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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
dc.contributor.author | Yung-Sen Chang | en |
dc.contributor.author | 張詠森 | zh_TW |
dc.date.accessioned | 2021-06-16T09:45:55Z | - |
dc.date.available | 2019-03-01 | |
dc.date.copyright | 2017-03-01 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-01-24 | |
dc.identifier.citation | Achenbach, T. M. (1992). Manual for the child behavior checklist/2-3 and 1992 profile. Burlington, VT, Department of Psychiatry, University of Vermont.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59934 | - |
dc.description.abstract | 背景
睡眠障礙在兒童異位性皮膚炎相當常見,是最常見造成這些病人生活品質降低的原因,同時也有可能對於神經認知功能及行為有負面影響。不過,異位性皮膚炎兒童睡眠障礙的機制尚不明朗,而且目前臨床上對於如何治療這些病童的睡眠障礙還沒有共識。本研究的目的為客觀的測量異位性皮膚炎病童睡眠障礙的特性,找出可能造成睡眠障礙的因子及可以協助臨床醫師預測病童有睡眠障礙的因子,並評估以口服或外用褪黑激素治療異位性皮膚炎及其睡眠障礙的可能性。 研究方法及結果 第一部分:客觀評估異位性皮膚炎病童睡眠障礙的特色及可能造成睡眠障礙的因子 我們共召集72名異位性皮膚炎病童及32位健康受試者參與測量,年齡介於1至18歲之間。我們以腕動錶及多層次睡眠儀測量多項客觀的睡眠指數,並測量尿液中褪黑激素的代謝物6-sulfatoxymelatonin的量,及血清中細胞激素及免疫球蛋白E的數值。客觀睡眠量測結果顯示,異位性皮膚炎病童睡眠效率較差,需要較長的時間才能入睡,睡眠較為片段,且較少非快速動眼期睡眠。腕動錶及多層次睡眠儀量測的結果高度相關。異位性皮膚炎的嚴重度和睡眠障礙顯著相關(r = 0.55-0.7),且如果病人異位性皮膚炎嚴重度指數(SCORAD)≥ 48.7,即可預測病童會有較差的睡眠效率,其敏感性83.3%,特異度75%(P = 0.001)。異位性皮膚炎病童中,夜晚褪黑激素分泌較低者,睡眠障礙較嚴重。另外,癢,搔抓,較高的血清免疫球蛋白E值,及對於塵蟎及金黃色葡萄球菌內毒素過敏,也都和睡眠障礙有顯著相關。 第二部分:以隨機雙盲試驗評估褪黑激素治療異位性皮膚炎及其睡眠障礙之療效 這是一個隨機雙盲對照交叉試驗,於2012年8月至2013年1月間於台大醫院小兒部執行。我們召集了73位1至18歲,經醫師診斷為異位性皮膚炎且皮膚病兆面積超過5%體表面積的病童參與,其中有48位被隨機分配,而有38位(79%)完成試驗。試驗當中沒有受試者因為藥物之不良反應而退出。受試者以1:1的比例被隨機分配至兩組,ㄧ組每晚吃3毫克的褪黑激素,ㄧ組則吃安慰劑。結束後休息兩週,再交換至另一個治療。評估的主要結果為異位性皮膚炎的嚴重度(以SCORAD測量),而次要結果為腕動錶及多層次睡眠儀測量的多項客觀睡眠指數,主觀的睡眠及皮膚炎是否改善,夜晚尿液中褪黑激素的量,及血清中免疫球蛋白E及細胞激素的數值。我們發現褪黑激素治療後,入睡的時間相較於安慰劑後,縮短了21.4分鐘(95%信賴區間: -38.6至-4.2),而且皮膚炎嚴重度指數也較安慰劑減少了9.1(95%信賴區間: -13.67至-4.57)。SCORAD改善的程度及入睡時間改善的程度無顯著相關。長處和困難問卷當中的親社會行為分數,在褪黑激素治療後也有顯著改善。整個試驗過程中都沒有副作用或不良反應發生。 第三部分:以動物實驗評估外用褪黑激素治療異位性皮膚炎是否有效 我們使用DNCB於Balb/c老鼠以誘發異位性皮膚炎的老鼠模型,來評估外用褪黑激素治療異位性皮膚炎是否有效。老鼠隨機分至四組:對照組,DNCB組,DNCB+3%外用褪黑激素組,DNCB+5%外用褪黑激素組,比較各組組織學切片的皮膚炎嚴重度,血清免疫球蛋白E數值,及皮膚細胞激素IL-4,IL-13,及IL-17的mRNA表現量。試驗結果發現,3%及5%外用褪黑激素治療後皮膚組織學嚴重度分數顯著降低(3%外用褪黑激素組相較於DNCB組P = 0.04,5%外用褪黑激素組相較於DNCB組P = 0.02)。每十個高倍顯微鏡視野下T細胞的數目,於3%及5%外用褪黑激素治療後也都顯著降低(3%外用褪黑激素組相較於DNCB組P = 0.03,5%外用褪黑激素組相較於DNCB組P = 0.0007)。血清免疫球蛋白E數值於5%外用褪黑激素治療後也顯著降低(P = 0.02)。 結論 睡眠障礙於異位性皮膚炎很常見,且和皮膚炎嚴重度顯著相關。可能造成異位性皮膚炎病童睡眠障礙的原因包括:夜間較少的褪黑激素分泌,癢及搔抓,較高的血清免疫球蛋白E數值,及對於塵蟎及金黃色葡萄球菌內毒素過敏。口服補充褪黑激素可以顯著改善異位性皮膚炎嚴重度及縮短入睡時間,所以是個極有潛力的新療法。動物實驗初步結果也顯示外用褪黑激素可能也可用於異位性皮膚炎之治療。 | zh_TW |
dc.description.abstract | Background
Sleep disturbance is common in children with atopic dermatitis (AD) and is a major factor leading to impaired quality of life. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors, and to evaluate the effectiveness of oral or topical melatonin in treating patients with AD and their sleep disturbance. Methods and Results Part I. Cross-Sectional Study to Evaluate the Characteristics and Contributing Factors of Sleep Disturbance in Children with Atopic Dermatitis Sleep parameters were measured by actigraphy and polysomnography in 72 AD patients and 32 controls aged 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. The objective measurements showed that the AD patients had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less non-rapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55-0.7), and a Scoring Atopic Dermatitis (SCORAD) index of ≥ 48.7 predicted poor sleep efficiency (sensitivity 83.3%, specificity 75%, area under the curve = 0.81, P = 0.001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the AD patients. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins. Part II. Randomized Controlled Trial to Evaluate the Effect of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbance A randomized, double-blind, placebo-controlled crossover study was conducted. Seventy-three children with physician-diagnosed AD involving at least 5% of the total body surface area, aged between 1 and 18 years were recruited, 48 children were randomized, and 38 (79%) completed the study. None withdrew due to adverse effects. Participants were randomized (1:1) to melatonin 3 mg or placebo daily for 4 weeks. After a 2-week washout period, they crossed over to the alternative treatment. The primary outcome was the AD disease severity evaluated using the Scoring Atopic Dermatitis (SCORAD) index. Secondary outcomes included sleep parameters measured by actigraphy, subjective sleep and dermatitis change, the sleep parameters measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, serum immunoglobulin E levels, serum cytokine levels, and behavior analysis scores. After melatonin treatment, the sleep onset latency shortened 21.4 minutes more than placebo (95%CI: -38.6 to -4.2). Moreover, the SCORAD index decreased 9.1 more than placebo (95%CI: -13.67 to -4.57). The improvement in the SCORAD index did not significantly correlate with the change in the sleep onset latency. The scoring of prosocial behavior also significantly improved after melatonin treatment. No adverse event was reported throughout the study. Part III. Animal Study to Evaluate the Effectiveness of Topical Melatonin for the Treatment of Atopic Dermatitis The DNCB-induced dermatitis in Balb/c mice, the animal model for AD, was used to evaluate the effectiveness of topical melatonin for the treatment of AD. Mice were randomly assigned to one of four groups: the control, DNCB, DNCB + 3% topical melatonin, and DNCB + 5% topical melatonin. Gross and histological dermatitis severity, serum IgE levels, and skin mRNA expression of the cytokines IL-4, IL-13, and IL-17 were measured. There was significant improvement in pathology scoring in both the 3% and 5% topical melatonin treatment group (P = 0.04 for 3% melatonin compared with DNCB-stimulated, and P = 0.02 for 5% melatonin compared with DNCB-stimulated). T cell infiltration of the skin was significantly reduced after either 3% or 5% topical melatonin treatment (P = 0.03 and P = 0.0007 for 3% and 5% melatonin compared with DNCB group, respectively). Moreover, the serum total IgE level significantly reduced after 5% melatonin treatment compared with the DNCB-stimulated group (P = 0.02). Conclusions In AD patients, sleep disturbance is strongly associated with disease severity, and posslible contributing factors include lower nocturnal melatonin secretion, pruritus and scratching, and allergic sensitization to dust mite and Staphylococcal enterotoxins. Oral melatonin supplement is potentially a safe and effective way to improve the sleep onset and skin condition simultaneously. Preliminary animal studies also suggest that topical melatonin could be effective in the treatment of AD. | en |
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dc.description.tableofcontents | 口試委員會審定書............................................................................i
誌謝............................................................................................... ii 中文摘要………………………………………………………………………….......... iii 英文摘要…………………………………………………………………………............ vi 博士論文內容 第一章 緒論 Introduction.........…………………………………….................1 1.1 Introduction to Atopic Dermatitis……………......…………………..... 1 1.2 Sleep Disturbance in Patients with Atopic Dermatitis and Tools for Evaluation ……......………………………………………………………........ 4 1.3 The Impact of Sleep Disturbance in Children with AD .......... 6 1.4 Mechanism of Sleep Disturbance in Children with AD........... 8 1.5 Melatonin and Sleep Disturbance in Atopic Dermatitis..........15 1.6 Management of Sleep Disturbance in Children with AD........17 1.7 Use of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbances......................................................................18 1.8 Objectives of this study.........................................................20 1.9 Importance and Novelty of this Study................................... 23 第二章 研究方法與材料 Materials and Methods............................25 2.1 Cross-Sectional Study to Evaluate the Characteristics and Contributing Factors of Sleep Disturbance in Children with Atopic Dermatitis ...................................................................................25 2.2 Randomized Controlled Trial to Evaluate the Effect of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbance..................................................................................31 2.3 Animal Study to Evaluate the Effectiveness of Topical Melatonin for the Treatment of Atopic Dermatitis.......................38 第三章 結果Results .....................................................................44 3.1 Cross-Sectional Study to Evaluate the Characteristics and Contributing Factors of Sleep Disturbance in Children with Atopic Dermatitis .................................................................................. 44 3.2 Randomized Controlled Trial to Evaluate the Effect of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbance.................................................................................50 3.3 Animal Study to Evaluate the Effectiveness of Topical Melatonin for the Treatment of Atopic Dermatitis.......................55 第四章 討論 Discussion ............................................................. 58 4.1 Cross-Sectional Study to Evaluate the Characteristics and Contributing Factors of Sleep Disturbance in Children with Atopic Dermatitis .................................................................................. 58 4.2 Randomized Controlled Trial to Evaluate the Effect of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbance.................................................................................68 4.3 Animal Study to Evaluate the Effectiveness of Topical Melatonin for the Treatment of Atopic Dermatitis.......................77 4.4 Implications for the Treatment of Sleep Disturbance in AD. 81 第五章 展望 Perspectives............................................................84 第六章 論文英文簡述 Summary.................................................................................... 95 參考文獻 Reference.................................................................................. 115 圖表Figures and Tables....................................................................................... 147 Figure 1. Skin lesions in atopic dermatitis. ................................147 Figure 2. Study protocol for the randomized controlled trial to evaluate the effect of melatonin for the treatment of atopic dermatitis and sleep disturbance.............................................. 148 Figure 3. Protocol for the induction & treatment of AD in BALB/c mice with DNCB.........................................................................149 Figure 4. Correlation of AD disease severity with sleep parameters................................................................................ 150 Figure 5. Correlation of an objective SCORAD and pruritus score with sleep parameters................................................................151 Figure 6. ROC curve for predicting poor sleep efficiency by SCORAD.....................................................................................152 Figure 7. Limb movement index of each sleep stage in AD patients and controls......................................................................................153 Figure 8. Nocturnal melatonin level in AD patients and its association with sleep disturbance............................................154 Figure 9. Relationship between behavior in AD patients and .dermatitis severity and sleep disturbance. ..............................155 Figure 10. Size and darkness of allergic shiners in AD patients and its association with sleep disturbance. ..............................156 Figure 11. Randomization and follow-up of the study participants of the clinical trial.......................................................................157 Figure 12. AD disease severity and sleep onset latency before and after melatonin treatment (combining all the patients).......158 Figure 13. Other sleep parameters before and after melatonin treatment (combining all the patients). .....................................159 Figure 14. Nocturnal urinary 6-sulfatoxymelatonin levels after melatonin supplement. .............................................................160 Figure 15. Change of SCORAD and sleep onset latency before and after melatonin or placebo treatment according to high or low nocturnal urinary 6-sulfatoxymelatonin after melatonin treatment....................................................................................161 Figure 16. Change of SCORAD and sleep onset latency before and after melatonin or placebo treatment according to high or low baseline nocturnal urinary 6-sulfatoxymelatonin. ....................162 Figure 17. Serum cytokine levels before and after melatonin treatment.................................................................................163 Figure 18. Gross findings of DNCB-stimulated mice skin with and without melatonin treatment....................................................164 Figure 19. Clinical score and ear thickness measurements in a DNCB-stimulated AD mouse model with and without melatonin treatment..................................................................................165 Figure 20. Histological findings in a DNCB-stimulated AD mouse model with and without melatonin treatment............................166 Figure 21. Pathology scores in a DNCB-stimulated AD mouse model with and without melatonin treatment............................167 Figure 22. Mast cell infiltration evaluated with toluidine blue stain in a DNCB-stimulated AD mouse model with and without melatonin treatment..................................................................168 Figure 23. Immunohistochemistry staining for anti-CD3 in a DNCB-stimulated AD mouse model with and without melatonin treatment..................................................................................169 Figure 24. Serum total IgE level in a DNCB-stimulated AD mouse model with and without melatonin treatment............................170 Figure 25. mRNA expression of IL-4, IL-13, and IL-17 in the skin in a DNCB-stimulated AD mouse model with and without melatonin treatment....................................................................................171 Figure 26. Mechanism of sleep disturbance in atopic dermatitis and possible treatment implications..........................................172 Table 1. Definitions of sleep parameters recorded with actigraphy and polysomnography................................................................173 Table 2. Sequence of the primers used for experiment............174 Table 3. Demographic data and actigraphy results in patients and controls......................................................................................175 Table 4. Results from the questionnaire for subjective sleep condition....................................................................................176 Table 5. Polysomnography results in patients and controls.....177 Table 6. Correlation of sleep parameters obtained by actigraphy and polysomnography...............................................................178 Table 7. Correlation of total and allergen-specific IgE levels with sleep parameters.......................................................................179 Table 8. Serum cytokine levels and their relationship with sleep parameters................................................................................180 Table 9. Correlation of behavior and quality of life with disease severity and sleep parameters in AD patients............................181 Table 10. Comparison of behavioral evaluation in AD patients and controls.....................................................................................182 Table 11. Baseline characteristics of the patients of the clinical trial at randomization.................................................................183 Table 12. Effects of melatonin versus placebo in the two study periods (before and after the crossover) ..................................184 Table 13. Effects of melatonin versus placebo, combining all the patients.....................................................................................185 Table 14. Serum cytokine and chemokine levels before and after melatonin treatment..................................................................186 Table 15. Behavior and quality of life scores after melatonin and placebo treatment.....................................................................187 Table 16. Sequence and period effects for each outcome from the linear mixed model....................................................................188 Table 17. Subjective improvement of symptoms after treatment with melatonin or placebo.........................................................189 Table 18. Summary of pathological scoring in the AD mouse model treated with and without topical melatonin.....................190 附錄:博士班修業期間所發表之相關論文......................................191 | |
dc.language.iso | en | |
dc.title | 異位性皮膚炎兒童之睡眠障礙及褪黑激素之角色與應用 | zh_TW |
dc.title | Sleep Disturbance in Children with Atopic Dermatitis and the Role and Applications of Melatonin | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 楊崑德(Kuender Yang),葉國偉(Kuo-Wei Yeh),王莉芳(Li-Fang Wang),周祖述(Tzuu-Shuh Jou) | |
dc.subject.keyword | 異位性皮膚炎,褪黑激素,睡眠,兒童, | zh_TW |
dc.subject.keyword | atopic dermatitis,melatonin,sleep,children, | en |
dc.relation.page | 191 | |
dc.identifier.doi | 10.6342/NTU201700232 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-01-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
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