Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV ₁, MEF₂₅ and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.     

Nutritional Aspects of Breath Testing Based on Stable Isotopes

Stable isotope methodologies offer a number of possibilities for the nutritional assessment of many different processes and metabolic pathways. The application of stable isotopes has been boosted by the development of new mass spectrometers, lower costs of probes, and the risks associated with radioactive tracers. The use of ¹³C as a tracer offers all the advantages of stable isotopes and has been widely applied for measuring various types of metabolic processes. This review is focused on clinical and nutritional assessments using ¹³C breath tests.     

慢性阻塞性肺疾病的肺生物学标记物研究进展

与慢性阻塞性肺疾病（COPD）有关的很多炎症细胞、介质,正逐渐为人们所熟知。本文讨论支气管活组织切片、痰液、支气管肺泡灌洗液、呼出气凝物等方面的有关生物标记在COPD研究中的进展。     

EVALUATION OF INDOCYANINE GREEN RETENTION AND AMINOPYRINE BREATH TESTS IN PATIENTS WITH MALIGNANT BILIARY OBSTRUCTION

Impaired hepatic function is a major contributory factor to the high incidence of postoperative morbidity and mortality in patients with malignant biliary obstruction. Dynamic hepatic function tests such as indocyanine green (ICG) retention and aminopyrine breath tests were evaluated in such patients to define whether they were clinically useful for prediction of postoperative morbidity and mortality. Forty-four patients with malignant biliary obstruction undergoing surgery for relief of obstructive jaundice were recruited into the study. Indocyanine green retention and aminopyrine breath tests were carried out in all patients pre-operatively and repeated in 36 patients postoperatively. The ICG retention was abnormal in all patients before surgery and there was significant improvement 2 weeks after surgery (32.8 ± 2.5%vs 18.3 ± 2.8%, P= 0.001). The change in ICG retention levels correlated with the serum bilirubin levels but the pre-operative ICG retention value could not predict postoperative morbidity and mortality. The aminopyrine breath test was abnormal in all but one patient. It correlated with pre-operative prothrombin time of the patients before surgery but it did not improve significantly after surgery and was not predictive of postoperative outcome. It is concluded that both ICG retention and aminopyrine breath tests have limited clinical value in the pre-operative evaluation of patients with malignant biliary obstruction.     

Intranasal steroid reduces exhaled bronchial cysteinyl leukotrienes in allergic patients

BACKGROUND: Allergic rhinitis (AR) precedes and is often associated with bronchial asthma. Indeed, local and systemic inflammations in both conditions are very similar. Cysteinyl-leukotrienes (cys-LTs) are generated during early- and late-phase allergic reactions and induce smooth-muscle contraction, microvascular leakage, and mucous hypersecretion. Cys-LTs are detected in exhaled breath condensate (EBC) of asthmatics and regardless of bronchial symptoms, they are also found in EBC of rhinitic patients. OBJECTIVE: To evaluate cys-LTs in EBC of allergic patients and to assess the activity of nasal fluticasone propionate (FP) on EBC cys-LTs levels. METHODS: Cys-LTs coefficient of variation (CV) was evaluated from different EBC in 5 healthy volunteers. Cys-LTs levels from EBCs in 13 healthy controls and 56 allergic rhinitic (n=31) and rhinitic/asthmatic (n=25) patients were also evaluated at baseline. Subsequently patients were randomized to receive either FP 100 microg/day per nostril or placebo for 2 weeks and then re-evaluated for EBC cys-LTs. RESULTS: The CV was 14.12%. EBC cys-LTs in allergic patients were significantly higher than in healthy subjects (70.9 vs. 20.6 pg/mL (median), P<0.05), while it did not differ between asthmatic/rhinitic and purely rhinitic patients. Treatment significantly reduced cys-LTs (from 93.6 to 19.9 pg/mL, P<0.001). This effect was evident both in asthmatic/rhinitic and in rhinitic patients. CONCLUSION: Treatment of AR with FP significantly reduces the levels of cys-LTs, major noninvasive markers of lower airway inflammation, suggesting that upper and lower airway inflammation is present and should be thus treated as a whole in subjects with AR with and without asthma.     

短期用药对幽门螺杆菌检测结果的影响

目的：研究短期不规则用药对幽门螺杆菌(Hp)检测结果的影响。方法：136名慢性胃炎及消化性溃疡的住院患，根据病史分为服药组即Hp检查前一周内接受过铅剂、抑酸剂治疗的患，共四例。对照组即Hp检查前未接受过药物治疗的患考，共37例。Hp检查方法包括①血清学方法；②快速尿素酶试验(RUT)；③组织学方法；④13c—尿素呼气试验(13C—UBT)。结果：服药组RUT，组织学，13C—UBT方法Hp检出率分别为9．0％，21．2％，27．3％，均显低于对照组相应Hp检出率37．8％、40．5％、48．6％(P＜0．01，P＜0．05，P＜0．05)。两组血清学方法Hp IgG、IgM阳性率各为48．5％，51．5％和54．1％，54．1％(P＞0．05)。单独服用质子泵抑制剂组RUT，组织学方法Hp检出率4．0％，16．0％显低于对照组相应方法Hp检出率(P＜0．01，P＜0．05)。单独服用枸橼酸铋钾、H2受体拮抗剂患中各方法Hp检出率与对照组检出率无显性差异(P＞0．05)。单独服用枸橼酸铋钾、H2受体拮抗剂、质子泵抑制剂三组Hp感染率14．3％、15．0％、16．0％均显低于对照组Hp感染率46．0％(P＜0．05)。结论：Hp检查前短期使用铋剂、抑酸剂可导致Hp检出率下降，短期使用质子泵抑制剂可显降低RUT、组织学方法Hp检出率；各方法中快速尿素酶试验检出率最低。血清学方法检测Hp抗体不受药物影响。     

肺心病慢性呼吸性酸中毒合并代谢性酸碱失衡判断方法探讨(附80例次血气分析)

目的：对42例肺心病慢性呼吸性酸中毒患者的80例次血气测定结果。方法：用不同的酸碱图（卡）及代偿公式进行酸碱类型的初步差别分析。结果：结合临床表现、各种影响因素与治疗反应等作出综合判定。结论：比较二种判定的差异，并提出较为实用、可靠的判断建议，以助于复合型呼吸性酸碱失衡的临床诊断与处理。     

Clinical studies of asthma phenotypes focusing on the role of leukotrienes

Introduction: Inflammation in the airways in connection to asthma is complex and the mechanisms underlying the associated clinical symptoms involve the interaction of many different kinds of cells and mediators, giving rise to different phenotypes. Objective: The objective of the present thesis was to investigate the molecular and cellular mechanisms that result in two of these phenotypes, i.e. aspirin‐intolerant asthma (AIA) and allergic asthma. The main focus was on leukotrienes. Materials and Methods: (i) Thirty‐three subjects with diagnosed AIA were challenged with celecoxib, a selective inhibitor of cyclooxygenase (COX)‐2. (ii) With the ultimate objective of finding a marker that could be used to identify patients with leukotriene‐associated asthma, the capacity to produce leukotrienes and the responsiveness to inhaled leukotrienes were determined in 20 subjects with mild asthma and in 10 healthy control individuals. (iii) Eight individuals with mild allergic asthma were challenged repeatedly with low doses of allergen in an experimental model aimed at mimicking the natural exposure to allergen. Exhaled nitric oxide was measured throughout the study. (iv) Thirteen patients with allergic asthma were subjected to bronchial challenges with methacholine and leukotriene D₄ (LTD₄) prior to and after administration of 500‐µg fluticasone twice daily for 2 weeks, and their levels of exhaled nitric oxide and urinary leukotriene E₄ (LTE₄) were determined. Results: (i) Both escalating doses from 5–100 mg (administered in a blinded, placebo‐controlled study) and an open‐label challenge with 200 + 200 mg celecoxib were tolerated well by AIA individuals. (ii) Neither group exhibited a correlation between the formation of leukotriene B₄ by their whole blood in response to ex vivo stimulation or urinary levels of LTE₄ and airway responsiveness to LTD₄. (iii) The level of nitric oxide in the air that they exhaled rose significantly. At the same time, these subjects did not report any symptoms of asthma, did not require rescue by bronchodilator medication, and did not display any change in the calibre of their airways. (iv) Inhalation of glucocorticoid attenuated the responsiveness to methacholine and reduced the level of exhaled nitric oxide, but neither the responsiveness to LTD₄ nor urinary excretion of LTE₄ was affected. Conclusions: (i) This finding indicates that the intolerance reaction leading to broncho‐constriction in patients with AIA is caused by inhibition of COX‐1 and, furthermore, provides a scientific basis for administration of selective inhibitors of COX‐2 to alleviate prostaglandin‐mediated pain and inflammation in these patients. (ii) In further attempts to predict which asthmatic patients will respond well to anti‐leukotriene treatment, investigations on the capacity for leukotriene synthesis, responsiveness to these agents and expression of their specific receptors in the lungs are being performed. (iii) Monitoring of exhaled nitric oxide on a daily basis may allow for early detection of exacerbation in subjects with allergic asthma. (iv) Neither the release nor the actions of leukotrienes appear to be sensitive to inhaled glucocorticoids, strengthening the rationale for using a combination of glucocorticosteroids and anti‐leukotrienes to treat allergic asthma.     

Trimethylaminuria in a girl with Prader-Willi syndrome and del(15)(q11q13)

We report on an individual with trimethyl-aminuria, Prader-Willi syndrome, and del(15) (q11q13). To our knowledge, such an association has never been reported. Skin sores secondary to choline-rich foods and amenable to dietary control have not been described in trimethylaminuria, although they are seen in some patients with Prader-Willi syndrome. Pathogenesis, clinical diagnosis, and management of reported cases with trimethylaminuria are reviewed. Serious social and behavioral problems may result from strong body odor. Amelioration of the “fish odor” by dietary choline restriction makes trimethylaminuria detection important. Association of trimethylaminuria with Prader-Willi syndrome and del(15) (q11q13) in this patient is of particular interest. It may represent a contiguous gene syndrome, or deletion of the normal allele leading to expression of a single recessive trimethylaminuria gene, or an unrelated association, such as in Noonan syndrome. However, recent development of mapping of flavin-containing monooxygenase 2 (FMO2), the likely enzyme that is defective in fish odor syndrome, to chromosome 1q probably excludes pathogenetic association of fish odor syndrome with the Prader-Willi syndrome. © 1993 Wiley-Liss, Inc.     

Heterogeneity of FeNO response to inhaled steroid in asthmatic children

Background Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti‐inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern. Objective The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs. Methods Exhaled nitric oxide (FeNO), lung function, bronchial hyper‐responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double‐blind, placebo‐controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren. Results Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600. Conclusion Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high‐dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti‐inflammatory control in asthmatic children.