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研究生:王怡人
研究生(外文):I-Jen Wang
論文名稱:小兒異位性皮膚炎之環境因子及生物標記
論文名稱(外文):Environmental Factors and Biomarkers for Pediatric Atopic Dermatitis
指導教授:陳保中陳保中引用關係
指導教授(外文):Pau-Chung Chen
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:122
中文關鍵詞:異位性皮膚炎神經增長因子基因多形性懷孕期香煙暴露
外文關鍵詞:atopic dermatitisnerve growth factorgenetic polymorphismsgestational smoke exposure
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Part I
神經介質作為異位性皮膚炎之預測因子

背景: 關於異位性皮膚炎的預測因子之研究大多致力於基因和免疫學方面。神經介質的角色仍然未明,需被進一步探討。
宗旨: 評估神經增長因子(NGF), 血管腸生肽(VIP) 和介質P (SP) 是否能預估小兒異位性皮膚炎及探討他們和內因性和外因性異位性皮膚炎的相關性。
方法: 我們進行一建立在臺灣出生世代上之病例對照研究。臍帶血和母血及相關問卷在出生時即被收集。在後續追蹤期間,我們找到了40個異位性皮膚炎案例,並從出生世代這群人中取80個當對照組。用免疫酵素分析法(ELISA)來驗臍帶血和母血中IgE、NGF、VIP 和SP的濃度。由ROC曲線來看各生物標記是否能精確預估異位性皮膚炎。
結果: NGF濃度在異位性皮膚炎患者明顯高於對照組(平均值及標準差在臍帶血為 65.47±44.45比49.21±12.18 pg/ml;在母血為89.68±41.04比66.96±23.05 pg/ml) (P<0.05)。VIP和SP濃度也會升高但統計上並不顯著。血漿NGF比IgE是一個更好的預估異位性皮膚的生物標記(ROC曲線下之區域在臍帶血為0.65比0.61;在母血為0.69比0.61)。母親NGF濃度在內因性患者(96.18±48.15 pg/ml)和外因性患者(86.18±37.23 pg/ml)皆顯著高於對照組(66.96±23.05 pg/ml) (P<0.05)。懷孕期間之壓力和母親NGF濃度間有顯著之相關(r=0.22, P=0.02)。
結論: 我們的結果建議,NGF可提供預估小兒異位性皮膚炎生物標記之另類選擇。


Part II
懷孕期香煙暴露對小孩異位性皮膚炎之影響-以cotinine當客觀性生物標記

背景:煙對兒童呼吸系統和出生結果有害是眾所周知。但是,香煙暴露包括二手煙(ETS)及母親懷孕期抽煙對異位性皮膚炎的影響不是很清楚。
宗旨:這項研究的目的將依據臍帶血cotinine值來評估懷孕期香煙暴露對小孩異位性皮膚炎之影響。
方法: 在2004年我們收集了261對母親和新生兒。臍帶血和孩子的資料在出生時即被取得。在2歲時收集後天環境暴露資料及判定小孩是否得過異位性皮膚炎。我們用高性能色層分析質譜儀(HPLC-MS/MS)測量並比較得病與沒得病小孩之臍帶血及母血cotinine濃度。多重邏輯氏迴歸被用來評估cotinine濃度和異位性皮膚炎之關係。
結果: 150對母親和小孩完成了追蹤研究及抽血。38個(25.3%)孩子得異位性皮膚炎。2個(1.3%)母親在懷孕期間抽煙, 38個(25.3%)母親在懷孕期間有二手煙之暴露。臍帶血Cotinine濃度和母親血濃度高度相關(r=0.71,p<0.001)。我們發現當臍帶血cotinine值上升時,異位性皮膚炎之風險便會增加,且以劑量趨勢反應方式增加(p for trend=0.01)。尤其對於暴露濃度高於第75百分位者,異位性皮膚炎的風險更是顯著增加。
結論: 懷孕期香煙暴露會增加小孩異位性皮膚炎的風險。產前避免香煙暴露對於早期預防異位性皮膚炎是很重要的。


Part III
GSTM1及GSTP1基因多形性和懷孕期香煙暴露對小孩異位性皮膚炎之影響

背景: 近年來異位性皮膚炎盛行率的增加可能和基因易感族群之特殊暴露有關。
宗旨: 這項研究的目的將依據臍帶血cotinine值來評估Glutathione S-transferase (GST)基因多形性和懷孕期香煙暴露對小孩異位性皮膚炎之影響。
方法: 在2004年我們收集了261對母親和新生兒。臍帶血和孩子的資料在出生時即被取得。在2歲時收集後天環境暴露資料及判定小孩是否得過異位性皮膚炎。我們將cotinine濃度分層,比較得病與沒得病小孩之GTM1和GSTP1多形性。多重邏輯氏迴歸被用來評估基因多形性和cotinine濃度對異位性皮膚炎之影響。
結果: 我們發現當臍帶血cotinine值上升時,異位性皮膚炎之風險便會增加,且以劑量趨勢反應方式增加。GSTM1 null及GSTP1 Ile/Ile基因型被發現會增加異位性皮膚炎之風險。對於臍帶血cotinine值小於0.1 ng/ml的小孩, GSTP1 Ile/Ile基因型會增加異位性皮膚炎之風險。對於大於等於0.1 ng/ml的,GSTM1 null基因型與異位性皮膚炎風險有顯著相關。
結論: GSTM1和GSTP1基因多形性可解釋懷孕期香煙暴露對小孩異位性皮膚炎易感性的不同。


Part IV
施打流行性感冒嗜血桿菌疫苗會增加過敏疾病之風險嗎?

背景: 對疫苗接種和過敏疾病之關係流行病學研究結果並不一致。
宗旨: 這項研究的目的將評估全面施打白喉破傷風百日咳小兒痲痺疫苗之後,接種流行性感冒嗜血桿菌疫苗對過敏疾病的影響。
方法: 我們在西元2005年用多層次系統取樣方法從臺灣全國出生登記中抽取24,200對之母親及小孩。在健兒手冊疫苗卡上查明疫苗接種狀態,在6個月大時藉由問卷收集過敏疾病之危險因子,並詢問是否有被醫師診斷過異位性皮膚炎及反覆喘鳴(大於3次,排除免疫缺失和氣管結構異常問題)。多重邏輯氏迴歸被用來估計流行性感冒嗜血桿菌疫苗和過敏疾病的關係。
結果: 在6個月時,有21,010個(86.8%)參加者完成追蹤研究。1460個(6.9%)嬰兒有異位性皮膚炎, 154個(0.8%)嬰兒有反覆喘鳴之現象。11156個(53.1%)嬰兒接受了至少一劑量之流行性感冒嗜血桿菌疫苗之接種。在單變量的分析上,流行性感冒嗜血桿菌疫苗接種會增加異位性皮膚炎的風險(勝算比1.65; 95%信賴區間1.48-1.85)。在調整各種潛在的干擾因子後仍具統計意義(勝算比1.29; 95%信賴區間1.15-1.45) 。流行性感冒嗜血桿菌疫苗也可能會增加反覆喘鳴之危險性(勝算比1.31; 95%信賴區間0.94-1.83),雖統計上不鮮著。
結論: 結果顯示流行性感冒嗜血桿菌疫苗接種會潛在性的增加過敏病的風險。但是,是否這些副作用大過它在公共衛生上防治傳染病的重要性有待進一步驗證。
Part I
Neuro-mediators as predictors of pediatric atopic dermatitis

Background: Attempts to identify predictors of atopic dermatitis (AD) have focused on genetic and immunologic factors. However, the role of neuro-mediators remains to be elucidated.
Objective: To evaluate nerve growth factor (NGF) and vaso-active intestinal peptide (VIP) in predicting pediatric AD and assess their correlation with intrinsic and extrinsic types of AD.
Methods: We performed a nested case-control study in the prospective Taiwan birth panel cohort study. Cord and maternal plasma and questionnaires were gathered at birth. During follow-up, we identified 40 available AD cases, which were matched to 80 unaffected controls chosen from this cohort. The concentration of IgE, NGF, and VIP in cord and maternal plasma of these subjects were performed by enzyme-linked immuno-sorbent assay (ELISA). Receiver-operating-characteristic (ROC) curves were generated to see how well each biomarker could predict AD.
Results: The NGF levels were significantly higher in AD patients than controls (mean ± SD: 65.47 ± 44.45 vs. 49.21 ± 12.18 pg/ml for cord plasma and 89.68 ± 41.04 vs. 66.96 ± 23.05 pg/ml for maternal plasma) (P<0.05). VIP levels were also higher but not statistically significant. Plasma NGF may be a better biomarker than IgE in detecting pediatric AD (area under the ROC curve = 0.65 vs. 0.61 for cord plasma and 0.69 vs. 0.61 for maternal plasma). Maternal NGF levels were significantly higher in patients with both intrinsic (96.18 ± 48.15 pg/ml) and extrinsic (86.18 ± 37.23 pg/ml) types of AD compared to controls (66.96 ± 23.05 pg/ml) (P<0.05). We assessed a significant correlation between self-reported stress during pregnancy and maternal NGF levels (r=0.22, P=0.02).
Conclusions: Our results suggest that NGF is a good alternative biomarker in predicting children with risk of AD.


Part II
The effect of gestational smoke exposure on atopic dermatitis in the offspring – using cotinine as an objective biomarker

Background: The adverse impact of smoking on respiratory diseases and birth outcomes in children is well-known. However, the influence of smoke exposure including environmental tobacco smoke (ETS) and maternal smoking during pregnancy on atopic dermatitis (AD) is not clear.
Objective: The purpose of this study was to evaluate the effect of gestational smoke exposure on the development of AD in the offspring on the basis of the maternal and cord blood cotinine.
Methods: We recruited 261 mother and newborn pairs in 2004. Cord blood and information on perinatal factors of children were gathered at birth. At 2 years of age, information about development of AD and environmental exposures were collected. We compared AD with non-AD children for the concentration of cotinine in cord and maternal blood measured by high performance chromatography-mass spectrometry (HPLC-MS/MS). Multiple logistic regressions were performed to estimate the relationship of cotinine levels and AD.
Results: 150 mother and child pairs completed the follow-up study and specimen collection with 38 (25.3%) children developing AD. Two (1.3%) out of 150 mothers smoked during pregnancy while 38 (25.3%) mothers reported having ETS exposure. Cotinine levels in cord blood and maternal blood were highly correlated (r=0.71, p<0.001). The risk of AD was found to increase with maternal and cord blood cotinine levels in a dose-response-manner (p for trend=0.01). Children exposed to high levels (> 75th percentile) had a significantly increased risk of AD.
Conclusions: Smoke exposure during pregnancy might increase the risk of AD in children. Avoidance of prenatal smoke exposure may be warranted for early prevention.


Part III
Effects of GSTM1 and GSTP1 polymorphisms and gestational smoke exposure on atopic dermatitis in the offspring

Background: The evidence that both genes and environment play etiologic roles suggests that the increase in atopic dermatitis (AD) prevalence is likely to involve changes in specific exposures among the population of genetically susceptible individuals. The purpose of this study was to evaluate the effect of Glutathione S -transferase (GST) genotypes polymorphisms and gestational smoke exposure on pediatric AD on the basis of the cord blood cotinine.
Methods: We recruited 261 mother and newborn pairs in 2004. Cord blood and information on perinatal factors of children were gathered at birth. At 2 years of age, information about development of AD and environmental exposures were collected. We compared AD with non-AD children for GTM1 and GSTP1 polymorphisms stratified by the cotinine level. Multiple logistic regressions were performed to estimate the association of genotypes polymorphisms and cotinine levels with AD.
Results: The risk of AD was found to increase with cord blood cotinine levels in a dose-response manner (p for trend=0.02). GSTM1 null and GSTP1 Ile/Ile genotypes showed a significant increase in the risk of AD with OR(95% CI) of 3.61 (1.40–9.31) and 3.11 (1.30–7.46) respectively. In children with cotinine level<0.1 ng/ml, the risk of AD increased for those carrying two GSTP1 Ile-105 alleles (OR = 6.63, 95% CI 1.46-30.18). In children with cotinine level≧0.1 ng/ml, GSTM1 null genotype was significantly related to AD (OR = 5.21, 95% CI 1.32–20.58).
Conclusion: Genetic polymorphism in GSTM1 and GSTP1 may be responsible for children differences in susceptibility to AD with regard to gestational smoke exposure.


Part IV
Does Haemophilus influenzae type b vaccination increase the risk of atopic disease?

Background: Epidemiologic evidence for an association between vaccinations and atopy development is inconsistent.
Objective: The aim of this study was to determine the influence of neonatal Haemophilus influenzae type b (Hib) vaccination on the prevalence of atopic disorders in addition to diphtheria-pertussis-poliomyelitis- tetanus (DPPT) vaccination and other neonatal vaccinations.
Methods: We used multistage, stratified systematic sampling to recruit 24,200 mother–newborn pairs from the Taiwan national birth registration in 2005. Vaccination status was ascertained through officially vaccine cards while risk factors for atopic disorders were gathered by questionnaires at 6 months of age. Information about development of physician-diagnosed atopic dermatitis (AD) and recurrent wheezing (> 3 episodes, excluding immune deficiencies and structural airway abnormalities) was also collected. Multiple logistic regression was performed to estimate the association of Hib vaccination and atopic disorders.
Results: There were 21,010 (86.8%) participants completed the follow-up study at the age of 6 months. AD was noted in 1460 (6.9%) infants while recurrent wheezing was found in 154 (0.8%). 11156 (53.1%) of the infants received at least one dose of Hib vaccination. In the univariate analysis, Hib vaccination was associated with a higher risk of AD (OR, 1.65; 95% CI, 1.48-1.85). Statistical significance retained even after adjusting for various potential confounders (adjOR, 1.29; 95% CI, 1.15-1.45). Hib vaccination was positively associated with recurrent wheezing (adjOR, 1.31; 95% CI, 0.94-1.83), though failed to reach statistical significance.
Conclusion: These results demonstrate a potential of Hib vaccination to increase the risk of atopic disorders in the early life in addition to DPPT vaccination. However, whether these adverse effects outweigh its importance in public health for infectious diseases spreading warrants further investigation.
Overview……………………………………………………………… 1

Part I: Neuro-mediators as predictors of pediatric atopic dermatitis
Chinese Abstract ……………………………………………… 9
English Absract ………………………………………………… 10
Chapter 1 Introduction …………………………………………12
Chapter 2 Methods ……………………………………………… 14
Chapter 3 Results … …………………………………………… 19
Chapter 4 Discussion …………………………………………… 22
Reference ……………………………………………………………27
Tables
Table 1 ……………………………………………………………… 32
Table 2 …………………………………………………………… 33
Figures
Figure 1 …………………………………………………………… 34
Figure 2 ………………………………………………………………35


Part II: The effect of gestational smoke exposure on atopic dermatitis in the offspring – using cotinine as an objective biomarker
Chinese Abstract ……………………………………………………36
English Absract………………………………………………………37
Chapter 1 Introduction ………………………………………… 39
Chapter 2 Methods …………………………………………………41
Chapter 3 Results………………………………………………… 45
Chapter 4 Discussion………………………………………………47
Reference …………………………………………………………… 53
Tables
Table 1 …………………………………………………………… 58
Table 2 …………………………………………………………… 59
Table 3 ………………………………………………………………60
Figures
Figure 1 ……………………………………………………………61


Part III: Effects of GSTM1 and GSTP1 polymorphisms and gestational smoke exposure on atopic dermatitis in the offspring
Chinese Abstract……………………………………………………62
English Absract…………………………………………………… 63
Chapter 1 Introduction …………………………………………65
Chapter 2 Methods…………………………………………………67
Chapter 3 Results ……………………………………………… 73
Chapter 4 Discussion ……………………………………………75
Reference ………………………………………………………… 81
Tables
Table 1 ………………………………………………………………85
Table 2 ………………………………………………………… 87
Table 3 …………………………………………………………… 88


Part IV: Does Haemophilus influenzae type b vaccination increase the risk of atopic diseases?
Chinese Abstract………………………………………………………… 89
English Absract…………………………………………………………… 90
Chapter 1 Introduction ……………………………………… 92
Chapter 2 Methods……………………………………………… 94
Chapter 3 Results …………………………………………… 98
Chapter 4 Discussion………………………………………… 100
Reference ……………………………………………………… 106
Tables
Table 1 ………………………………………………………… 110
Table 2 ……………………………………………………… 111
Table 3…………………………………………………………… 113
Figures
Figure 1 ………………………………………………………… 114


Appendix
A. Publications …………………………………………… 115
B. Grants and Awards ………………………………………… 117
C. International presentations …………………………… 118
D. Conference abstracts and published papers
Part V: Exposure to air pollution and early childhood allergic health.(abstract) ……………………………………119
Part VI: The association of Glutathione S -transferase gene polymorphisms with pediatric atopic dermatitis(abstract)………………………………………………………… 121
Part VII: Environmental risk factors for early infantile atopic dermatitis
Part VIII: Genetic and environmental predictors for pediatric atopic dermatitis
Part I
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17. Kjellman NI. Prediction and prevention of atopic allergy. Allergy 1998; 53:67–71.
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22. Bonini S, Lambiase A, Bonini S, Levi-Schaffer F, Aloe L. Nerve growth factor: an
important molecule in allergic inflammation and tissue remodelling.
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23. Bonini S, Rasi G, Bracci-Laudiero ML, Procoli A, Aloe L. Nerve growth factor: neurotrophin or cytokine? Int Arch Allergy Immunol 2003; 131:80-4.
24. Haddad J, Vilge V, Juif JG et al. Beta-nerve growth factor levels in newborn cord sera. Pediatr Res 1994; 35:637-9.
25. Kimata H. Enhancement of allergic skin wheal responses in patients with atopic eczema/dermatitis syndrome by playing video games or by a frequently ringing mobile phone. Eur J Clin Invest 2003; 33: 513-7.
26. Aloe L, Bracci-Laudiero L, Alleva E, Lambiase A, Micera A, Tirassa P. Emotional stress induced by parachute jumping enhances blood nerve growth factor levels and the distribution of nerve growth factor receptors in lymphocytes. Proc Natl Acad Sci USA 1994; 91:10440–4.
27. Kimata H. Suckling reduces allergic skin responses and plasma levels of neuropeptide and neurotrophin in lactating women with atopic eczema/dermatitis syndrome. Int Arch Allergy Immunol 2003;132: 380-3.
28.Tometten M, Klapp BF, Joachim R et al. Nerve growth factor and its functional receptor TrkA are up-regulated in murine decidual tissue of stress-triggered and substance P-mediated abortion. Am J Reprod Immunol 2004; 51: 86–93.
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Part II
1. Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers. Pediatrics 1992: 89:21–6.
2. Evans D, Levison MJ, Feldman CH, et al. The impact of passive smoking on emergency room visits of urban children with asthma. Am Rev Respir Dis 1987:135:567–72.
3. Perez-Stable EJ, Benowitz NL, Marin G. Is serum cotinine a better measure of cigarette smoking than self-report? Prev Med 1995: 24:171-9.
4. DeLorenze GN, Kharrazi M, Kaufman FL, Eskenazi B, Bernert JT. Exposure to environmental tobacco smoke in pregnant women: the association between self-report and serum cotinine. Environ Res 2002: 90: 21-32.
5. Benowitz NL. Biomarkers of environmental tobacco smoke exposure. Environ Health Perspect 1999: 107: 349-55.
6. Benowitz NL, Jacob P 3rd. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994: 56: 483-93.
7. Nafstad P, Kongerud J, Botten G, et al. Fetal exposure to tobacco smoke products: a comparison between self-reported maternal smoking and concentrations of cotinine and thiocyanate in cord serum. Acta Obstet Gynecol Scand 1996: 75: 902-7.
8. Pichini S, Basagana XB, Pacifici R, et al. Cord serum cotinine as a biomarker of fetal exposure to cigarette smoke at the end of pregnancy. Environ Health Perspect 2000: 108:1079-83.10.
9. Wen CP, Levy DT, Cheng TY, Hsu CC, Tsai SP. Smoking behavior in Taiwan. Tob Control 2001: 14 : i51-5.
10. Kharrazi M, DeLorenze GN, Kaufman FL, et al. Environmental tobacco smoke and pregnancy outcome. Epidemiology 2004: 15: 660-70.
11. Krämer U, Lemmen CH, Behrend H, et al. The effect of environmental tobacco smoke on eczema and allergic sensitization in children. Brti J Dermatol 2004: 150:111-8.
12. Schafer T, Dirschedl P, Kulz B, Ring J, Uberla K. Maternal smoking during pregnancy and lactation increases the risk for atopic eczema in the offspring. J Am Acad Dermatol 1997: 36: 550-6.
13. Magnusson CG. Maternal smoking influences cord serum IgE and IgD levels and increases the risk for subsequent infant allergy. J Allergy Clin Immunol 1986: 78: 898–904.
14. Mills CM, Srivastava ED, Harvey IM, et al. Cigarette smoking is not a risk factor in atopic dermatitis. Int J Dermatol 1994: 33: 33–4.
15. Miyake Y, Ohya Y, Tanaka K, et al. Home environment and suspected atopic eczema in Japanese infants: the Osaka Maternal and Child Health Study. Pediatr Allergy Immunol 2007:18: 425-32.
16. Magnusson LL, Olesen AB, Wennborg H, Olsen J. Wheezing, asthma, hayfever, and atopic eczema in childhood following exposure to tobacco smoke in fetal life. Clin Exp Allergy 2005: 35: 1550-6.
17. Linneberg A, Simonsen JB, Petersen J, Stensballe LG, Benn CS. Differential effects of risk factors on infant wheeze and atopic dermatitis emphasize a different etiology. J Allergy Clin Immunol 2006: 117: 184-9.
18. Noakes P, Taylor A, Hale J, et al.The effects of maternal smoking on early mucosal immunity and sensitization at 12 months of age. Pediatr Allergy Immunol 2007:18:118-27.
19. Chan HH, Pei A, Van Krevel C, Wong GWK, Lai CKW. Validation of the Chinese translated version of ISAAC core questions for atopic eczema. Clin Exp Allergy 2001: 31: 903.
20. Benn CS, Benfeldt E, Andersen PK, Olesen AB, Melbye M, Bjorksten B. Atopic dermatitis in young children: diagnostic criteria for use in epidemiological studies based on telephone interviews. Acta Derm Venereo 2003: l 83: 347-50.
21. Nelson PR, deBethizy JD, Davis RA, et al. Where there''s smoke? Biases in the use of nicotine and cotinine as environmental tobacco smoke biomarkers. In: Proceedings of the 1991 Environmental Protection Agency/Air and Waste Management Association International Symposium: Measurement of toxic and related air pollutants. Pittsburgh, PA: Air and Waste Management Association, 1991: 449-54.
22. Pirkle JL, Flegal KM, Bernert JT, Brody DJ, Etzel RA, Maurer KR. Exposure of the US population to environmental tobacco smoke: the Third National Health and Nutrition Examination Survey, 1988 to 1991. JAMA 1996: 275:1233-40.
23.Government Information Office, Taiwan. http://www.gio.gov.tw/info/taiwan-story/society/down/3-4.htm.
24. Jacob P III, Yu L, Wilson M, Benowitz NL. Selected ion monitoring method for determination of nicotine, cotinine, and deuteriumlabeled analogs: absence of an isotope effect in the clearance of (S)-nicotine-3''-3''-d2 in humans. Biol Mass Spectrom 1991: 20 :247-52.
25. Benowitz NL, Jacob P 3rd. Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther 1993: 53: 316-23.
26. Davis RA, Stiles MF, deBethizy JD, Reynolds JH. Dietary nicotine: a source of urinary cotinine. Food Chem Toxicol 1991: 29: 821-7.
27. Kulig M, Luck W, Wahn U. The association between pre- and postnatal tobacco smoke exposure and allergic sensitization during early childhood. Hum Exp Toxicol 1999: 18: 241–4.
28. Donnenfeld AE, Pulkkinen A, Palomaki GE, Knight GJ, Haddow JE. Simultaneous fetal and maternal cotinine levels in pregnant women smokers. Am J Obstet Gynecol 1993:168(3 Pt 1):781-2.
29. Seymour BW, Pinkerton KE, Friebertshauser KE, Coffman RL, Gershwin LJ. Second-hand smoke is an adjuvant for T helper-2 responses in a murine model of allergy. J Immunol 1997: 159: 6169–75.
30. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003: 58: 1053–8.
31. Roemer E, Stabbert R, Rustemeier K, et al. Chemical composition, cytotoxicity and mutagenicity of smoke from US commercial and reference cigarettes smoked under two sets of machine smoking conditions. Toxicology 2004: 951: 31–52.
32. Harkavy J. Tobacco allergy in cardiovascular disease: a review. Ann Allergy 1968: 26: 447-59.


Part III
1.Chen CF, Wu KG, Hsu MC, Tang RB. Prevalence and relationship between allergic diseases and infectious diseases. J Microbiol Immunol Infect 2001; 34:57-62.
2.Wang IJ, Guo YL, Hwang KC, Hsieh WS, Chuang YL, Lin SJ et al. Genetic and Environmental Risk Factors for Pediatric Atopic Dermatitis. Acta Pediatrica Tw 2006; 47: 5.
3.Chiang LC, Chen YH, Hsueh KC, Huang JL. Prevalence and severity of symptoms of asthma, allergic rhinitis, and eczema in 10- to 15-year-old schoolchildren in central Taiwan. Asian Pac J Allergy Immunol 2007; 25:1-5.
4.Holgate ST, Church MK, Lichtenstein LM. 2001. Allergy. 2nd edition. London: Mosby.
5.Wen CP, Levy DT, Cheng TY, Hsu CC, Tsai SP. Smoking behaviour in Taiwan, 2001. Tob Control. 2005; 14 Suppl 1: i51-55.
6. Schafer T, Dirschedl P, Kulz B, Ring J, Uberla K. Maternal smoking during pregnancy and lactation increases the risk for atopic eczema in the offspring. J Am Acad Dermatol 1997: 36: 550-556.
7. Krämer U, Lemmen CH, Behrendt H, Link E, Schäfer T, Gostomzyk J et al. The effect of environmental tobacco smoke on eczema and allergic sensitization in children. Brti J Dermatol 2004: 150:111-118.
8. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003; 58: 1053–1058.
9. Wang IJ, Hsieh WS, Wu KY, Guo YL, Hwang YH, Jee SH et al. The effect of gestational smoke exposure on atopic dermatitis in the offspring. Pediatr Allergy Immunol (in press).
10. Hayes JD, Strange RC. Glutathione s-transferase polymorphisms and their biological consequences. Pharmacology 2000; 61:154–166.
11.Sheehan D, Meade G, Foley VM, Dowd CA. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 2001; 360(Pt 1):1–16.
12.Lee YL, Hsiue TR, Lee YC, Lin YC, Guo YL. The association between glutathione S-transferase P1, M1 polymorphisms and asthma in Taiwanese schoolchildren. Chest 2005; 128:1156–1162.
13.Gilliland FD, Li YF, Dubeau L, Berhane K, Avol E, McConnell R et al. Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med 2002; 166:457-463.
14.Vavilin VA, Safronova OG, Lyapunova AA, Lyakhovich VV, Kaznacheeva LF, Manankin NA et al. Interaction of GSTM1, GSTT1, and GSTP1 genotypes in determination of predisposition to atopic dermatitis. Bull Exp Biol Med 2003;136: 388-391.
15.Safronova OG, Vavilin VA, Lyapunova AA, Makarova SI, Lyakhovich VV, Kaznacheeva LF et al. Relationship between glutathione S-transferase P1 polymorphism and bronchial asthma and atopic dermatitis. Bull Exp Biol Med 2003;136:73-75.
16. Chan HH, Pei A, Van Krevel C, Wong GWK, Lai CKW. Validation of the Chinese translated version of ISAAC core questions for atopic eczema. Clin Exp Allergy 2001: 31: 903.
17. Benn CS, Benfeldt E, Andersen PK, Olesen AB, Melbye M, Bjorksten B. Atopic dermatitis in young children: diagnostic criteria for use in epidemiological studies based on telephone interviews. Acta Derm Venereo 2003: l83: 347-350.
18. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM et al. Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 1994; 300: 271-276.
19. Ghobadloo SM, Yaghmaei B, Bakayev V, Goudarzi H, Noorinayer B, Rad FH et al. GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. J Gastrointest Surg 2004; 8:423-427.
20. Kharrazi M, DeLorenze GN, Kaufman FL, Eskenazi B, Bernert JT, Jr., Graham S, et al. Environmental tobacco smoke and pregnancy outcome. Epidemiology 2004;15:660-670.
21. Donnenfeld AE, Pulkkinen A, Palomaki GE, Knight GJ, Haddow JE. Simultaneous fetal and maternal cotinine levels in pregnant women smokers. Am J Obstet Gynecol 1993;168:781-782.
22. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet 2001; 357:1076–1079.
23. Briganti S, Picardo M. Antioxidant activity, lipid peroxidation and skin diseases. What''s new. J Eur Acad Dermatol Venereol 2003; 17:663-669.
24. Paquet P, Piérard GE.Glutathione-S-transferase pi expression in toxic epidermal necrolysis: a marker of putative oxidative stress in keratinocytes. Skin Pharmacol Physiol 2007; 20:66-70.
25. McCarty KM, Chen YC, Quamruzzaman Q, Rahman M, Mahiuddin G, Hsueh YM et al. Arsenic methylation, GSTT1, GSTM1, GSTP1 polymorphisms, and skin lesions. Environ Health Perspect 2007; 115:341-345.
26. Leite JL, Morari EC, Granja F, Campos GM, Guilhen AC, Ward LS. Influence of the glutathione s-transferase gene polymorphisms on the susceptibility to basal cell skin carcinoma. Rev Med Chil 2007; 135: 301-306.
27. Tsukahara H, Shibata R, Ohshima Y, Todoroki Y, Sato S, Ohta N et al. Oxidative stress and altered antioxidant defenses in children with acute exacerbation of atopic dermatitis. Life Sci 2003; 72:2509-2516.
28. Breton CV, Kile ML, Catalano PJ, Hoffman E, Quamruzzaman Q, Rahman M et al. GSTM1 and APE1 genotypes affect arsenic-induced oxidative stress: a repeated measures study. Environ Health 2007; 6:39.
29. Whyatt RM, Jedrychowski W, Hemminki K, Santella RM, Tsai WY, Yang K et al. Biomarkers of polycyclic aromatic hydrocarbon-DNA damage and cigarette smoke exposures in paired maternal and newborn blood samples as a measure of differential susceptibility. Cancer Epidemiol Biomarkers Prev 2001; 10:581–588.
30. Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomized, placebo-controlled crossover study. Lancet 2004; 363:119–125.
31. Mwenifumbo JC, Tyndale RF. Genetic variability in CYP2A6 and the pharmacokinetics of nicotine. Pharmacogenomics 2007; 8:1385-1402.
32. Benowitz NL. Biomarkers of environmental tobacco smoke exposure. Environ Health Perspect 1999: 107: 349-355.
33. Pichini S, Basagaña XB, Pacifici R, Garcia O, Puig C, Vall O et al. Cord serum cotinine as a biomarker of fetal exposure to cigarette smoke at the end of pregnancy. Environ Health Perspect 2000: 108:1079-1083.


Part IV
1. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma:executive summary of the GINA Dissemination Committee Report. Allergy 2004;59:469-78.
2. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology. 2004;112:352-63.
3.Adler UC.The influence of childhood infections and vaccination on the development of atopy: a systematic review of the direct epidemiological evidence. Homeopathy 2005;94:182-95.
4. Koppen S, De Groot R, Neijens HJ, Nagelkerke N, Van Eden W, Ru¨mke HC. No epidemiological evidence for infant vaccinations to cause allergic disease. Vaccine 2004;22:3375–3385.
5. Bernsen RM, de Jongste JC, Koes BW, Aardoom HA, van der Wouden JC. Diphtheria tetanus pertussis poliomyelitis vaccination and reported atopic disorders in 8-12-year-old children. Vaccine. 2006;24:2035-42.
6. Balicer RD, Grotto I, Mimouni M, Mimouni D. Is childhood vaccination associated with asthma? A meta-analysis of observational studies. Pediatrics. 2007;120:e1269-77.
7.Nakajima K, Dharmage SC, Carlin JB, Wharton CL, Jenkins MA, Giles GG, Abramson MJ, Haydn Walters E, Hopper JL. Is childhood immunisation associated with atopic disease from age 7 to 32 years? Thorax. 2007;62:270-5.
8. Mommers M, Weishoff-Houben M, Swaen GM, Creemers H, Freund H, Dott W, van Schayck CP. Infant immunization and the occurrence of atopic disease in Dutch and German children: a nested case-control study. Pediatr Pulmonol 2004;38:329–334.
9. Laubereau B, Grote V, Holscher G, Holscher B, Frye C, Wichmann HE, Heinrich J. Vaccination against Haemophilus influenzae type B and atopy in East German schoolchildren. Eur J Med Res 2002;7:387–392.
10. DeStefano F, Gu D, Kramarz P, Truman BI, Iademarco MF, Mullooly JP, Jackson LA, Davis RL, Black SB, Shinefield HR, Marcy SM, Ward JI, Chen RT. Vaccine Safety Datalink Research Group. Childhood vaccinations and risk of asthma. Pediatr Infect Dis J 2002;21:498–504.
11.Bernsen RM, Koes BW, de Jongste JC, van der Wouden JC. Haemophilus influenzae type b vaccination and reported atopic disorders in 8-12-year-old children. Pediatr Pulmonol. 2006;41:463-9.
12.Kummeling I, Thijs C, Stelma F, Huber M, van den Brandt PA, Dagnelie PC. Diphtheria, pertussis, poliomyelitis, tetanus, and Haemophilus influenzae type b vaccinations and risk of eczema and recurrent wheeze in the first year of life: the KOALA Birth Cohort Study. Pediatrics. 2007;119:e367-73.
13. Kamboj KK, King CL, Greenspan NS, Kirchner HL, Schreiber JR. Immunization with Haemophilus influenzae type b-CRM(197) conjugate vaccine elicits a mixed Th1 and Th2 CD(4+) T cell cytokine response that correlates with the isotype of antipolysaccharide antibody. J Infect Dis 2001; 184:931–5.
14.Benn CS, Benfeldt E, Andersen PK, Olesen AB, Melbye M, Bjorksten B. Atopic dermatitis in young children: diagnostic criteria for use in epidemiological studies based on telephone interviews. Acta Derm Venereol 2003; 83:347-50.
15. Chan HH, Pei A, Van Krevel C, Wong GWK, Lai CKW. Validation of the Chinese translated version of ISAAC core questions for atopic eczema. Clin Exp Allergy 2001; 31; 903.
16. Remes ST, Castro Rodriguez JA, Holberg CJ, et al. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol. 2001;108: 509–515
17. Wright AL, Sherrill D, Holberg CJ, et al. Breast-feeding, maternal IgE, and total serum IgE in childhood. J Allergy Clin Immunol. 1999;104:589–594.
18. McDonald KL, Huq SI, Lix LM, Becker AB, Kozyrskyj AL. Delay in diphtheria, pertussis, tetanus vaccination is associated with a reduced risk of childhood asthma. J Allergy Clin Immunol. 2008;121:626-31.
19. Ryan M, Murphy G, Ryan E, et al. et al. Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children. Immunology 1998;93:1–10.
20. Mark A, Bjorksten B, Granstrom M. Immunoglobulin E responses to diphtheria and tetanus toxoids after booster with aluminium-adsorbed and fluid DT vaccines. Vaccine 1995;13:669–73.
21. Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W. A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian selfhsp70 homologue. J Immunol 2000;164: 2711–7.
22. Prakken BJ, Wendling U, van der Zee R, Rutten VP, Kuis W, van Eden W. Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins. J Immunol 2001;167:4147–53.
23. Holt PG, Macaubas C, Prescott SL, Sly PD. Primary sensitization to inhalant allergens. Am J Respir Crit Care Med 2000;162(3 Pt 2):S91–94.
24. Schijns VE. Mechanisms of vaccine adjuvant activity: initiation and regulation of immune responses by vaccine adjuvants. Vaccine 2003;21:829–31.
25. Ada G. Vaccines and vaccination. N Engl J Med 2001;345:1042–53.
26. Nossal GJ. Host immunobiology and vaccine development. Lancet 1997;350:1316–9.
27. Charman CR, Williams HC. Epidemiology. In: Bieber T, Leung DYM, eds. Atopic Dermatitis. New York, NY: Marcel Dekker;2002:21–42
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