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Lorsbach, R. 8., W. J. Murphy, et al. (1993). "Expression of the nitric oxide synthase gene in mouse macrophages altivated for tumor cell killing. Molecular lasis for the synergy between interfero-n-garnma and lipopolysaccharide." Journal of Biological Chemistry 268(3): 1908-13. Lotvall, J., M. Inman, et al. (1993). "Measurement of airway hyperresponsiveness: new considerations." @ 53(5): 419-24. Louahed, J., M. Todu,? uL (2000). "Interleukin-9 upregulates mucus ex-pression in the airways." Louahed,J.,Y.n9p'o-otesinfluxandlocalmaturationof eosinophils." B!.oos! 97 (4): 1035-42, [,ouis, R., J. Sele, et at. (2002). "Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive aithma: distribution and relationship with methacholine bronchial hyperresponsiveness. " A!!4y 57( 10): 907 -L2' Louis, R., J. Shute, et al. Oggr. "Clll infiltration, ICAM-I expression, and eosinophil chemotactic activity in asthmatic sputum." Care Medicine 155(2): 466-72. Loukides, S., S. Kharitonov, et al. (1993). "Effect of arginine on mucociliary function in 352(9 125): 37 | -2' primary cili ary dyskinesi a. " @! Lovell, S. L., H. Stevenson, et at. (ZOOO). "bxhaled nitric oxide during incremental and constant workload exercise in chronic cardiac failure." European Journal of Clinical Investigation 30(3): l8l-7. Lowenstein, C. J. unA S. H. Snyder (lgg2). "Nitric oxide, a novel biologic messenger." Q!! 70(5): 705-7. Lowhagen, O., A. M. Wever, et al. (2002). "The inflammatory marker serum eosinophil cationic protein (ECp) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patients." Respiratory Medicine 96(2):95-101. Ludviksdottir, D., C. Janson, et al. (1999). "Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. BHR-Study Group." Respiratory Medicine 93(8): 552-6. Lugosi, E., G. Halmerbauer, et al. (lgg7). "Urinary eosinophil protein X in relation to disease activity in childhood asthma." AIIglgy 52(5): 584-8' Lundberg, J. b., T. Farkas-Szallasi, eial.-(1995). "High nitric oxide production in human paranasal sinuses." Nature Medicine. 1(4): 370-3' Lundbeig, J. O., p. M. Hellstrom, et al. (1994). "Greatly increased luminal nitric oxide in ulcerative colitis." Lancet 344(893 8): 167 3-4' Lundberg, J. O., S. L. Nordvall, et al. (1996). "Exhaled nitric oxide in paediatric asthma and .lrtir fibrosis." Archives of Disease in Childhood. 4(75): 323-6. Lundberg, J. o., r. ninao, dLlgg4). "Nasally exhaled nitric oxide in humans originates riainly in the paranasal "t sinuses.i Acta Phvsiologica Scandinavica. Apr: 152(4): 431- 2. Lundberg, J. O., J. Rinder, et al. (1997). "Heavy physical exercise decreases nitric oxide levels in the nasal airways in humans." Acta Physiologica ScandinaYica 159(1): 51-7' Lundberg, J. O., E. Weitzberg, et al. (Lgg4). "Intragastric nitric oxide production in humans: measurements in expelled air." @1 35(l l): 1543-6' Lundberg, J. O., E. Weitzbirg, et al. (19%). "Nitric oxide in exhaled air. [Review] [71 refs]"' European Respiratory Journal. 9(12): 267 L -80' tunou"rgJ. o., E5"it"b"tg, .t al. (199a). "Primarily nasal origin of exhaled nitric oxide and absence in KartagJner's syndrome." European Respiratory Jou-rqal. 7(8): 15014' Lundgren, R., M. Soderber:g, et al. (1983). "Morphological studies of bronchial mucosal - biopsies from asthmaiics before and after tenyears of treatment with inhaled steroids." European Respiratory Journal 1(10): 883-9' 317
Lymar, S. V. and J. K. Hurst (1996). "Carbon dioxide: physiological catalyst for peroxynitrite-mediatedcellulardamageorcellularprotectant?''@ Toxicology 9(5): 845-50. Lyons, C. R., G. J. Orloff, et al. (1992). "Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line." Journal of Biological Chemistry 267 (9): 637 04. Macfarlane, A. J., O. M. Kon, et al. (2000). "Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin." Journal of Allergy & Clinical Immunology 105(1 Pt 1): 99-L07. Machado, R. F., J. K. Stoller, et al. (2N2). "Low levels of nitric oxide and carbon monoxide inalphal-antitrypsindeficiency.''93(6):203843, Mackie, A. 8., J. E. McDowall, et al. (2000). "Pharmacokinetics of fluticasone propionate inhaled via the Diskhaler and Diskus powder devices in healthy volunteers." Clinig,gl Pharmacokinetics 39 Suppl l: 23-30. MacMicking, J., Q. W. Xie, et al. (1997). "Nitric oxide and macrophage function." Annual Review of Immunology 15:323-50. MacMicking, J. D., C. Nathan, et al. (1995). "Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase." Cell 81(4): 641-50. MacMcking, J. D., R. J. North, et al. (1997). "Identification of nitric oxide synthase as a protective locus against tuberculosis." hoceedings of the National Academ], of Sciences of the United States of America 94(10): 5243-8. Maejima, K., T. Suzuki, et al. (1992). "Toxicity to rats of methanol-fueled engine exhaust inhaled continuously for 28 days." Joumal of Toxicology & Environmental Health 37(2):293-312. Maestrelli, P., C. Paska, et al. (2003). "Decreased haem oxygenase-l and increased inducible nitric oxide synthase in the lung of severe COPD patients." European Respiratory Journal 2l(6):971-6. Maestrelli, P., M. Saetta, et al. (1995). "Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage." American Journal of Respiratory & Critical Care Medicine 152(6 ft 1): 1926-3I. Mahabee-Gittens, E. M., D. T. Bachman, et al. (1999). "Chest radiographs in the pediatric emergency department for children < or = 18 months of age with wheezing." Clinical Pediatrics 38(7): 395-9. Mahut, B., C. Delacourt, et al. (2004). "Increase in alveolar nitric oxide in the presence of symptoms in childhood asthma." Chest 125(3): 1012-8. Mahut, B., C. Delclaux, et al. (2004). "Both inflammation and remodeling influence nitric oxide output in children with refractory asthma." Immunolo gy ll3(2): 252-6. Mahut, B., E. Escudier, et al. (2006). "Impairment of nitric oxide output of conducting airwaysinprimaryciliarydyskinesia.''@4|(2):l58-63. Mai, X. M., M. F. Bottcher, et al. (2005). "Urinary inflammatory mediators and inhalation of hypertonic saline in children." Allggy 60(1): 60-4. Malinski, T., F. Bailey, et al. (1993). "Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion." Journal of Cerebral Blood Flow & Metabolism 13(3): 355-8. Malinski, T. and Z. Taha (1992). "Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor." \41ture 358(6388): 67 6-8. Malinski, T,2. Taha, et al. (1993). "Diffusion of nitric oxide in the aorta wall monitored in situ by porphyrinic microsensors." Biochemical & Bioph)rsical Research Communications 193(3): I07 6-82. Mallory, G. 8., Jr. (2006). "Pitfalls in non-therapeutic research in children." Pediatric Pulmonology 41( 1 1 ): 10 14-6; discussion lOlT -20. 318
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UNIVERSITV OF AUCKI'AND Abstract -
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There was no significant difference
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This is Dedicated: Dedication To th
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New Zealand The Paediatric Departme
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Contents Abstract ........tr Dedica
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6.5.4 The subjects............... .
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XIV
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List of Figures Figure l.l: Top l0
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List of Abbreviations ABPA allergic
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LADA N*N* dimethyl L-arginine LFA1
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t}ryem(eNoS)Typeltrendothelialnifti
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area, some of it has been expanded
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In addition, both of these groups a
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studies conducted throughout the Un
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Video clips of infants with a varie
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the Paediatric Society of New 7*ala
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inhaled anti-cholinergic agents and
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ecommended to monitor asthma at hom
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improvement to 70Vo PEF would have
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Furthermore, investigators have als
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poorer predictor of a diagnosis of
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Bronsky et al. 1998), and a long-te
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SIGN guideline (SIGN 2005) stated "
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In brief, the human airway can be d
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The ability to biopsy has led to st
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small proportion of cells recovered
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methodology of sputum induction and
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et al. 1999; Giannini, Di Franco et
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over a six month treatment prograrn
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There are other studies suggesting
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So is induced sputum in adults and
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asymptomatic patients independent o
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onchial hyper-responsiveness (Reich
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led to research which looked for le
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analyser machines. This thesis pres
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The pollution of the 'great smog of
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adults greater than 65 years (Ostro
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levels compared to those children l
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More recently 'Air Quality Indexes'
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acetylcholine. These were known to
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cyclase does not produce significan
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Garthwaite l99l), and the non adren
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significant complication, this trea
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locus for the enzyme is a susceptib
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NO synthesis and in so doing blocke
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3.1 Chapter 3: The synthesis, react
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BHa = tetrahyrobiopterin, FAD = fla
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(Knowles, McWeeny et al. 1974) and
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more potent at low oxygen tensions
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toxic products such as isoprostanes
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Figure 3.3: The nitric oxide syntha
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providing NO as a neurotransmitter
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The enzyme of this second pathway -
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inappropriate production from comme
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Nicotinamide adenosine dinucleotide
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enzyme and are competitively revers
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4.1 Introduction Chapter 4: Methods
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4.4 Nitrite and nitrate The measure
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insensitive (Braker and Mossman 197
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A group of instruments have been de
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The original group demonstrated tha
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equired it. For example, there was
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helium for 30 minutes to remove Oz.
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(Postlethwait and Bidani 1990; Post
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is set at 5ppm (AIHA 1966) based on
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5.1 Chapter 5: Methodological asses
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wanted to compare the patterns of e
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in different colours that became th
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an advisor for this work and main s
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Delay time: the time between turnin
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led to an increased water content t
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Chapter 6: Methodological studies o
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pulmonary circulation appeared to c
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al found levels of 10.3ppb compared
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Authors and Pap€r Sublect numbers
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only those measured by mouth or low
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6. Check that the pens work. Fill w
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keys but it is currently in the mid
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Calibration pressures: the test por
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T-piece: tO The first figure shows
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the rotameter. Tracings of each par
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Figure 6.6: Mean exhaled NO levels
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NO and COz results from single exha
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6.6.4 (iii) Comparison of exhaled n
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Figure 6.11b: COz levels at peak NO
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I also considered whether the diffe
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the direct to the indirect method l
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need for methodological experiments
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The exhalations were carried out in
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Figure 7.2: Example of the tracing
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7.4.4 Results There was an increase
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Table 7.3: NO, COz and duration of
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The second set of exhalations invol
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Figure 7.6: Photographs of the chan
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Table 7.5: Exhaled NO results with
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the NO concentrations taken pre and
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Figure 7.10: Hyperbolic relationshi
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pressure over the likely range enco
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subjects with respiratory disease,
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8.1 Chapter 8: Exhaled nitric oxide
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standard error of the mean (SEM), s
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T-piece sampling system to analyser
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Figure 8.2a: Comparison of peak exh
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if yes who? if yes who? if yes who?
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There are limitations with regard t
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significantly between research grou
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controls. Kharitinov et al reported
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direct method in asthmatic children
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Figure 8.4a: The eftect of commenci
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had last used her p2 agonist inhale
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higher level of exhaled NO at 4.9pp
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9.1 Introduction Chapter 9: Exhaled
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For the oral measurements options i
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Table 9.1: The recommended standard
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taken from the available literature
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compartment correlated with the ser
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measurement with variable expirator
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to settle. We may have been measuri
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9.5 Off-line measurement NO determi
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(Hyde, Geigel et al. 1997; Tsoukias
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9.6 Nasal nitric oxide measurement
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measured over two 24 hour periods,
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women who coincidently experienced
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While these cross-sectional and the
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symptoms. Steroid response was sign
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'difficult asthma' also had higher
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season and then reduced down to bas
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of cross sectional studies with a t
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Ciabattoni et al. 2004; Petersen, A
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FEV9.5, symptom score and airways r
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Indomethacin - This medication alte
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89Vo for PCD, and above that exclud
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This low NO occurs despite higher t
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patients were followed through one
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differences noted based on filter,
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9.L6 Nitric oxide levels in exercis
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another study of 111 school childre
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Almost all studies used sedation, w
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peak exhaled NO production in the f
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flow and to minimize nasal contamin
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ecruit blood vessels in the lung. S
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Chapter 10: Reflections The outcome
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and I enrolled 52 asthmatic childre
Page 289 and 290: Edwards EA, Douglas C, Broome S, Je
Page 291 and 292: o Cass Byrnes & Nicky Holt. "Drugs
Page 293 and 294: o Byrnes CA. Paediatric fibreoptic
Page 295 and 296: Appendix 2: Questionnaire for enrol
Page 297 and 298: Al-Ali, M. K. and P. H. Howarth (20
Page 299 and 300: Archer, S. L., P. J. Shultz, et al.
Page 301 and 302: Baraldi, E., N. M. Azzolin, et al.
Page 303 and 304: Belda, J., P. Hussack, et al. (2001
Page 305 and 306: Bongers, T. and B. R. ODriscoll (20
Page 307 and 308: Brown, G. C. and C. E. Cooper (1994
Page 309 and 310: Castro-Rodriguez, J. A., C. J. Holb
Page 311 and 312: Cockcroft, D. W., D. N. Killian, et
Page 313 and 314: de Blic, J., V. Marchac, et al. (20
Page 315 and 316: Donaldson, S. H., W. D. Bennett, et
Page 317 and 318: Emi-Miwa, M., A. Okitani, et al. (1
Page 319 and 320: Frey, U., J. Stocks, et al. (2000).
Page 321 and 322: Gershman, N. H., H. Liu, et al. (19
Page 323 and 324: Grasemann, H., E. Michler, et al. (
Page 325 and 326: Hashimoto, T., K. Minoguchi, et al.
Page 327 and 328: Holgate, S. T., D. E. Davies, et al
Page 329 and 330: Iriso, R., P. M. Mudido, et al. (20
Page 331 and 332: Jones, A. W., M. Fransson, et al. (
Page 333 and 334: Kercsmar, C. M. (2006). Wheezing in
Page 335 and 336: Kleinert, H., T. Wallerath, et al.
Page 337 and 338: Lamblin, C., P. Gosset, et al. (199
Page 339: Li, X. and J. W. Wilson (1997). "In
Page 343 and 344: Massaro, A. F., S. Mehta, et al. (1
Page 345 and 346: Miyabara, Y., R. Yanagisawa, et al.
Page 347 and 348: contribute to impaired endothelium-
Page 349 and 350: ODell, T. J., R. D. Hawkins, et al.
Page 351 and 352: Panza, J. A., C. E. Garcia, et al.
Page 353 and 354: Peters, S. P. (2006). "Safety of in
Page 355 and 356: Prieto, L., L. Bruno, et al. (2003)
Page 357 and 358: Ribbons, K. A., X. J. Zhang, et al.
Page 359 and 360: Sacco, O., R. Sale, et al. (2003).
Page 361 and 362: Sessa, W. C., K. Pritchard, et al.
Page 363 and 364: Silvestri, M., F. Sabatini, et al.
Page 365 and 366: Stamler, J. S. (1994). "Redox signa
Page 367 and 368: Stuehr, D. J., N. S. Kwon, et al. (
Page 369 and 370: Tierney, W. M., J. F. Roesner, et a
Page 371 and 372: Upchurch, G. R., G. N. Welch, et al
Page 373 and 374: Wadsworth, R., E. Stankevicius, et
Page 375 and 376: Williams, O., R. Y. Bhat, et al. (2
Page 377 and 378: Yates, D. H., S. A. Kharitonov, et
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