Rozprawy doktorskie na temat „Exhaled nitric oxide”

O objetivo do presente estudo foi avaliar o papel de um programa de condicionamento físico nos aspectos relacionados à qualidade de vida, níveis de ansiedade e depressão, sintomas e óxido nítrico exalado de pacientes com asma persistente moderada ou grave. Foram avaliados 39 pacientes divididos aleatoriamente em grupo controle (GC; N=20) e grupo treinado (GT; N=19). Foram avaliados a capacidade aeróbica máxima (VO2max), função pulmonar, qualidade de vida, sintomas, ansiedade, depressão e percepção subjetiva de esforço e óxido nítrico exalado com um intervalo de 3 meses. Não houve diferença entre os grupos antes do tratamento. O treinamento físico melhorou as capacidades máximas e submáximas ao esforço e os níveis de depressão (p < 0,05). O treinamento físico reduziu os níveis de ansiedade-traço (p < 0,05), mas não a ansiedade-estado. O treinamento físico também melhorou os domínios limitação física, freqüência de sintomas, psicossocial e escore total dos HRQL (p < 0,001). Houve aumento no número de dias livres de sintomas (p < 0,001) e nos valores de óxido nítrico exalado (p < 0,001) no grupo treinado. Nossos resultados sugerem que o condicionamento físico para pacientes asmáticos pode ser benéfico para reduzir sintomas e melhorar os escores de qualidade de vida e a co-morbidade psicossocial. Estes dados sugerem que o treinamento físico pode ter um papel adjuvante importante no controle clínico de pacientes com asma persistente moderada ou grave
The aim of the present study was to evaluate the effect of aerobic training on quality of life, functional capacity and exhaled nitric oxide (NOex) in patients with moderate and severe asthma. Twenty nine subjects were randomly divided in control group (n 20) (educational program + breathing exercises) and training group (n 19) (control + aerobic training, 70% maximal VO2peak) and followed during 3 months, twice a week. Aerobic capacity (VO2peak), quality of life, anxiety, depression, and pulmonary function were evaluated before and after treatment. FENO and symptoms were evaluated monthly. There was no change in inhaled glucocortiscosteroid during treatment. Our results show that patients submitted to an aerobic training presented a decrease on physical limitation (p < 0.05), frequency and gravity score, decrease in psychosocial limitation an increse in global score of quality of life (p < 0.05) as well as an improvement on VO2peak (p=0,001) when compared with control group. Compared with control group, training group also presented a increase in number of days without symptoms (p < 0,001). FENO it was also decreased (p < 0,001) after training in training group. No change was observed in lung function in both groups after treatment. Our results suggest that aerobic improves quality of life and decreases symptoms and exhaled nitric oxide on asthmatic patients reinforcing its importance on asthma treatment

RESUMO:A determinação da fracção exalada de óxido nítrico (FENO) é amplamente utilizada como um biomarcador da inflamação eosinofílica das vias aéreas. Alguns estudos sugerem que a produção de óxido nítrico (NO) é influenciada pelas variações cíclicas hormonais na mulher,porém os dados não são consensuais. Deste modo, o objectivo do nosso estudo foi avaliar como varia a FENO ao longo do ciclo menstrual. Com esta finalidade, avaliamos um grupo de 20 voluntárias, em idade fértil, com ciclo menstrual regular, não fumadoras, que não utilizavam contraceptivos hormonais, nem suplementos alimentares e/ou medicamentosos e que não se encontravam grávidas, nem a amamentar. Todas referiram não ter conhecimento de qualquer patologia que afecte a FENO. A existência de atopia foi controlada através de testes cutâneos por prick, tendo-se excluído as participantes que apresentaram testes positivos. Realizamos quatro visitas de estudo, com base na periodicidade do ciclo de cada participante, nas quais, efectuamos a determinação da FENO, a quantificação dos níveis plasmáticos de óxido nítrico e nitratos (NO/NO3 -) e o doseamento hormonal de 17 -estradiol e progesterona. As avaliações realizaram-se no período da manhã, em jejum absoluto, tendo respeitado uma dieta pobre em nitratos no dia anterior e abstido da prática de exercício vigoroso uma hora antes da avaliação. Com este trabalho, verificamos um aumento significativo da FENO na fase secretora (17.97 ppb ± 5.8) comparativamente com a fase menstrual e proliferativa (16.48 ppb ± 3.6 e 15.95 ppb ±2.8, respectivamente). Não observamos variações significativas dos níveis plasmáticos de NO/NO3 - ao longo do ciclo. Constatamos uma correlação positiva entre a FENO e os níveis plasmáticos de NO/NO3 - durante a ovulação e verificamos que, para a nossa amostra, os níveis hormonais de estradiol e progesterona não são preditores do valor da FENO, nem dos níveis plasmáticos de NO/NO3-. Os resultados deste trabalho mostram uma variação da FENO ao longo do ciclo, ainda assim, mantendo-se os seus valores dentro do intervalo de referência, reforçando a fiabilidade deste biomarcador.--ABSTRACT:The determination of fractional exhaled nitric oxide (FENO) is widely used as a biomarker of eosinophilic airway inflammation. Some studies suggest that nitric oxide (NO) is influenced by cyclical hormonal changes in women, but those are not consensual. The aim of our study was to assess how FENO varies throughout the menstrual cycle. With this purpose, we studied a group of 20 volunteers within childbearing age, with regular menstrual cycle, non-smokers, who were not taking any medications including hormonal contraception and food supplements and who were not pregnant or breast-feeding. All participants reported not being aware of any condition that could affect the FENO. The presence of atopy was controlled by a skin prick test, having been excluded participants with positive test. We conducted four study visits, based on the periodicity of the cycle of each participant. In each visit, we made the determination of the FENO, the quantification of plasmatic levels of nitric oxide and nitrates (NO/NO3 -) and the blood levels of hormone estradiol-17 and progesterone. The evaluations occurred at morning, after overnight fasting. The participants were request to follow a low-nitrate diet in the previous day and refrained from vigorous exercise, for at least one hour before the visit We found a significant increase of FENO on secretory phase (17.97 ppb ± 5.8) compared with the menstrual and proliferative phase (16.48 ppb ± 3.6 and 15.95 ppb ± 2.8, espectively). No significant variations were found throughout the menstrual cycle in plasmatic levels of NO/NO3 -. We found a positive correlation between FENO and plasmatic levels of NO/NO3 - during ovulation. Finally, in our sample, the levels of oestradiol and progesterone are not predictors of FENO value nor of plasmatic levels of NO/NO3-. This study shows a variation of FENO over the menstrual cycle, nevertheless, the values remain within the reference range, reinforcing the reliability of this biomarker.

Abstract Advances in perinatal treatment practices—such as antenatal corticosteroids, surfactant replacement therapy, and gentler ventilator modalities—have improved the survival of infants born preterm. Consequently, later morbidity and pulmonary outcome for survivors has attracted increasing interest. The incidence of bronchopulmonary dysplasia (BPD) remains high and the condition is manifesting in infants born at earlier gestational weeks than before. This so-called new BPD results from the arrest of alveolar development and is associated with less structural airway injury and interstitial fibrosis than previously. Long-term follow-up data on lung function, lung structure and respiratory morbidity of children treated with modern methods is insufficiently known. We performed a follow-up study of 88 preterm-born children and 88 matched term-born controls at school age. Children born preterm had lower values in lung function measurements than term-born peers. Reductions were most marked in those with a history of BPD. In accordance with the foetal origins hypothesis, children with intrauterine growth restriction (IUGR) had lower lung function than gestation-controls. This indicates that poor growth in utero is an additional burden on pulmonary health. Both IUGR and BPD predicted lower lung function independently. High-resolution computed tomography of the lung was obtained from 21 children with a history of BPD. Structural abnormalities were common, children with severe BPD being most affected. Preterm children were hospitalised more often than controls, mainly because of wheezing disorders. However, BPD did not influence the hospitalisations. According to the meta-analysis of the contemporary data available, the respiratory outcome of children who had only mild BPD may have improved in comparison to old follow-up data, whereas the results for those without BPD or moderate-to-severe BPD have remained remarkably stable despite progress in treatment practices during early life. In conclusion, preterm children had subtle impairments in lung function at school age. Although they were fairly asymptomatic, concern about the possible long-term effects of preterm birth on pulmonary health is justified. It has been proposed that BPD may predispose individuals to an early COPD-like disorder. Preterm children must be protected from any additional burden on respiratory health and should be monitored appropriately for early detection of lung disease
Tiivistelmä Keskosten tehohoito on kehittynyt viime vuosikymmeninä merkittävästi, ja yhä epäkypsempänä syntyvät keskoset selviävät hengissä syntymän jälkeen. Keskosten pitkäaikainen keuhkosairaus, bronkopulmonaalinen dysplasia (BPD), on perinteisesti johtunut hengityskonehoidon ja happikaasun aiheuttamasta keuhkovauriosta ja johtanut keuhkokudoksen arpeutumiseen. Aiempaa ennenaikaisemmilla keskosilla esiintyy kuitenkin nykyään niin sanottua uutta BPD:tä, jonka ajatellaan johtuvan enemmän keuhkorakkuloiden kehityshäiriöstä kuin hoitojen aiheuttamasta keuhkovauriosta. Selvitimme, miten nykyaikaisilla menetelmillä hoidettujen keskosten keuhkojen rakenne ja toiminta kehittyvät kouluikään mennessä. Seurantatutkimukseemme osallistui 88 ennenaikaisena syntynyttä, kouluikään ehtinyttä lasta ja 88 täysiaikaisena syntynyttä, kaltaistettua verrokkia. Keskosena syntyneiden lasten keuhkofunktio oli kouluiässä huonompi kuin täysiaikaisena syntyneiden verrokkien. Alhaisin keuhkofunktio oli niillä keskosena syntyneillä lapsilla, jotka olivat sairastaneet vastasyntyneenä BPD:n. Myös kohdunsisäiseen kasvuhäiriöön (intrauterine growth restriction, IUGR) liittyi alentunut keuhkofunktio. BPD ja IUGR ennustivat alentunutta keuhkofunktiota toisistaan riippumatta. Tutkimuksessa tehtiin myös keuhkojen ohutleiketietokonekuvaus 21 keskoselle, jotka olivat sairastaneet BPD:n. Lähes kaikilla havaittiin poikkeavia löydöksiä – eniten niillä, joilla oli ollut vastasyntyneenä BPD:n vaikea tautimuoto. Keskosina syntyneet joutuivat kahden ensimmäisen vuoden aikana verrokkeja useammin sairaalahoitoon. Yleisimpiä syitä olivat hengityksen vinkumista aiheuttavat taudit kuten ilmatiehyttulehdus, ahtauttava keuhkoputkitulehdus tai akuutti astmakohtaus. Vastasyntyneenä sairastettu BPD ei kuitenkaan lisännyt todennäköisyyttä joutua sairaalahoitoon. Tutkimuksessa tehtiin myös meta-analyysi nykyaikaisilla menetelmillä hoidettujen keskosten keuhkofunktiosta: lievää BPD:tä sairastavien tulokset näyttävät parantuneen, kun taas keskivaikeaa tai vaikeaa tautimuotoa sairastavien ja ilman BPD:tä selvinneiden keuhkofunktio ei ole muuttunut uusien hoitojen myötä. Yhteenvetona voidaan todeta, että keskosten keuhkojen toimintakyky on jonkin verran alentunut täysiaikaisiin verrattuna. Lievästi alentunut keuhkofunktio ei kuitenkaan yleensä aiheuttanut koululaisille oireita. Keskosena syntyneiden lasten hengityselinten toimintaa on syytä seurata, sillä niin sanotun uuden BPD:n pitkäaikaisesta ennusteesta ei ole vielä tietoa

Liu Kin Hang.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 88-98).
Abstracts in English and Chinese.
Abstract (in English) --- p.i
Abstract (in Chinese) --- p.iii
Acknowledgement --- p.v
Table of Contents --- p.vi
List of Tables --- p.ix
List of Figures --- p.x
Glossary of Terms and Abbreviations --- p.xi
Chapter Section I: --- Overview --- p.1
Chapter Chapter 1: --- Introduction --- p.2
Chapter 1.1 --- Asthma and Assessment of A irway Inflammation --- p.2
Chapter 1.1.1 --- Assessment of A irway Inflammation --- p.4
Chapter 1.1.2 --- Invasive and Noninvasive Methods --- p.4
Chapter 1.1.3 --- Exhaled Nitric Oxide as a Diagnostic Marker and Its Correlation with Other Markers of Inflammation --- p.6
Chapter 1.1.4 --- Normal Reference Studies of Exhaled Nitric Oxide --- p.8
Chapter 1.2 --- Aim of Study --- p.10
Chapter Chapter 2: --- Plan of Study --- p.11
Chapter Section II: --- Literature Review --- p.13
Chapter Chapter 3: --- Nitric Oxide Biology --- p.15
Chapter 3.1 --- Exhaled Nitric Oxide Production in Airway --- p.15
Chapter 3.2 --- Nitric Oxide Production and Function --- p.16
Chapter 3.3 --- Nitric Oxide Synthase Pathway --- p.18
Chapter 3.4 --- Factors Affecting Exhaled Nitric Oxide Level --- p.21
Chapter 3.4.1 --- Procedure-related Factors --- p.22
Chapter 3.4.1.1 --- Nasal Nitric Oxide Contamination --- p.22
Chapter 3.4.1.2 --- Exhalation Procedure 226}0´ؤؤStarting Lung Volumes --- p.23
Chapter 3.4.1.3 --- Exhalation Procedure 226}0ؤ Flow --- p.23
Chapter 3.4.1.4 --- Circadian Rhythm --- p.25
Chapter 3.4.2 --- Patient Factors --- p.26
Chapter 3.4.2.1 --- Sex --- p.26
Chapter 3.4.2.2 --- Upper Respiratory Tract Infection --- p.26
Chapter 3.4.2.3 --- Diet and Exhaled Nitric Oxide --- p.27
Chapter 3.4.2.4 --- Effect of Spirometry and Exercise --- p.28
Chapter 3.4.3 --- Environmental Factors --- p.28
Chapter Chapter 4: --- Exhaled Nitric Oxide in Asthmatics and Its Relationship to Anti-inflammatory Treatment --- p.31
Chapter Chapter 5: --- Relationship of Exhaled Nitric Oxide with Other Inflammatory Markers --- p.33
Chapter 5.1 --- Correlation of Findings from Biopsy and Bronchoalveolar Lavage with Exhaled Nitric Oxide --- p.33
Chapter 5.2 --- "Exhaled Nitric Oxide, Induced Sputum Analysis and Sputum Eosinophil Cationic Protein" --- p.35
Chapter Section III: --- Original Study --- p.37
Chapter Chapter 6: --- Methodology --- p.38
Chapter 6.1 --- Study Population --- p.38
Chapter 6.2 --- The International Study of Asthma and Allergies in Childhood --- p.40
Chapter 6.3 --- ISAAC Questionnaires --- p.42
Chapter 6.4 --- Standardized Approach for Answering Questions in the Field --- p.44
Chapter 6.5 --- Anthropometric Measurements --- p.45
Chapter 6.6 --- Exhaled Nitric Oxide Measurement --- p.46
Chapter 6.6.1 --- "NIOY® (Aerocrine AB, Stockholm, Sweden)" --- p.46
Chapter 6.6.2 --- Calibration Procedures --- p.47
Chapter 6.6.3 --- Exhaled Nitric Oxide Measurement --- p.48
Chapter 6.7 --- Classification of Subjects --- p.51
Chapter 6.8 --- Statistical Analysis --- p.53
Chapter Chapter 7: --- Results --- p.54
Chapter 7.1 --- Subjects and Demography --- p.54
Chapter 7.2 --- Exhaled Nitric Oxide in Chinese Children --- p.58
Chapter 7.3 --- Exhaled Nitric Oxide in Caucasians and Other Ethnic Groups --- p.66
Chapter Chapter 8: --- Discussion --- p.69
Chapter Chapter 9: --- Conclusion and Further Studies --- p.76
Appendix 1 Questionnaires (Chinese Version) --- p.80
Appendix 2 Questionnaires (English Version) --- p.84
References --- p.88

BACKGROUND: Pulmonary Hypertension (PH) is a common form of high blood pressure in the lungs. It affects the pulmonary arteries, which normally allow blood to flow from the right heart to the lungs. Nitric Oxide (NO) is a potential mediator for establishing PH and decreasing its availability is implicated in the pathogenesis of PH. HYPOTHESIS: We tested the hypothesis that Fractional Exhaled Nitric Oxide (FeNO) is a good indicator to assess disease severity that may add to understanding the disease. METHODS: The aim of the study was to measure FeNO levels in consecutive PH patients and seek correlations with the 6 Minute walk distance (6MWD) within different World Health Organization (WHO) groups and New York Health Association Function Class (NYHA FC). Assignment to groups I or IV was done respecting the current guidelines. All values were taken at Tufts Medical Center PAH clinic visits. FeNO levels were measured utilizing the NIOX device. RESULTS: FeNO levels were highest in WHO Group 1 and lowest in WHO Group 5 patients. There was a strong inverse correlation between FeNO and 6MWD for each NYHA FC. (Pearson correlation of -0.986, p = 0.014). Within WHO Groups, we found significantly inverse correlations between FeNO and 6MWD in PH Group 4 (p= 0.012) and PH Group 5 (p=0.001). NYHA FC correlated with 6MWD across all WHO Groups (P=0.001). CONCLUSION: We report for the first time FeNO levels in all WHO Groups of PH. FeNO levels are low in early disease. FeNO levels correlate inversely with the severity of PH in WHO Group 4 and 5 patients. The increase in FeNO in more severe patients may reflect the degree of oxidative stress and inflammation in severe PH. Further studies to determine whether FeNO may be a biomarker in early disease, especially in PH Group 4 and 5 warrants further investigation.

Background Nitric oxide (NO) was well known to be a component of air pollution, often in the form of nitrogen dioxide (NO2). However its importance in biological systems altered dramatically with the discovery in 1987 that it was the 'endothelial-derived relaxing factor'. Since then there has been an explosion of research on NO demonstrating that this gaseous molecule was a widespread physiological mediator and was simultaneously recognised as a vital component of immune function contributing to macrophage-mediated cytotoxicity. NO was therefore a key molecule in modulating inflammation, including airway inflammation. The aim of this thesis was: 1. To adapt a NO chemiluminscence analyser from measuring airway pollution to measuring exhaled air in human subjects. 2. To measure NO levels in exhaled air in adult subjects. 3. To evaluate whether altering measurement parameters altered the levels of NO obtained. 4. To adapt this technique from adults to measure exhaled NO in children. 5. To compare levels of NO from healthy children to groups of asthmatic children on either bronchodilator therapy only, or on regular inhaled corticosteroids. 6. To compare the levels of NO in a pilot group of asthmatic children before and after commencement of inhaled corticosteroids. Methods A Dasibi Environmental Corporation Model 2107 chemiluminescence analyser was adapted specifically requiring a reduction in response time, which was achieved by modification of the circuitry and re-routing of the analogue signal directly to a chart recorder, achieving a reduction of the response time by 80%. Addition of a number of analysers allowed the measurement of exhaled NO, carbon dioxide (CO2), mouth pressure and flow for each exhalation from total lung capacity. Twenty adult subjects (in total) were then studied looking at direct (NO, CO2, mouth pressure) versus t-piece (with the addition of flow) measurements making five exhalations from total lung capacity, at 3-minute intervals (direct/t-piece/direct or t-piece/direct/t-piece in series). The area of NO under the curve versus the peak of the NO trace was compared and the exhalation pattern of NO versus CO2 was compared. Measurement conditions were altered to evaluate the effect of individual parameters on the exhaled NO result. This included separately assessing different expiratory flows, different expiratory mouth pressures, the effect of a high versus a low background NO level and the effect of drinking water (of varying temperatures) prior to exhalation. Healthy control children were then enrolled to the study from a local school (Park Walk Primary School) and compared with asthmatic children enrolled from outpatient clinics at the Royal Brompton Hospital. The asthmatic children were further divided into those on bronchodilator treatment only and those on regular inhaled corticosteroid therapy. NO was also measured before and two weeks after commencing inhaled corticosteroid therapy in previously steroid-naive asthmatics. Results It was possible to modify a chemiluminescence analyser to enable measurement of exhaled NO. In 12 healthy subjects (mean age 32 years, 6 males) peak direct NO levels were 84.8 parts per billion (ppb) (standard error of the mean (SEM) 14.0ppb), significantly higher than 41.2ppb (SEM 10.8ppb) measured via the t-piece system. The exhaled NO rose to an early peak and plateau while the CO2 levels continued to rise to peak late in the exhalation. The mean times to peak NO levels were 32.2 seconds (s) (direct) and 23.1s (t-piece), which was significantly different from the mean times to peak CO2 levels at 50.5s (direct) and 51.4s (t-piece, p<0.001). At peak NO level, the simultaneous CO2 level of 4.9% (SEM 0.47%, direct) and 5.2% (SEM 0.18, t-piece) were significantly lower than the peak CO2 achieved of 5.8% (SEM 0.21%, direct, p<0.001) and, 6.2% (SEM 0.28, t-piece, p<0.001). There was no difference between repeat direct or t-piece measurements. With regard to varying measurement conditions, the mean peak concentrations of NO decreased by 35ppb (95% confidence intervals 25.7-43.4) from a mean of 79ppb (SEM 15.4ppb) at an expiratory flow rate of 250mls/min to 54.1ppb (SEM 10.7ppb) at 1100mls/min. The mean peak concentration of NO did not change significantly when mouth pressure was increased in eight of ten subjects, although in two it did decrease in the highest pressure. The mean NO concentration with machine and subjects sampling from a low NO reservoir was 123ppb (SEM 19.4), which was an increase from results obtained before at 81.9ppb, SEM 10.2ppb, p=0.001 95%, CI -19.9 to -62.7) and after at 94.2ppb(SEM 18.3ppb, p=0.017, 95% CI 6.0-5.18) sampling with high ambient NO levels. The mean peak NO concentration decreased from 94.4ppb (SEM 20.8) to 70.8ppb (SEM 16.5, p=0.002 95% CI 12.9 -33.1) with water consumption. In 39 healthy pre-pubertal children with a mean age of 9.9 years (range 9-11 years, 23 girls) the mean direct exhaled No level was 49.6ppb (SD 37.8ppb, range 11.5-197.2ppb) compared with mean exhaled No via t-piece sampling of 29.2ppb (SD 27.1ppb, range 5.1-141.2ppb). There was no significant difference between boys and girls for either the direct or the t-piece recordings. In comparison with normal children, 15 asthmatic children on bronchodilator therapy only had much higher levels of exhaled NO at 126.1ppb via the direct system (SD 77.1ppb, p<0.001) and 109.5ppb via the t-piece system (SD 106.8ppb, p<0.001). In 16 asthmatics on regular inhaled corticosteroids the mean peak exhaled levels were significantly lower at 48.7ppb via the direct method (SD 43.3ppb, p<0.001) and via the t-piece system at 45.2ppb (SD 45.9ppb, p<0.01). There was no difference between the normal children and the asthmatic children who were on regular inhaled corticosteroids (p=0.9 direct, p=0.2 t-piece).There was no significant difference in CO2, mouth pressure, duration of expiration and expiratory flows between the three groups or between the two methods (direct and t-piece). In six asthmatic children the mean peak exhaled NO levels fell from a medium peak level of 124.5ppb to 48.6ppb when measured before and two weeks after commencement of inhaled corticosteroids on treatment. Discussion This research showed it was possible to modify an NO chemiluminescence analyser to enable measurement of exhaled NO in adult and paediatric subjects. Furthermore, it was possible to measure both healthy and asthmatic children. There were significant differences between the exhalation pattern of NO and CO2 suggesting that NO was produced in the airways, not at alveolar level, unlike CO2. The measurement of exhaled NO required a standardised approach as exhaled NO levels decreased with increasing expiratory flow, when measuring at a time of high ambient NO concentration, and with consumption of either hot or cold water immediately preceding exhalation (such as might be given if a subject was coughing). The findings with expiratory mouth pressure were less certain, with a difference seen in only two of ten subjects. The levels of exhaled NO measured in children aged 9-11 years were lower than that measured in the adult subjects. There was no difference between boys and girls, or with other parameters such as having a personal history of atopy, a family history of atopy, or the presence of a smoker or furry pets within the house-hold. These findings may have altered with increased numbers in this group and could possibly be a type two statistical error. The results of exhaled NO in asthmatic children on bronchodilator therapy only were significantly elevated compared to both normal children and asthmatic children treated with regular inhaled corticosteroids. The exhaled NO level also fell significantly by two weeks following the commencement of inhaled corticosteroid treatment in steroid-naive asthmatic children. These results suggested that the methods of measuring exhaled NO required standardization and that it could potentially be a non-invasive measure of airway inflammation to follow - particularly in children with asthma who were commencing inhaled steroid treatment.

碩士
國立陽明大學
公共衛生研究所
87
Asthma is a chronic inflammatory disease of the airway. Recently, studies have found that exhaled nitric oxide (eNO) was correlated with airway inflammation. We used eNO measurement and questionnaire to clarify the effect of air pollution on asthma and airway disease in schoolchildren. Our study subjects were third grade students from 石牌國小 in Taipei and 淡水國小 in Tamshui. We recruited 256 students (male: 133, female: 123) from the two schools. Study was performed between October 1998 and Apr 1999. The effect of children''s atopy or airway disease on eNO, and the effect of air pollutants and children''s eNO were analyzed. Finally, We compared the effect of air pollutants on children with or without atopic airway disease. In the study subjects, 10.2% children had physician-diagnosed asthma, 19.1% children had wheezing, 24.6% children had physician-diagnosed allergic rhinitis, and 5.4% children had physician-diagnosed dermatitis. Family factors that influenced eNO: children''s father with higher education, mother with allergic rhinitis, and sibling with allergic rhinitis would increase children''s eNO level. Children''s factors affecting eNO included: physician-diagnosed asthma, wheeze, allergic rhinitis, dermatitis, cough in the past year, and upper airway infection (at the time of examination) would increase children''s eNO level. Air pollution: Ozone concentration, ambient temperature, and particulate matter would decrease eNO level, but ambient nitric oxide concentration would increase eNO level. We also found that eNO level was continually increasing from October 1998 to Mar 1999. And it was decreased from Mar 1999 to Apr 1999. URI, sulfur dioxide, and particulate matter had more pronounced effect on nonatopic students. We also found that atopic students were more sensitive to ambient temperature. We concluded that atopy, airway disease and air pollution were correlated with eNO. The most important factor in air pollution that influenced children''s eNO was ambient temperature. We also found that eNO had a time-dependent trend. In conclusion, ozone concentration, ambient temperature, ambient nitric oxide, URI, and allergic rhinitis were important on eNO level.

The consensus in the literature is that exercise-induced hypoxemia (EIH) occurs secondary to ventilation-perfusion (VA/Q) inequalities and diffusion limitations resulting from elevated pulmonary pressures causing the development of interstitial pulmonary edema, or decreased pulmonary transit time in the pulmonary vasculature. Endogenously produced pulmonary nitric oxide (NO) has been hypothesized to have several physiological functions including VA/Q matching and maintenance of low pulmonary vascular resistance. Respiratory derived NO is detectable in exhaled gases. Inhaled NO, a selective pulmonary vasodilator is used in the treatment of diseases characterized by pulmonary hypertension and hypoxemia. Short-term inhalation of NO causes selective pulmonary vasodilation without any systemic effects. Given that athletes with EIH are thought to have altered pulmonary hemodynamics during exercise, the relationship between endogenously produced and exogenously delivered NO and EIH was examined in two separate studies. It was hypothesized that subjects with EIH would have a decreased production rate of NO (VNO) compared to subjects who maintained normal oxyhemoglobin saturation (SaO2) and that SaO2 would be correlated with VNO. A group of highly-trained male cyclists (n = 18), some of whom develop EIH performed a maximal cycle test. VNO was determined during the cycle test. No significant differences were observed between those with and those without EIH. There was also no observed linear relationship between delta SaO2 and delta VNO. It can be concluded that NO present in exhaled air is not related to the etiology o f EIH. In a subsequent study, delivery of NO was accomplished using highly trained male cyclists (n = 7) with EIH who performed four 5-min cycle tests at VO2max under conditions of normoxia (N), normoxia + 20 ppm nitric oxide (N/NO), hypoxia (H), and hypoxia + 20 ppm nitric oxide (H/NO). It was hypothesized that: (i) inhaled NO would reverse EIH during normoxia, and (ii) inhaled NO would improve arterial oxygenation during hypoxia. Inhalation of NO during normoxic or hypoxic conditions did not significantly affect gas exchange, cardiorespiratory variables, or power output. These findings imply that pulmonary capillary blood volume reaches a maximal morphological limit during exercise and further dilation is not possible.

碩士
國防醫學院
公共衛生學研究所
106
Aim: We assessed the relations between heavy metals, polycyclic aromatic hydrocarbons exposure and plasma nitric oxide, fractional exhaled nitric oxide, and lung function among shipyard workers. Methods: This study was a longitudinal study. All of 354 workers were recruited from the shipyard in Taiwan from 2014 to 2016. After excluded female workers, there were 333 workers include in this study finally. Personal air sampling was collected at the first day; FeNO and lung function test were collected at the second day. In order to analyze urine heavy metals and plasma NO, we also collected blood and urine from workers in both days. Results: In generalized estimating equation analysis, adjusting for age, waist, smoking status, time, and urinary creatinine, negative significant were found between log urinary nickel and log plasma NO (β=-0.079, 95%CI: -0.149 to -0.009, p=0.026). After adjusting for age, waist, smoking status, and time, negative significant were found between log PM2.5 and log FeNO (β=-0.051, 95%CI: -0.087 to -0.016, p=0.004). After adjusting for age, waist, smoking status, time, and urinary creatinine, negative significant were found between log urinary manganese and log FeNO (β=-0.068, 95%CI: -0.13 to -0.006, p=0.032); negative significant were found between log urinary cadmium and log plasma NO (β=-0.133, 95%CI: -0.221 to -0.045, p=0.003); negative significant were found between log urinary 1-OHP and log FeNO (β=-0.123, 95%CI: -0.233 to -0.014, p=0.028); negative significant were found between log urinary nickel and FVC% (β=-20.015, 95%CI: -34.836 to -5.194, p=0.008); FEV1 % (β=-19.159, 95%CI: -32.079 to -6.239, p=0.004); FEV1/FVC % (β=-1.983, 95%CI: -3.898 to -0.067, p=0.043). Conclusion: In conclusion, this study showed biomarkers of exposure to Mn, Cd, Ni, and PAH are associated with decreased plasma NO, FeNO, and lung function indicators. We suggest to wearing personal protective equipment may decrease adverse health effects from occupational exposure.

碩士
中州科技大學
保健食品系
103
Background：Betel nut chewing is common in Taiwan and exhaled nitric oxide (eNO) is most important in our heath. It is make vessel dilatation to adjust blood pressure in cardiac vascular system. To control coagulation and cardiac contraction function. The peripheral nerve system can adjust vessel dilatation, respiratory, digestive and urological function with penis erection. In the immune system against bacteria, cancer cells and other pathogens, kill a variety of pathogens and protection mechanisms, and can provide a powerful defense system in vivo. Studies published in a patient suffering from asthma increased exhaled nitric oxide concentrations in the air in 1993, but if the patient has to take steroid drugs to reduce the concentration of exhaled nitric oxide. With so many articles when studies show respiratory irritation detect exhaled nitric oxide concentration, the concentration was found to increase nitric oxide can induce inflammatory inference eosinophil activity sphere. It is not known whether betel nut chewing affects eNO with contains constituents known to inhibit inducible NO synthase which releases exhaled. May be associated with respiratory inflammation related to this study will help to understand the impact of chewing betel nut of the human immune defense mechanism. Objective：To assess the effects of betel nut chewing on eNO levels. Methods：Nineteen regular betel nut chewers were studied. eNO levels were measured using a portable analyser (MiniNIOX) prior to and immediately after chewing a betel nut preparation, and at 30 min intervals up to 3 hr. Results：Data analysis and display chew whether fractional exhaled nitric oxide concentration (FeNO Value) will cause respiratory irritation reaction before and after the betel nut, exhaled nitric oxide in each group, are no significant differences. Whether the instrument detects lung function FEV1 (L) can cause airway contractile response in each group, are no significant differences. The possible reasons: 1. regional betel different contents of its relevance. 2. Oral cancer is not through this oncogenic pathway for inflammation. 3. Cha Ye component having polyphenolic compounds with antioxidant activity activity, further inhibit inflammation. Conclusions and Clinical Relevance：In this study, chewing betel nut, after their respiratory exhaled nitric oxide concentration FEV1 testing and data analysis, the results showed no statistical significance, followed by studies can then be blood test specific immunoglobulin E (Allergen Specific -IgE) data, the relative analysis of betel nut chewing further estimate whether the subjects of their respiratory inflammation, in order to facilitate the clinical diagnosis as the reference data.

碩士
輔仁大學
公共衛生學系碩士班
96
Background： According to the epidemiological studies, it demonstrated that the prevalence and incidence rate of asthma were increasing gradually every year. People spent over 80 % of their time indoors. Indoor and outdoor air pollutants such as particular matter（PM）, volatile organic compounds（VOCs）, sulfur dioxide（SO2）, ozone（O3）had been proved to be significantly correlated with the increased incidence of respiratory symptoms in asthmatic children. Collection of exhaled gas was a simple and noninvasive technique for sampling of nitric oxide（NO）and airway lining fluid that can be used as indicators of exacerbation of respiratory diseases. This study was to evaluate the impaction of indoor and outdoor air pollutants on pulmonary function by measuring NO levels and exhaled breath condensate（EBC）pH in exhaled gas. Methods： This panel study recruited 15 asthmatics and 15 healthy children, aged between 7 and 12 years old, from outpatient department of Chang Gung Memorial Hospital in 2006. Self-reported questionnaires included personal information, family allergic history, blood allergy index, and home/life characteristics. Air quality in domestic environment was measured with the dust monitor（GRIMM particle size analyzer model l.108, Germany）, air quality monitor（I.A.Q, KD Engineerings AirBoxx, USA）, and VOCs monitor（ppbRAE, RAE Systems model PGM-7600, USA）. Exhaled NO levels in schoolchildren were monitored by a chemiluminescence analyzer （CLD 77 AM, ECO Physics, Dürnten, Switzerland）. EBC pH was analyzed after collecting EBC from subjects using an exhaled breath condensate collector（ECoScreen, Jaeger-Toennies, Germany）. Pulmonary function tests were performed every three months to evaluate the variation of lung functions. The concentrations of outdoor air pollutants measured at the ambient air monitoring site operated by Taiwan Environmental Protection Agency（EPA）that located in district of Songshan were also collected. All the data were analyzed by SPSS software. Result： This study was to monitor indoor air quality of domestic environment in schoolchildren with asthma and healthy controls in autumn and winter. Air temperature in domestic environment of asthmatics was higher than the recommended value of indoor air quality guideline. Our results demonstrated that mean eNO concentrations in asthmatics（41.62 ppb in autumn and 48.75 ppb in winter）were significantly higher than those in healthy individuals（14.90 ppb in autumn and 14.94 ppb in winter）（ p＝0.001 in autumn and p＜0.001 in winter）. There was not a statistically significant difference in EBC pH between asthmatics（pH=6.76 in autumn and 6.61 in winter）and healthy children （pH=7.12 in autumn and 6.82 in winter） （ p＝0.112 in autumn and p＝0.412 in winter）, but EBC pH had a lower tendency found in children with asthma than normal controls in this study. In addition, forced expiratory volume time on one second (FEV1), peak expiratory flow (PEF) and forced expiratory flow25% ~ 75%, (FEF25% ~ 75%) in asthmatics had a decreased trend compared to healthy controls in both autumn and winter. From our findings, it was indicated that air pollutants were associated with eNO level, EBC pH and pulmonary function test. NO association was found between eNO level and EBC pH in schoolchildren. Conclusion： Exhaled gas analysis is a noninvasive, duplicated, and safety monitoring technique. Measurements of exhaled NO and EBC pH would react with airway inflammation correlated to indoor and outdoor air pollutants exposure.

碩士
中國文化大學
應用化學研究所
87
Nitric oxide (NO) can be detected in the exhaled air of humans. Several recent studies have demonstrated that the concentration of exhaled NO is increased in patients with asthma, but reduced after patients were treated with inhaled glucocorticoids. In this thesis, we would like to build up a data bank and a method for measurement of exhaled NO concentrations of asthmatic patients in Taiwan. Exhaled NO determinations were performed via a on-line restricted exhaled breath method in 57 normal and 82 asthmatic subjects by a chemiluminescence analyzer. The exhaled NO level in the normals was 16.4 * 6.7 ppb, while the levels in the asthmatics, before and after treated with an inhaled bronchodilator, were 32.1 * 27.6 and 30.3 * 11.4 ppb, respectively. Obviously, the exhaled NO concentrations determined in patients with asthma were significantly elevated above those of normal subjects. However, there was no statistically significant change ( p > 0.05 ) in NO contents of asthmatic paitents, before and right after treated with a bronchodilator, no matter what age, sex, or level of exhaled NO. It is known that the difference in exhaled NO of normal subjects and asthmatics derives from a difference in NO concentration present in the lower airway, and reflects the inflammatory microenvironment of the asthmatic airway wall. Thus, the measurement of nitric oxide concentrations in exhaled air may represent a noninvasive measure of lower airway inflammation. And, it will be a useful way of monitoring the anti-inflammatory effects of glucocorticoids and other anti-inflammatory treatments in asthma.

博士
中山醫學大學
醫學研究所
101
Objective: To evaluation the usefulness of FeNO measurement in patients with eosinophilic inflammatory airway disease, such as bronchial asthma and chronic cough. Material and Method: A nitric oxide analyzer (NOA 280i) was used to conduct five experiments. In the first experiment, 249 Taiwanese non-smoking healthy adults were enrolled to determine the reference values of FeNO in Taiwan. In the second experiment, the correlations between offline and online FeNO data of 56 patients were evaluated. In the third experiment, the correlations between FeNO level and % of major basic protein (MBP) positive sputum cells (eosinophils) were compared. In the fourth experiment, we investigated possible correlations between ACT scores and FeNO values in 73 outpatient visits made by 60 asthmatic patients. In the fifth experiment we reviewed the medical records of 81 patients with chronic cough, to compare the FeNO level and the response to inhaled corticosteroid treatment in these patients. Results: The result of the first experiment showed that the mean FeNO in 249 Taiwanese non-smoking healthy adults was 27.9ppb. In multivariate regression analyses, age and lung function (FVC or FEV1) were positively associated with the FeNO values. In the second experiment, a high correlation between online and offline FeNO levels (r = 0.908, p < 0.001) were observed. The predicted online FeNO level (ppb) = 2.233 × offline FeNO level (ppb) - 6.236. In the third experiment, no correlation between FeNO level and percentage of major basic protein (MBP) positive sputum cells (eosinophils) were seen, but in 19 and 16 patients, the % of MBP positive cells was higher than 3% and 5% respectively. The result of the fourth experiment showed the mean FeNO value was higher in patients reported their ACT scores were≧20 than those who reported the ACT scores were＜20. There was a negative correlation between ACT scores and FeNO values (r = -0.596). In the fifth experiment, significant difference in FeNO value was seen in patients whose cough responded good to ICS treatment.ROC analysis showed that a FeNO of 33.9 ppb was the best cut-off value for using ICS (sensitivity 94.7%, specificity 76.3%). Conclusions: After conducting these five experiments, we found that FeNO measurement is a versatile, easy-to-use, non-invasive diagnostic tool for assessing inflammatory airway diseases. By using the reference FeNO value and the formula for predicting online data that we have devised, FeNO measurement can be applied to patients for evaluating eosinophilic inflammation of the airways.

Introduction: People with asthma suffer from lower fitness levels when compared to their peers. The abnormal respiratory response to exercise, known as exercise induced bronchoconstriction (EIB), in the majority of people with asthma is a barrier to improving fitness levels. EIB severity can be increased with airway inflammation, which can be measured by exhaled nitric oxide (eNO). One exercise protocol, high intensity interval exercise (HIIE), may decrease the risk of developing EIB in people with asthma. HIIE warm up studies have demonstrated that HIIE is feasible and reduces the incidence of EIB in subsequent exercise bouts. HIIE may be ideal for people with asthma because it can decrease the duration of high ventilation that can trigger EIB, and improve their fitness levels. The purpose of this study is to compare the acute respiratory effects of traditional constant workrate exercise to a novel HIIE protocol in adults with asthma. Methods: 5 females and 2 males with asthma were recruited to perform two randomly assigned exercise protocols: HIIE (30 seconds of 140% the peak workrate and 90 seconds at 20%) and constant workrate exercise (CWR) (60% peak workrate). Workrates were determined by a peak cardiopulmonary exercise test. Measures of pulmonary function and airway inflammation were done pre and post exercise protocols. During exercise protocols, operational lung volumes, heart rate, rating of perceived exertion (RPE) was obtained. Results: FEV1 decreased significantly in both exercise protocols (HIIE 3.91± 0.65 to 3.33 ± 0.61 vs. CWR 3.90 ±0.50 to 3.09 ± 0.63). eNO measurements decreased after both exercise protocols (HIIE 40.4± 34.8 vs. CWR 42.1 ± 36.3. Conclusion: FEV1 and eNO findings are similar in HIIE and CWR exercise in adults with asthma, therefore, the novel HIIE is a feasible exercise protocol to help improve fitness levels of adults with asthma.