Master of Science in Medicine / Rationale: Asthma management aims to achieve optimal control on the minimal effective dose of medication. We assessed the effectiveness of two algorithms to guide ICS dose in well-controlled patients on ICS+LABA in a double-blind study, comparing dose adjustment guided by exhaled nitric oxide (eNO) to clinical care algorithm(CCA) based on symptoms and lung function. Methods: We randomised non-smoking adult asthmatics on minimum FP dose 100μgs daily +LABA to ICS adjustment using eNO or CCA, assessed over 5 visits during 8 months treatment. Primary endpoints were asthma-free days and asthma related quality of life (QOL). Analysis was by mixed model regression and generalised estimating equations with log link. Results: 69 subjects were randomised (eNO:34, CCA:35) and 58 completed the study. At baseline mean FEV1 was 94% pred., mean eNO (200ml/sec) 7.1 ppb, median ACQ6 score 0.33. Median ICS dose was 500 μg (IQR 100-500) at baseline and 100 μg on both eNO (IQR 100-200) and CCA arms (IQR 100–100) at end of study. There were no significant differences between eNO and CCA groups in asthma-free days (RR=0.92, 95% CI 0.8–1.01), AQL (RRAQL<median = 0.95, 95% CI 0.8–1.1) or exacerbation-free days (HR = 1.03, 95%CI 0.6–1.7). Neither clinic FEV1 (overall mean difference FEV1 % pred. -0.24%, 95% CI -2.2–1.7) nor a.m. PEF (mean difference 1.94 L/min (95% CI -2.9–6.8) were significantly different. Similar proportions of subjects were treated for ≥1 exacerbation (eNO: 50%, 95% CI 32.1–67.9; CCA: 60%, 95% CI 43.9–76.2). Conclusion: Substantial reductions in ICS doses were achieved in well controlled asthmatics on ICS+LABA, with no significant differences in outcomes between eNO or clinically based algorithms.

Inhalation of organic dust, including endotoxin, has been associated with inflammatory response of the pulmonary system. Limited studies have evaluated the work shift effects of endotoxin on respiratory outcomes for workers in the dairy industry, such as spirometry changes. Measurement techniques for exhaled nitric oxide (eNO) have been standardized by the American Thoracic Society (ATS) and used as a biomarker to identify diseases marked with lung inflammation. Dairy parlor workers are known to work long hours in one location with little job variability. The objectives of this study were to quantify exposure concentrations of inhalable dust and endotoxin among dairy parlor workers, evaluate acute cross-shift changes in respiratory status using spirometry, and assess the effectiveness of exhaled nitric oxide for detecting cross-shift bronchial inflammation changes. The cross-sectional study recruited 62 dairy parlor workers from 10 large herd dairy farms across Iowa, Minnesota, Wisconsin, and South Dakota. Data collected before and after the work shifts included spirometry tests, eNO measurements, and pulmonary symptom questionnaires. Personal breathing zone exposure to inhalable dust was assessed during the shift using Button Aerosol Samplers. Gravimetric analysis was used to determine airborne concentrations of inhalable dust and endotoxin concentration was determined using the recombinant factor C assay. Inhalable dust concentrations ranged from 0.09 - 4.95 mg/m3 with a geometric mean of 0.58 mg/m3. Inhalable endotoxin concentrations ranged from 4-1968 EU/m3 with a geometric mean of 117 EU/m3. The study participants pre-shift forced expiratory volume in the first second (FEV1) as a percentage of predicted was an average of 93.4%. Study group cross-shift FEV1 decreased by -1.16%. Six participants with moderate post-shift concentrations of eNO had an average FEV1 cross-shift change of -3.19%. Dairy parlor workers are exposed to concentrations of organic dusts that may adversely impact health. Future studies should test interventions in milking parlors to reduce dust exposure among dairy workers.

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.

<p>Two thirds of patients with diabetes avoid regularly monitoring their blood glucose levels because of the painful and invasive nature of current blood glucose detection. As an alternative to blood sample collection, exhaled breath condensate (EBC) has emerged as a promising non-invasive sample from which to monitor glucose levels. However, the inconsistency in the methods used to collect EBC significantly impacts the reliability of reported analyte concentrations in EBC. Furthermore, this dilute sample matrix requires a highly sensitive glucose biosensor to enable robust and accurate glucose detection at the point-of-care. Together, a reliable collection method and sensitive detection system can enable accurate modeling of glucose transport from blood to breath that is reflective of airway glucose homeostasis.</p> <p> I address this research gap by simultaneously designing a standardized EBC collection method that allows for separation of dead space and alveolar air and developing a competitive fluorescent biosensor that can resolve micromolar glucose concentrations changes. First, I develop a low-cost, automated condenser that selectively collects exhaled breath that has been exchanged with lung fluid based on the detection of higher breath temperatures that are characteristic of the lower respiratory regions. Using this device, I investigate the relationship between blood and EBC glucose in diabetic and normoglycemic human subjects. Next, I engineer the exquisitely sensitive <i>E. coli</i> glucose binding protein (GBP) with a chemo-enzymatic tag to selectively conjugate it to highly photostable quantum dots (QDs). Finally, I take advantage of the competitive binding of glucose (K_D=0.35 µM) and galactose (K_D=1.4 µM) to GBP to develop a fluorescent glucose biosensor using the GBP-QD conjugate.</p>

The aim of this study was to evaluate the relationship of oxidative stress (OS) marker s in exhaled breath condensate (EBC) in adult patients with cystic fibrosis (CF) to the severity of lung disease, nutritional status and systemic antioxidants and inflammatory markers, as well as to short - and medium - term development of pulmonary function and nutritional status, and finally to assess the response to treatment with inhaled corticosteroids (ICS). Methods: CF patients were examined in a stable phase of the disease during routine outpatient controls. EBC was collected using E C oScreen device (J aeger) in CF patients and in control group members. Nitrites and nitrates and 8 - isoprostane were examined using liquid chromatography and competitive enzyme immunoanalysis, respectively, in EBC as OS markers. Demographic data including the dominant pathogen of airway colonization and ICS treatment were recorded in CF patients. Lung function tests, chest X-ray s, nutritional statuses and systemic antioxidants and inflammatory markers were also examined using standard methods. The values of OS markers in EBC in patients with CF were compared with the control group and correlated to clinical parameters. Lung function tests and nutritional status es in CF patients were examined in one, three and five years intervals...

The ultimate goal of this research is to develop an efficient, reproducible and low cost method for analysis of VOCs in complex mixtures such as those in exhaled breath and in headspace of fungi cultures. In Chapter I; analytical methods for volatile biomarkers identification is reviewed In Chapter II, active SPME GCMS was employed to analyze VOCs in the breath of a single healthy male and a single female. The goal was to determine the extent of intra-individual variations in the VOC profiles. In Chapter III, a preliminary study was carried out in a greenhouse to determine the pathogenicity of different isolates of M. phaseolina on soybeans. This will allow, in future studies, the matching of VOC profiles of different isolates of M. phaseolina with their relative pathogenicity. This is a key step towards the development of an early warning system for the detection of pathogenic M. phaseolina fungus contaminations.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13579号 / 論医博第2301号 / 新制||医||1069(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 古川 壽亮, 教授 大鶴 繁, 教授 平井 豊博 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

My thesis installation emerged from an interest in visualizing breath. The resulting work came to exist at the intersection between art, biology, and performance. The unicorn tapestries were used as a generative point of departure to explore the preservation and transformation of images through time, by time, and with time. Reproductions of the six tapestries were each etched into paper and then submerged into solutions of Phenol Red dye, Ferric Ferrocyanide (also known as Prussian Blue), and various forms of sodium chloride. Exhaled breath was used to encrust these images of the tapestries into physical objects which gradually crystallized and changed colors in response to viewers within the surrounding space. An invasive plant species native to Richmond, Virginia was utilized as a catalyst to re-absorb Carbonic acid from exhaled breath and convert the objects back to their original (or not so original) states. The final piece became the active remnants from an inquiry which quickly snowballed into so much more than I had initially planned. The following text is written as a supplemental reading to trace some of my influences at the periphery of the piece while mapping my thought processes.

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

Background: Carbon monoxide (CO) is a toxic gas, but it is also produced endogenously when haem is degraded. When produced in vivo, CO is believed to have positive biological effects. For example it activates the production of cyclic guanosine mono-phosphate and causes vasodilatation. CO is also believed to have anti-inflammatory properties by binding to Mitogen activated protein (MAP) kinase. Several studies in cells, mice and rats support this opinion regarding both the circulatory as well as the anti-inflammatory properties. However, studies in larger animals regarding circulatory effects have demonstrated contradictory results. The only study in humans regarding anti-inflammatory properties of CO could not demonstrate such effects. Methods: This thesis consists of four different models. In paper I a method for analysis of CO in blood was developed using gas chromatography. In paper II a porcine model was used to investigate the elimination time for CO. The pigs in paper II had a high concentration of CO administered via blood, and CO concentrations were followed over time and kinetically parameters calculated. Circulatory parameters were also measured to evaluate if there were any circulatory changes after CO administration. In paper III CO´s anti-inflammatory properties were investigated in an endotoxin-induced systemic inflammatory model in pigs. Paper III was a randomized study where one group inhaled CO and the other group served as controls. Plasma cytokine concentrations were measured and followed over time as an indication of the inflammatory state. In paper IV, CO concentrations in blood from blood donors at the Blood Centre in Umeå were investigated. The blood donors also completed a questionnaire about age, smoking history and other possible sources for exogenous contamination of CO in the blood. Results and conclusions: In paper I we developed a method suitable for analysis of low concentrations of CO in blood. The half-life of CO at levels of 250 µM in pigs was found to be 60 minutes. CO did not show anti-inflammatory effects after an endotoxin-induced systemic inflammation in pigs. In banked blood CO was present at concentrations up to six times higher than normal concentrations. This could be a risk when transfusing such blood to susceptible patients.