of adult Sleep Apnea Syndrome. New developments in the reduction of the size and noise levels of current therapeutic devices, however, preclude mass production of the bellows-type pump because of its size disadvantage. The custom nasal mask and exhalation valve, control system, pressure-monitoring alarm system, and the controlled humidifier of the positive-displacement pump should be incorporated within the present fanâ type Nasal Continuous Positive Airway Pressure (NCPAP) system to provide quieter, more comfortable, and safer NCPAP therapy. Before the design and development of the positive displacement NCPAP pump is detailed in this thesis, however, the problem of adult Sleep Apnea Syndrome is introduced, available therapies are investigated, and the current NCPAP therapy system is examined. / Master of Science

<p>Poremećaji disanja tokom spavanja (Sleep disordered breathing &ndash; SDB) obuhvataju spektar bolesti koje nastaju usled povećanog otpora u gornjem disajnom putu i reflektuje se na spavanje. Najveća podgrupa SDB su prekidi disanja tokom spavanja ili sleep apnea sindrom (Sleep Apnea Syndrome &ndash; SAS). SDB su prisutni kod 20% op&scaron;te populacije, dok je 82% mu&scaron;karaca i 93% žena koje imaju umerenu i te&scaron;ku OSA nedijagnostikovano. Kako osnovna dijagnostička metoda, polisomnografija, zahteva stručan kadar i adekvatnu laboratorijsku opermu nameće se potreba za brzom, efikasnom i jeftinom skrining metodom pri dijagnostici SAS. Cilj ove studije jeste da se uradi validacija i prevođenje &ldquo;STOP BANG&ldquo; upitnika sa engleskog na srpski jezik i utvrdi njegova specifičnost i senzitivnost u odnosu na vrednosti AHI indeksa kod odraslih ispitanika pri dijagnostikovanju SAS i da se utvrdi senzitivnost i specifičnost &ldquo;STOP BANG&ldquo; upitnika i Epfortove skale pospanosti zajedno. Istraživanje je u potpunosti sprovedeno u Centru za patofiziologiju disanja sa medicinom sna Instituta za plućne bolesti Vojvodine, Sremska Kamenica. Studijsku grupa se sastojala od 102 ispitanika koji su popunjavali oba upitnika, a potom je svima urađena polisomnografija. Testiranje &bdquo;STOP BANG&ldquo; upitnikom, kao i retest nakon mesec dana uradilo 30 ispitanika. Rezultati istraživanja pokazuju da su u uzorku dominirale osobe mu&scaron;kog pola 69,6%. Prosečna starost je iznosila 50,1&plusmn;13,8 godina. Najveći broj ispitanika je imao poremećaj disanja tokom spavanja (73,5%). Prema stepenu težine najveći broj ispitanika (30,4%) je bolovao od te&scaron;kog oblika (apnea/hipopnea indeks- AHI&gt;30), a prema tipu poremećaja dominirali su opstruktivni poremećaji sa 66,7% u ukupnom uzorku. Prekomerna dnevna pospanost, merena Epfortovom skalom pospanosti, bila je prisutna kod 58,8% ispitanika i korelirala je sa stepenom težine poremećaja (r=0,43). Dobijena senzitivnost i specifičnost za &bdquo;STOP BANG&ldquo; upitnik je iznosila 62,7% i 51,9% respektivno. &bdquo;STOP BANG&ldquo; upitnik je preveden na srpski jezik, a zatim je urađen test i retest upitika gde nije bilo razlike u odgovorima. Dobijena je granična vrednost za &bdquo;STOP BANG&ldquo; upitnik koja iznosi 4.5, a senzitivnost i specifičnost testa za različit stepen težine SAS je zadovoljavajuća i iznosila je 70,7%/66,7% za laku, 78,6% /60,9% za umerenu i 87,4%/ 50,7% za te&scaron;ku sleep apneu. Pri poređenju oba upitnika zajedno dobijena je bolja specifičnost 85,2%, 76,1%, 69,0% ali lo&scaron;ija senzitivnost 53,3%, 58,9% ,71,0% za laku , umerenu i te&scaron;ku sleep apneu respektivno u grupi ispitanika koji su imali vrednosti oba upitnika iznad graničnih vrednosti. U grupi ispitanika gde je jedan od upitnika imao vrednosti iznad granične vrednosti dobijena je bolja senzitivnost ali lo&scaron;ija specifičnost u odnosu na samo &bdquo;STOP BANG&ldquo; upitnik. Istraživanjem je utvrđen skrining metod -&ldquo;STOP BANG&ldquo; upitnik, koji stratifikuje pacijente na osnovu kliničkih simptoma, fizičkog pregleda i prisustva faktora rizika, na one pacijente sa visokim rizikom kojima treba hitno uraditi polisomnografiju i uputiti ih dalje na lečenje i na one kojima polisomnografija nije potrebna.</p> / <p>Sleep disordered breathing (SDB) includes a spectrum of diseases occurring due to an increased resistance in the upper airway, which affects sleeping. The major SDB subgroup is sleep apnea syndrome (SAS). SDB is present in 20% of the general population, and among the subjects with a moderate or severe SAS, 82% of males and 93% of females remain undiagnosed. Since polysomnography - the basic diagnostic method, requires a well-trained staff and adequate laboratory equipment, the need for a fast, efficient and cheap screening method in the diagnosis of SAS has breen imposed. Objectives of the study are to evaluate and translate the &ldquo;STOP BANG&ldquo; questionnaire from English to Serbian, establish its specificity and sensitivity in relation to the apnea hypopnea index (AHI) values while diagnosing SAS in adults, and to assess the cumulative sensitivity and specificity of the &ldquo;STOP BANG&ldquo; questionnaire and Epworth Sleepiness Scale. The investigation has been entirely carried out in the Lung Function and Sleep Medicine Centre of the Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica. The study cohort included 102 subjects who were all, having answered both questionnaires first, submitted to polysomnography. Thirty subjects were tested by the &bdquo;STOP BANG&ldquo; questionnaire, and retested a month later. Results of the investigation show the male sex predominated in the study sample (69.6%). The subjects&#39; mean age was 50.1&plusmn;13.8 years. Most subjects had SDB (73.5%). The majority of ther subjects (30.4%) had a serious SDB form (AHI&gt;30). Obstuctive disorders prevailed, registered in 66.7% of the study population. Excessive daily sleepiness, measured by the Epworth sleepiness scale, was registered in 58.8% of the examined subjects, correlating well to the disorder severity level (r=0.43). Sensitivity and specificity obtained for the &bdquo;STOP BANG&ldquo; questionnaire amounted to 62.7% and 51.9% respectively. The &bdquo;STOP BANG&ldquo; questionnaire was translated to Serbian first, followed by testing an retesting using the questionairre, providing no differences in the obtained answeres. The obtained cut-off value for the &bdquo;STOP BANG&ldquo; questionnaire was 4.5, and the test sensitivity and apecificity for different SAS severity levels were satisfactory, amounting to 70.7%/66.7% for mild, 78.6% /60,9% for moderate, and 87.4%/50.7% for severe sleep apnea. The cumulative comparation of the two questionnaires has disclosed a better specificity of 85.2%, 76.1%, and 69.0%, but a worse sensitivity of 53.3%, 58.9%, and 71.0% for a mild, moderate and severe sleep apnea respectively in the group of subjects whose values for both questionnaires exceeded the cutoffs. In the group of subjects with one of the questionnaire values exceeding the cutoffs, a better sensitivity but a worse specificity were obtained related to only the &bdquo;STOP BANG&ldquo; questionnaire. The investigation has established the screening method &ndash; the &ldquo;STOP BANG&ldquo; questionnaire which (on the basis of the clinical symptoms, physical examination and present risk factors) stratifies the patients into the high risk group requiring urgent polysomnography and referral for further treatment, and to those requiring no polysomnography.</p>

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

Introdução: O conhecimento de parâmetros respiratórios em recém-nascidos a termo saudáveis pode contribuir para a construção de critérios poligráficos utilizados no diagnóstico da Apneia do Sono Central do Lactente. No período neonatal tais critérios não se encontram bem estabelecidos. Método: Foi realizado estudo descritivo de 60 poligrafias de recém-nascidos a termo saudáveis, entre 37 e 44 semanas de idade pósconcepcional, entre os anos de 2017 e 2018, com controle de variáveis maternas, do recém-nascido e variáveis ambientais durante a aquisição de exames. Eventos respiratórios foram identificados conforme critérios do Manual para estadiamento do sono e dos eventos associados da Academia Americana de Medicina do Sono. Foram adicionalmente contabilizados apneias centrais com durações >= 3 segundos, >= 10 segundos, >= 15 segundos, >= 20 segundos; episódios de dessaturação < 90% e 85%; bradicardia < 100 e < 80 batimentos por minuto (bpm). Resultados: A frequência cardíaca (FC) em sono variou entre 82 e 199 bpm, com média de 120,3 ± 10,6 bpm. Antecedente positivo para tabagismo materno prévio foi associado a menores valores de frequência cardíaca mínima, em relação ao antecedente negativo (94 ± 8,4 bpm x 104,9 ± 10,5 bpm). Não foram registrados eventos de bradicardia com FC < 80 bpm. A saturação de oxigênio (SatO2) em sono variou entre 85% e 100%, com média de 97,6% ± 1,5. Não houve episódio de dessaturação com SatO2 < 85%. O percentil 90 para o índice de apneias e hipopneias foi 41,4/hora, e para o índice de apneias centrais foi 10,8/hora. A maioria (90%) dos recém-nascidos apresentou respiração periódica ausente ou presente em < 3% do tempo total de sono. Indivíduos com menores perímetros cefálicos apresentaram maiores índices totais de apneias, e indivíduos com menores perímetros torácicos apresentaram maiores índices de apneias e hipopneias. Conclusões: Não houve episódio de dessaturação com SatO2 < 85% ou eventos de bradicardia com FC< 80 bpm em recém-nascidos a termo saudáveis, e eventos prolongados de apneia foram raros. O percentil 90 para o índice de apneias e hipopneias foi 41,4/hora, e para o índice de apneias centrais foi 10,8/hora. Respiração periódica esteve geralmente ausente ou ocupando menos que 3% do tempo total de sono. Menores perímetros cefálicos e menores perímetros torácicos estiveram associados a maiores índices de eventos respiratórios. / Introduction: The knowledge of respiratory parameters in healthy term newborns can contribute to construction of diagnostic polygraphic criteria in Central Sleep Apnea of Infancy. In the neonatal period these criteria are not well established. Methods: A descriptive study of 60 polygraphic recordings of healthy term newborns (37-44 weeks of postconceptional age) was carried out between 2017 and 2018, with control of maternal, newborn and environmental variables during exams acquisition. Respiratory events were identified according to the American Academy of Sleep Medicine criteria. Central apneas >= 3 seconds, >= 10 seconds, >= 15 seconds, >= 20 seconds were analyzed as well as desaturation <90% and 85%; bradycardia <100 and <80 beats per minute (bpm). Results: The heart rate in sleep ranged from 82 to 199 bpm, with an average of 120.3 ± 10.6 bpm. Previous maternal smoking was associated with lower values in minimum heart rate, as compared to negative antecedent (94 ± 8.4 bpm x 104.9 ± 10.5 bpm). No bradycardia of <80 bpm events was recorded. Oxygen saturation in sleep ranged from 85% to 100%, with an average of 97.6% ± 1.5. There was no episode of desaturation <85%. Central apneas longer than 10 seconds were rare. The 90th percentile for apnea and hypopnea index was 41.4/hour, and for central apnea index was 10.8/hour. The majority (90%) of the newborns did not experience periodic breathing or presented it in <3% of total sleep time. Lower cephalic perimeters were associated with higher total apnea indices, and lower thoracic perimeters with higher apnea and hypopnea indices. Conclusions: There were no episodes of desaturation <85% or bradycardia < 80 bpm in healthy term newborns and prolonged apneas were rare. The 90th percentile for apnea and hypopnea index was 41.4/hour, and for central apnea index was 10.8/hour. Periodic breathing was usually absent in normal term newborns occupying less than 3% of total sleep time. Lower cephalic perimeters and lower thoracic perimeters were associated with higher rates of respiratory events.

阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，睡眠过程中反复发作的气道阻塞，导致间歇性低氧血症。OSA 中的間歇性缺氧（IH）一直被视為一個主要致病因素。會影響神經認知功能，包括記憶障礙，遲鈍的反應和其它。以前的研究提示氧化应激产物（ROS）和细胞凋亡是間歇性缺氧引起的认知功能障碍的主要機制之一。然而，确切的机制仍然知之甚少，并没有得到解决。我们基于間隙性缺氧 （IH）的动物模型的实验结果首次发现，即在IH 模型中海馬長時程增強（LTP）的降低，以及腦源性神經營養因子（BDNF）的表达减少。同時我們發現，大脑内注射BDNF 可以有效地恢复LTP 的幅度。因此，我们的研究提供了一种新的可能机制，即在缺乏脑源性神经营养因子可能是阻塞性睡眠呼吸暂停導致的伴有脑功能障碍一个关键因素。 / Ampakine 是一種AMPA 受體調節劑，更重要的是可以增加腦內BDNF 的表達。在这项研究中，我們在不同缺氧時間處理的動物模型中通过腹部注射ampakine 來觀察其效應。我們使用了四组成年雄性小鼠，其中組接受7 天IH处理，另外两组接受14 天缺氧处理。所有四组均分别接受腹腔ampakine 和对照生理盐水注射。 IH 模式仍然是氧含量在90 秒内从21 降到10%，再回复到21%。缺氧时间是每天8 小時周期。从整个IH /正常氧环境的第一天开始，八臂放射迷宮被用来研究参考记忆和工作记忆的表现。然后，我们对脑源性神经营养因子，活性氧和细胞凋亡的分子标记和海马的树突棘形态的表达进行了检查， 海馬突触可塑性的表現，包括E-LTP，L-LTP 也都被檢測。 / Western blot 分析显示，ampakine 注射有效恢复了IH 導致的海马BDNF 水平下降。同时， 我們也發現在ampakine 注射組中ROS 的表达减少，细胞凋亡的减轻，其中包括内质网应激诱导的细胞凋亡。树突棘被認為是海马突触可塑性的结构基础之一。高尔基体染色也表明， ampakine 注射IH 成功回復了7 天IH 導致的較大的，成熟树突棘的減少。 / 此外，八臂放射迷宮的结果表明，无论是参考记忆和工作记忆在7 天IH和14 天IH 均有受損表現。但是，ampkine 的使用同樣挽救了IH 引起的這些记忆障碍。 / 最後，通過研究AMPA 受體調節劑（ampakines）對IH-誘導的神經認知功能障礙及長時程增強障礙影響，我們發現進一步的闡明BDNF 在OSA 所起的重要作用。這些結果也將探索新的藥物治療的OSA 了新的思路。 / 阿爾茨海默病（AD），也叫老年癡呆癥，在65 歲的人的失憶症中，是最常見的原因，也是最常見的神經退行性疾病。 AD 的原因並不清楚，其起病也並不明顯。它的特點是逐漸喪失記憶，語言障礙及其他認知功能障礙，這些症狀可能會變得明顯。在AD 中，兩種蛋白質聚集體的參與和特點的AD 病理澱粉樣斑塊，由澱粉樣蛋白-β 肽，並導致細胞外病變和tau 蛋白纏結，這是由過度磷酸化的絲微管相關蛋白tau，並導致細胞內的病變。 / 鐵是最豐富的微量金屬，在大腦中參與範圍廣泛的細胞過程的運作。然而，鐵臭名昭著的另一方面是其強大的氧化催化性能。事實上，失調的鐵已被發現與細胞老化和各種各樣的神經退行性疾病有牽連。鐵在突觸功能的重要性是對突觸的影響，例如其可以順行軸突運輸突觸功能區域，這也是阿爾茨海默病中的澱粉樣蛋白斑的沉積的起始部位。然而，到現在，鐵的積累是如何影響突觸功能以及更普及的大腦功能很少被研究。 / 為了調查是否高鐵食有任何正常或阿爾茨海默氏病的影響，我們在實驗中引入了APPswe/ps1 轉基因小鼠，這是一個經典的老年癡呆症的疾病的動物模型。研究中，我們使用四組動物模型，即野生型（WT）和APPswe/ps1 小鼠（TG），每組給予至少10 個月正常（ctrl）的食和高鐵（HI）食。 / 海馬LTP 記錄表明，野生小鼠與正常食（WT-HI）的海馬長時程增強下降。 Tg-ctrl 組也相比wt-ctrl 組顯示LTP 水準下降，包括E-LTP 和L-LTP。引人注目的是，高鐵食下的APPswe/ps1 下顯示了被提高和恢復的海馬長時程突觸可塑性。 / 八臂放射迷宮的結果還表明，與高鐵食的野生型以及正常食的APPswe/ps1，無論是在參考記憶體或工作記憶，比野生型與正常食組有較差的記憶水準。同樣，我們驚訝地發現，和APPswe/ps1 正常食的小鼠相比，給予高鐵食的APPswe/ps1 組的迷宮成績要好得多,几乎回复到和野生型对照组一样的水平。 / 這些結果表明，鐵在阿爾茨海默病的功能是非常複雜的，可能會對其神經可塑性顯示雙相調節作用特性。詳細機制有待進一步探討。 / Obstructive sleep apnea (OSA) is a common sleep disorder, characterized by repeated episodes of airway obstruction during sleep resulting in intermittent hypoxemia. Previous studies proposed that reactive oxygen species (ROS) and apoptosis caused by intermittent hypoxia (IH) contributed to cognitive deficits. However, the exact mechanism is still poorly understood and not settled. Our recent studies, for the first time, showed that there is decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and impairment in long-term potentiation (LTP). Intra-brain injection of BDNF can effectively restore the magnitude of LTP. Thus, our study provides a novel mechanism and insight in the etiology of OSA-induced brain dysfunction in that lacking BDNF could be a critical factor. / In this study, ampakine application was used as “BDNF raiser“ during 7-day IH and 14-day IH treatment by intraperitoneal (i.p.) injection. Four groups of adult male mice were used, two of them exposed to 7-day IH and two of them exposed to 14-day IH, each received either vehicle or ampakine i.p. injection. The paradigm of IH consisted of cycles of oxygen levels between 10% and 21% every 90s during the daytime for 8 hrs. Radial arm maze was used to investigate the performance of reference memory and working memory during the whole IH/ normoxia treatment from the first day. After that, expression of BDNF, ROS and molecular markers of apoptosis and morphology of hippocampal dendritic spines were examined, together with the investigation of both hippocamal synaptic plasticity, including early phase LTP (E-LTP) and late phase L-LTP (L-LTP). / Ampakine treatment restored the decreased level of hippocampal BDNF in the IH-treated group, as revealed by Western blot. Meanwhile, decreased ROS expression and alleviated cell death, including ER stress induced-apoptosis are all found in those ampakine injected groups. Golgi staining also showed that ampakine injection IH treatment rescued the decrease of mature dendritc spines, which is the structural basis of hippocampal synaptic plasticity, under 7-day IH treatment. Hippocampal long-term synaptic plasticity, which underlies the proposed mechanism of memory, was also found reversed in those ampakine injected groups, compared with groups under IH treatment. / Furthermore, results of radial arm maze showed that both the reference memory and working memory are impaired by 7-day IH treatment or 14-day IH treatment. However, the application of ampakine rescued IH-induced memory deficits. / Finally, by studying the effects of the ampakines on IH-induced neurocognitive dysfunction and LTP impairment, the role played by BDNF in OSA was further elucidated. These results were shed new lights on the exploration of novel pharmacological treatments in the OSA. / Alzheimer’s disease is the most common cause of dementia among aged people. The causes of AD are not clear and onset of the disease is also not obvious. Iron is the most abundant trace metal in the brain and dysregulation of iron has been implicated in cell aging and a wide variety of neurodegenerative diseases including Alzheimer disease. However, up to now, very little is known about how iron accumulation is involved in Alzheimer disease. / To investigate whether high iron diet has any effects on normal or Alzheimer’s disease, we introduced APPswe/ps1 transgenic mice, an Alzheimer’s disease animal model, and used four groups in our study, namely wild type (wt) and APPswe/ps1 mice (tg), each with normal (ctrl) diets and high iron (HI) diet for at least 10 months. / Hippocampal LTP recording showed that wild type with high iron diet (wt-HI) decreased than that of wt-ctrl group. Tg-ctrl group also displayed decreased LTP level, including E-LTP and L-LTP, than that of wt-ctrl group. Strikingly, that of APPswe/ps1 under HI diets rescued the impaired hippocampal long-term synaptic plasticity than that of APPswe/ps1 mice under normal diets. / Results from radial arm maze also showed that both APPswe/ps1 with normal diet and wild type with HI diet had worse performance, either in reference memory or working memory, than those of wild type with normal diets. Again, it is surprised to find that performances of tg-HI group were much better than APPswe/ps1 mice under normal diet. / These results showed that the function of iron are very complicated, may have different effects on neural function of normal and AD objects. The detailed mechanisms needs to be further explored. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xie, Hui. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 200-225). / Abstracts also in Chinese. / Declaration --- p.II / ABSTRACT OF THESIS ENTITLED --- p.III / 中文摘要 --- p.VII / Acknowledgements --- p.XI / List of abbreviations --- p.XIII / List of publications --- p.XVI / Chapter CHAPTER 1 --- INTRODUCTION --- p.4 / Chapter 1.1 --- Overview of the study --- p.4 / Chapter 1.2 --- Obstructive sleep apnea --- p.7 / Chapter 1.2.1 --- Epidemiology --- p.8 / Chapter 1.2.2 --- Pathogenesis --- p.10 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.11 / Chapter 1.2.4 --- Diagnosis --- p.14 / Chapter 1.2.5 --- Treatment --- p.15 / Chapter 1.3 --- Memory and long-term potentiation --- p.17 / Chapter 1.3.1 --- Memory --- p.17 / Chapter 1.3.2 --- Hippocampal Synaptic plasticity --- p.19 / Chapter 1.3.3 --- Dendritic Spines --- p.23 / Chapter 1.4 --- Brain-derived neurotrophic factor --- p.35 / Chapter 1.4.1 --- Introduction of BDNF --- p.35 / Chapter 1.4.2 --- BDNF and synaptic plasticity --- p.36 / Chapter 1.5 --- Intermittent hypoxia impaired memory and neuroplasticity --- p.38 / Chapter 1.5.1 --- Clinical and basic studies on IH-induced neurological dysfunction --- p.38 / Chapter 1.5.2 --- Current mechanisms of IH-induced neurological dysfunction --- p.39 / Chapter 1.5.3 --- ROS generation and intermittent hypoxia --- p.41 / Chapter 1.5.4 --- Critical role of decreased BDNF expression in chronic intermittent hypoxia --- p..46 / Chapter 1.6 --- Ampakine --- p.48 / Chapter 1.6.1 --- Effects of ampakine on receptor activities --- p.49 / Chapter 1.6.2 --- Effects of ampakine on synaptic transmission --- p.50 / Chapter 1.6.3 --- Effects of ampakine on long-term potentiation --- p.52 / Chapter 1.6.4 --- Ampakine, BDNF and neurological disease --- p.53 / Chapter CHAPTER 2 --- METHODS --- p.61 / Chapter 2.1 --- Experimental procedure --- p.61 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.62 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.62 / Chapter 2.1.2 --- Oxygen saturation measurement under normoxia and intermittent hypoxia --- p.64 / Chapter 2.1.3 --- Body weight during hypoxia treatment --- p.64 / Chapter 2.2 --- Western Blot Analysis --- p.65 / Chapter 2.3 --- ROS measurement --- p.67 / Chapter 2.4 --- Golgi staining --- p.67 / Chapter 2.4.1 --- Analysis of spine density --- p.68 / Chapter 2.4.2 --- Measurement of dendritic spines --- p.68 / Chapter 2.5 --- Electrophysiological Experiments --- p.69 / Chapter 2.5.1 --- Brain Slice Preparation --- p.69 / Chapter 2.5.2 --- Multi-electrode Recording Setup (MED64) --- p.70 / Chapter 2.5.3 --- Slice Superfusion --- p.72 / Chapter 2.5.4 --- Field Potential Recordings --- p.73 / Chapter 2.5.5 --- LTP Induction Protocol --- p.74 / Chapter 2.6 --- Radial arm maze --- p.76 / Chapter CHAPTER 3 --- RESULTS --- p.91 / Chapter 3.1 --- Molecular detection under IH treatment and ampakine injection --- p.91 / Chapter 3.1.1 --- BDNF expression under IH treatment and ampakine injection --- p.91 / Chapter 3.1.2 --- ROS measurement under IH treatment and ampakine injection --- p.92 / Chapter 3.1.3 --- Involvement of ER stress during IH treatment --- p.93 / Chapter 3.2 --- Changes of dendritic spines under IH treatment and ampakine injection --- p.100 / Chapter 3.2.1 --- Changes of total dendritic spine density under IH treatment and ampakine injection --- p.100 / Chapter 3.2.2 --- Changes of different dendritic spine density under IH treatment and ampakine injection --- p.101 / Chapter 3.2.3 --- Changes of dendritic spine morphology under IH treatment and ampakine injection --- p.103 / Chapter 3.3 --- IH-induced impairment in hippocampal synaptic plasticity --- p.110 / Chapter 3.3.1 --- E-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.110 / Chapter 3.3.2 --- L-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.111 / Chapter 3.3.3 --- E-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.112 / Chapter 3.3.4 --- L-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.113 / Chapter 3.4 --- Behavioral studies under IH treatment and ampakine injection --- p.119 / Chapter 3.4.1 --- Reference memory test under IH treatment and ampakine injection --- p.119 / Chapter 3.4.2 --- Working memory measurement under IH treatment and ampakine injection --- p..122 / Chapter CHAPTER 4 --- DISCUSSION --- p.140 / Chapter 4.1 --- Molecular changes under IH treatment and ampakine application --- p.140 / Chapter 4.1.1 --- Intermittent hypoxia down regulate BDNF expression in hippocampus while ampakine injection rescued IH-induced decreased BDNF level --- p.140 / Chapter 4.1.2 --- Ampakine injection against ROS and apoptosis --- p.143 / Chapter 4.1.3 --- Involvement of ER stress-induced apoptosis during IH treatment --- p.145 / Chapter 4.2 --- Changes of spine morphology and density under IH treatment and ampakine injection --- p.146 / Chapter 4.3 --- Ampakine rescued hippocampal synaptic plasticity --- p.152 / Chapter 4.4 --- IH impaired reference memory and working memory --- p.156 / Chapter 4.5 --- Summary --- p.160 / Chapter Chapter 5 --- Effects of High-iron diet in Alzheimer’s Disease --- p..164 / Chapter 5.1 --- Overview of the study --- p.164 / Chapter 5.2 --- Introduction --- p.166 / Chapter 5.2.1 --- Alzheimer's disease --- p.166 / Chapter 5.2.2 --- Function of iron in brain --- p.167 / Chapter 5.2.3 --- Involvement of iron in oxidative damage --- p.168 / Chapter 5.2.4 --- Role of iron in neurodegeneration diseases --- p.168 / Chapter 5.2.5 --- Role of iron in Alzheimer's disease --- p.169 / Chapter 5.2.6 --- Deleterious effects of iron in memory function --- p.171 / Chapter 5.3 --- Methods --- p.172 / Chapter 5.3.1 --- Experimental design --- p.172 / Chapter 5.3.2 --- T-maze --- p.172 / Chapter 5.4 --- Results --- p.174 / Chapter 5.4.1 --- Validation of animal model of Alzheimer's disease --- p.174 / Chapter 5.4.2 --- Examination of normal and high iron diet on body weight --- p.174 / Chapter 5.4.3 --- Effects of Aβ accumulation and high-iron diet on hippocampal synaptic plasticity --- p.175 / Chapter 5.4.4 --- Effects of Aβ accumulation and high-iron diet on spatial memory measured by T-maze --- p.177 / Chapter 5.4.5 --- Effects of Aβ accumulation and high-iron diet on reference memory and working memory measured by radial arm maze --- p.178 / Chapter 5.5 --- Discussion --- p.180 / Chapter Chapter 6 --- General discussion --- p.195 / Reference --- p.200

Ng, Mei. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves xvi-xlviii). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT / In English --- p.ii / In Chinese --- p.iv / LIST OF TABLES --- p.vi / LIST OF FIGURE --- p.viii / ABBREVIATIONS / For Units --- p.ix / For Prefixes of the International System of Units --- p.ix / For Terms Commonly Used --- p.X / Chapter CHAPTER 1 --- Overview of Childhood Obstructive Sleep Apnoea Syndrome (OSAS) / Chapter 1.1 --- Prevalence --- p.1 / Chapter 1.2 --- Clinical Features --- p.3 / Chapter 1.3 --- Definitions and Cutoffs --- p.4 / Chapter 1.4 --- Pathophysiology --- p.6 / Chapter 1.5 --- Risk Factors / Chapter 1.5.1 --- Gender --- p.8 / Chapter 1.5.2 --- Obesity --- p.9 / Chapter 1.5.3 --- Adenotonsillar Hypertrophy --- p.10 / Chapter 1.5.4 --- Genetic --- p.11 / Chapter 1.5.5 --- Atopic Diseases --- p.12 / Chapter 1.6 --- Complications / Chapter 1.6.1 --- Neurobehavioural Deficits --- p.13 / Chapter 1.6.2 --- Growth Defects --- p.14 / Chapter 1.6.3 --- Metabolic Disorders --- p.16 / Chapter 1.6.4 --- Systemic inflammation --- p.17 / Chapter 1.6.5 --- Cardiovascular Consequences --- p.19 / Chapter 1.7 --- Diagnosis --- p.20 / Chapter 1.8 --- Treatment / Chapter 1.8.1 --- Surgical Treatment --- p.22 / Chapter 1.8.2 --- Continuous Positive Airway Pressure (CPAP) --- p.24 / Chapter 1.8.3 --- Corticosteroids --- p.24 / Chapter 1.8.4 --- Leukotriene Receptor Antagonist --- p.25 / Chapter 1.8.5 --- Oral Appliances --- p.26 / Chapter 1.8.6 --- Weight Control --- p.27 / Chapter CHAPTER 2 --- OSAS and Cardiovascular Complications in Adults / Chapter 2.1 --- Mechanism / Chapter 2.1.1 --- Acute Cardiovascular Responses --- p.28 / Chapter 2.1.2 --- Chronic Cardiovascular Responses --- p.29 / Chapter 2.2 --- Hypertension / Chapter 2.2.1 --- Epidemiological and Clinical Data --- p.31 / Chapter 2.2.2 --- Characteristics --- p.32 / Chapter 2.2.3 --- Mechanisms --- p.33 / Chapter 2.2.4 --- Treatment --- p.34 / Chapter 2.3 --- Heart Failure --- p.35 / Chapter 2.4 --- Stroke --- p.37 / Chapter 2.5 --- Cardiac Arrhythmias --- p.39 / Chapter 2.6 --- Myocardial Ischemia and Vascular Disease --- p.41 / Chapter 2.7 --- Pulmonary Hypertension --- p.43 / Chapter CHAPTER 3 --- OSAS and cardiovascular complication in children / Chapter 3.1 --- Blood Pressure --- p.45 / Chapter 3.2 --- Ventricular Hypertrophy and Dysfunctions --- p.48 / Chapter 3.3 --- Heart Rate Variability --- p.50 / Chapter 3.4 --- Arterial Tone --- p.51 / Chapter 3.5 --- Endothelial Function --- p.51 / Chapter CHAPTER 4 --- Longitudinal follow-up study of children with OSAS - a cardiovascular perspective / Chapter 4.1 --- Introduction --- p.53 / Chapter 4.2 --- Methods / Chapter 4.2.1 --- Subjects and Study Design --- p.57 / Chapter 4.2.2 --- Polysomnography --- p.59 / Chapter 4.2.3 --- Ambulatory Blood Pressure Measurement --- p.61 / Chapter 4.2.4 --- Statistical Analysis --- p.62 / Chapter 4.3 --- Results / Chapter 4.3.1 --- Subject Characteristics --- p.64 / Chapter 4.3.2 --- Blood Pressure During Wakefulness --- p.71 / Chapter 4.3.3 --- Blood Pressure During Sleep --- p.76 / Chapter 4.3.4 --- Nocturnal Blood Pressure Dipping --- p.83 / Chapter 4.3.5 --- Blood Profile --- p.86 / Chapter 4.4 --- Discussion --- p.87 / Chapter 4.5 --- Conclusion --- p.99 / Reference List --- p.xvi

Leung, Kin Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 133-162). / Abstracts in English and Chinese. / CONTENTS --- p.i / ACKNOWLEDGEMENTS --- p.ii / ABBREVIATIONS --- p.iii / ABSTRACT --- p.vi / 論文摘要 --- p.ix / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Obstructive sleep apnea syndrome --- p.1 / Chapter 1.1.1 --- Symptoms of OSA --- p.2 / Chapter 1.1.2 --- Causes of OSA --- p.5 / Chapter 1.1.3 --- Complications of OSA --- p.6 / Chapter 1.1.4 --- Episodic hypoxia profile --- p.9 / Chapter 1.2 --- Hippocampus --- p.12 / Chapter 1.2.1 --- General structure of hippocampus --- p.12 / Chapter 1.2.2 --- The neuronal circuitry of hippocampus --- p.17 / Chapter 1.2.3 --- Cell types of hippocampus --- p.21 / Chapter 1.2.4 --- Functions of hippocampus --- p.24 / Chapter 1.3 --- Memory Formation and long term potentiation --- p.27 / Chapter 1.4 --- Neurotrophins --- p.33 / Chapter 1.5 --- Brain-derived neurotrophic factor (BDNF) --- p.38 / Chapter 1.5.1 --- Molecular characteristics of BDNF --- p.38 / Chapter 1.5.3 --- Functions of BDNF --- p.46 / Chapter 1.5.4 --- BDNF and neuronal plasticity --- p.46 / Chapter 1.6 --- Tissue plasminogen activator - plasmin system --- p.51 / Chapter 1.6.1 --- Molecular characteristics of tissue plasminogen activator - plasmin system --- p.51 / Chapter 1.6.2 --- Functions of tissue plasminogen activator - plasmin system --- p.54 / Chapter 1.7 --- Aim of the study --- p.59 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.61 / Chapter 2.1 --- Animal model of obstructive sleep apnea --- p.61 / Chapter 2.1.1 --- Intermittent hypoxia --- p.61 / Chapter 2.2 --- Electrophysiological recordings --- p.65 / Chapter 2.2.1 --- Preparation of brain slices --- p.65 / Chapter 2.2.1 --- Visualization of hippocampus CA1 Neurons --- p.66 / Chapter 2.2.3 --- Patch-clamp recordings --- p.66 / Chapter 2.3 --- Protein analysis - ELISA --- p.71 / Chapter 2.3.1 --- Isolation of mouse hippocampus total protein --- p.71 / Chapter 2.3.2 --- ELISA --- p.72 / Chapter 2.3 --- Protein analysis (II) - Western blot --- p.74 / Chapter 2.4.1 --- Isolation of mouse hippocampus total protein --- p.74 / Chapter 2.4.2 --- Western blot analysis --- p.75 / Chapter 2.5 --- Data analysis --- p.78 / Chapter CHAPTER 3 --- RESULTS --- p.79 / Chapter 3.1 --- Effect of intermittent hypoxia on passive and active properties of hippocampal CA1 neurons --- p.79 / Chapter 3.1.1 --- Passive properties --- p.79 / Chapter 3.1.2 --- Membrane excitability --- p.83 / Chapter 3.1.3 --- Action potential characteristics --- p.93 / Chapter 3.2 --- Effect of intermittent hypoxia on the expression of BDNF and related proteins --- p.104 / Chapter 3.2.1 --- "Levels of total BDNF, NGF, NT-3 and NT-4/5" --- p.104 / Chapter 3.2.2 --- Recovery study of the expression of BDNF after IH treatment --- p.110 / Chapter 3.2.3 --- Differential effect of IH on pro-BDNF and mature BDNF --- p.114 / Chapter 3.2.4 --- "Expressions of tissue plasminogen activator, plasmin and plasminogen" --- p.117 / Chapter Chapter 4 --- Discussion --- p.121 / Chapter 4.1 --- Changes in neuronal excitability of CA1 neurons under intermittent hypoxia --- p.121 / Chapter 4.2 --- Intermittent hypoxia-induced changes in BDNF level --- p.127 / Chapter 4.3 --- Conclusion --- p.130 / REFERENCES --- p.133