臺灣早產兒罹患肺支氣管發育不全症的潛在生物標記及 學齡前行為與情緒評估常模之初探

Abstract

第一章 研究背景：過去的研究顯示早產兒罹患肺支氣管發育不全症具有50%以上的變異度能夠被遺傳因素解釋，然而，過去的人類基因關聯性研究無一致的結論，並且在肺支氣管發育不全症內會受到改變的轉譯因子，仍然在動物模型的實驗階段。有鑑於過去研究的不足，探索與基因調控有關的遺傳因子，例如微小核醣核酸，作為肺支氣管發育不全症的生物標記，是值得嘗試的研究方向。目的：本研究的目的為探索罹患肺支氣管發育不全症之極低出生體重早產兒(出生體重低於1,500公克)，其周邊血液中的特異微小核醣核酸。方法：本研究搜集15位罹患肺支氣管不全症的極低出生體重早產兒及另15位性別配對之未罹病早產兒的周邊血液檢體，使用同步定量聚合鏈反應系統檢驗人類共365個微小核糖核酸於周邊血液的表現剪影。結果：研究結果顯示罹病早產兒在miR-133b及miR-7的表現比例上較未罹病早產兒多，然而在miR-152, miR-30a-3p, miR-650及miR-624則呈現較低比例的表現(所有p < 0.2)。此六個特異微小核醣核酸所構成的生物標誌對於肺支氣管不全症的發生具有高預測性，在調控與疾病相關的干擾因子後，仍可以高度區分肺支氣管發育不全症之罹病早產兒與未罹病早產兒(準確率 = 0.995)。由微小核醣核酸的基因預測資料庫內發現此六個特異微小核醣核酸共同協調41個基因標的，功能路徑分析結果發現其中17個基因標的互相作用於一個網絡內，並且與發育相關的功能與疾病有關，並可能參與Wnt/β-catenin 與axon guidance 的訊號路徑(兩者p < 0.05 )。結論：研究結果顯示周邊血液中的六個特異微小核醣核酸之表現剪影對於肺支氣管發育不全症的發生是可行的生物標誌。 第二章 研究背景：現行對於非西方國家之學齡前兒童的行為與情緒問題流行病學資料仍顯不足，並且國內於學齡前兒童的行為與情緒問題的資料闕如。目的：本研究使用一歲半至五歲版本之兒童行為檢核量表做為研究工具，目的為探討臺灣足月兒於學齡前期的行為與情緒問題，並且與美國及荷蘭兒童的行為問題之分數及盛行率做比較，以及檢驗行為問題的關聯因子。方法：三百零六位臺灣學齡前兒童(年齡介於二十至六十個月間)的母親填寫兒童行為檢核量表一歲半至五歲版本。此研究擷取過去研究中美國與荷蘭學齡前兒童的行為問題數據與台灣的數據做比較。結果：使用行為檢核量表一歲半至五歲版本測量台灣學齡前兒童的行為問題呈現良好的信度及因素效度。相較於美國與荷蘭兒童的行為問題資料，臺灣學齡前兒童於多數的問題行為特徵具有較高的行為問題分數，並且在內顯相關的行為問題及睡眠問題上有較高的盛行率。許多社會人口學因子，例如較年幼的兒童、男性及第一出生序較不利於問題行為的表現。女孩的行為問題分數會隨著年齡的增長而下降，然而男孩問題行為分數則隨著年齡增加而持續維持較高的分數表現。結論：本研究對於臺灣學齡前兒童的行為與情緒問題提供具參考價值的流行病學資料，有關跨文化比較及行為關聯因子的結果將有助於臨床上評估與處置具行為問題之學齡前兒童。

Chapter 1 Background: Genetic factors have been shown to account for more than 50% of the variation in bronchopulmonary dysplasia (BPD) in preterm infants. However, human genetic association studies have failed to show consistent associations, and altered expression of transcription factors has only been observed in animal studies. An emerging focus in the search for biomarkers of BPD has been on post-transcriptional regulator of messenger RNA translation such as microRNAs (miRNAs). Objective: This study aimed to identify differentially expressed miRNAs in the peripheral blood of very low birth weight (VLBW, birth weight < 1,500 g) preterm infants with and without BPD. Methods: Blood samples from 15 VLBW preterm infants with BPD and from 15 sex-matched controls were collected in early postnatal life, and 365 miRNA expression profiles were assessed using a quantitative real-time polymerase chain reaction system. Results: The BPD group was more likely than the non-BPD group to show increased expression of miR-133b and miR-7 and decreased expression of miR-152, miR-30a-3p, miR-650 and miR-624 (all p < 0.2). This 6-miRNA signature was highly predictive of the occurrence of BPD after controlling for the effects of confounders (accuracy = 0.995). Forty-one shared target genes were associated with the 6-miRNA signature, and seventeen of them were relevant to development-related functions and diseases. The Wnt/β-catenin and axon guidance signaling pathways were associated with the target genes (p < 0.05 for both). Conclusions: This 6-miRNA signature of peripheral blood might serve as a biomarker predictive of the occurrence of BPD in VLBW preterm infants. Chapter 2 Background: There has been limited epidemiologic information concerning non-Western preschoolers’ behavioral and emotional problems, and the data in Taiwanese preschoolers is lacking. Objective: This study aimed to investigate behavioral and emotional problems in a full-term population of Taiwanese preschoolers using the Child Behavior Checklist for Ages 1&frac12;-5 (CBCL/1&frac12;-5). The behavioral problems scores and prevalence of Taiwanese preschoolers were compared with those of American and Dutch preschoolers. The correlates of behavioral problems were also examined. Methods: Mothers of 306 Taiwanese preschoolers aged 20-60 months completed the CBCL/1&frac12;-5. The data of American and Dutch preschoolers were extracted from the previous studies and to compare with Taiwanese data. Results: The CBCL/1&frac12;-5 had satisfactory reliability and factorial validity for assessing Taiwanese preschoolers. Results of cross-cultural comparisons revealed that Taiwanese preschoolers exhibited higher behavioral problem scores on most of the behavioral syndromes and increased prevalence rates of internalizing-related syndromes and Sleep Problems. Younger age, male gender, and first birth order were unfavorable for behavioral performance. Girls’ behavioral problems decreased with age, whereas boys’ behavioral problems persistently high across ages. Conclusions: Results of cross-cultural comparisons and behavioral correlates are important to assist in clinical assessment and management of preschoolers’ behavioral and emotional problems.