5-羟色胺信号通路在反流致食管黏膜损伤中的作用
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摘要
研究背景：
胃食管反流(GER)是指胃内容物反流入食管甚至口咽部的一种生理现象,但如反流频率和持续时间增加到一定程度,达到病理状态和/或给机体带来不适时则称为胃食管反流病(GERD).典型的GERD症状往往认为与胃酸的反流有关,临床上采用抑制胃酸分泌作为常规治疗手段,其中质子泵抑制剂(PPI)常作为首选用药。但15-20%患者症状会持续,甚至增加剂量,许多患者在治疗期间还会发生酸或非酸反流。反流入食管的酸和非酸物质如不能有效清除,会导致食管黏膜的损伤,而引起反流性食管炎(RE)等并发症。
GERD属动力异常性疾病,其发病因素较多,发病机制尚未完全阐明。主要相关因素有：下食管括约肌(LES)功能失调、食管清除能力下降、食管黏膜屏障功能受损以及食管内脏高敏性。食管黏膜清除能力取决于食管动力功能,其在反流致食管黏膜损伤中起重要作用。正常食管蠕动功能有赖于食管平滑肌的协调性收缩和松驰,而其生理基础则是食管平滑肌对不同神经递质的正常反应性。有研究表明,酸反流或混合反流引起的RE与食管平滑肌反应性受损有关,认为食管平滑肌反应性受损是食管动力异常的关键因素。因此,食管平滑肌对不同神经递质的反应性在RE发病机制研究中受到重视。
研究发现,5-羟色胺(5-hydroxytryptamine,5-HT;亦称血清素serotonin)信号通路异常可导致胃肠道动力及分泌功能异常和内脏高敏感性,认为5-HT是调节胃肠道运动、分泌及感觉功能的重要神经递质。大约90%的5-HT储存于消化道黏膜,其合成、释放、再摄取和受体状态的异常,均可引起一系列病理生理改变。5-HT可通过与5-HT4受体(5-HT4R)结合,激活腺苷酸环化酶(AC),引起环磷酸腺苷(cAMP)增高,从而激活cAMP依赖性蛋白激酶A(PKA),引起平滑肌细胞超极化,Ca2+内流减少,而引起平滑肌松驰。食管平滑肌松驰在维持食管正常蠕动功能中发挥重要作用。5-HT4R部分激动剂替加色罗(tegaserod)可降低餐后食管酸反流；降低食管对机械扩张的疼痛阈值、减少反流发生；改善食管蠕动功能。5-HT转运体(SERT)抑制剂西酞普兰(citalopram),能降低食管对化学和机械刺激的敏感性。表明5-HT信号通路异常可能与GERD发病有关,但机制尚有待于阐明。
目的：
拟建立GER动物模型(部分贲门成形术),通过食管pH检测评价其反流程度；通过病理切片评估食管黏膜损伤程度；测定食管组织5-HT含量、SERT和5-HT4R mRNA及蛋白质水平的表达,探讨5-HT信号通路在反流致食管黏膜损伤中的作用,为GERD治疗提供新的方向。
方法：
选用清洁级8周龄雄性SD大鼠50只,随机分为GER模型组30只与假手术对照组20只。GER模型组参照文献采用食管下段喷门肌纵切横缝加胃底韧带结扎术建立GER模型。实验动物饲养至术后4周测定食管pH值后处死,肉眼观察食管黏膜大体变化及显微镜下病理组织学改变。采用高效液相色谱-电化学法(HPLC-ECD)测定食管组织5-HT及其主要代谢产物五羟吲哚乙酸(5-HIAA)的含量,运用荧光定量RT-PCR法检测SERT和5-HT4R mRNA的表达,采用Western-blot方法检测5-HT4R蛋白质的表达。进一步应用SERT抑制剂氢溴酸西酞普兰对GER模型大鼠进行干预,评价其疗效。
结果：
术后4周GER模型组大鼠存活27只,死亡3只,平均体重增长与食管下端pH值均低于对照组,差异均具有统计学意义。GER模型组食管黏膜大体观可见不同程度黏膜充血、部分可见糜烂,对照组黏膜均光滑完整。食管黏膜病理切片GER模型组中20例可见不同程度的炎症改变(食管炎,RE组),7例未见明显炎症表现(无食管炎,NE组)。对照组食管黏膜均未见炎症改变。食管组织5-HT含量RE组较对照组和NE组升高,差异有统计学意义；NE组和对照组之间差异无统计学。5-HIAA含量RE组和NE组均较对照组显著升高,差异有统计学意义。SERT mRNA表达量RE组和NE组均较对照组显著增加,差异有统计学意义,而RE组又高于NE组,差异有统计学意义。RE组、NE组和对照组之间5-HT4R mRNA表达的差异无统计学意义。5-HT4R蛋白质的表达RE组低于对照组,差异有统计学意义；而NE组和对照组之间差异无统计学意义。氢溴酸西酞普兰20mg/kg组和10/kg组食管黏膜炎症情况均较未给药模型组明显改善,与10/kg组相比,20mg/kg组并未表现出更佳的治疗效果。
结论：
5-HT信号通路异常在反流致食管黏膜损伤中发挥作用。5-羟色胺转运体抑制剂可望用于治疗反流性食管炎。
Gastroesophageal reflux (GER) is defined as the gastric contents reflux into the esophagus or oropharyngeal area. It is usually known as a physiological phenomenon. However, when the frequency and duration of reflux exceed a certain extent, leading to the pathological condition and (or) discomfort in individuals, it was termed gastroesophageal reflux disease (GERD). Typical GERD symptoms are often considered to be associated with the reflux of gastric acid, therefore decreasing the gastric acid secretion is clinically used as a routine treatment, including proton pump inhibitor (PPI) as the preferred drug. However,15-20% of patients had acid reflux or non-acid reflux during the treatments even after the dose was increased. If the refluent acid and non-acid materials were not effectively removed from the esophagus, it would induce the esophageal mucosal damage and even reflux esophagitis (RE).
GERD is a motility disorder disease. Its pathogenesis is still unclear. The main etiological factors related to GERD are lower esophageal sphincter (LES) dysfunction, decreased esophageal clearance capacity, esophageal mucosal barrier dysfunction and esophageal visceral hypersensitivity. Scavenging capacity of esophageal mucosa depends on esophageal motor function, which may play an important role in the reflux-induced esophageal mucosal injury. Normal esophageal peristalsis depends on the coordination of esophageal smooth muscle contraction and relaxation, and its physiological basis is the normal reaction of esophageal smooth muscle to different neurotransmitters. Some studies reported that RE induced by acid reflux or mixed reflux was associated with impaired esophageal smooth muscle reactivity, while the impaired esophageal smooth muscle reactivity is a key factor in esophageal motility disorders. Therefore, much attention should be paid to the role of esophageal smooth muscle reactivity to different neurotransmitters in the pathogenesis of RE.
It is found that 5-hydroxytryptamine (5-HT; serotonin) signaling pathway dysfunction might lead to gastrointestinal motility and secretion abnormalities and visceral hypersensitivity. Therefore 5-HT was an important neurotransmitter to regulate gastrointestinal motility, secretion and sensory function. About 90% of 5-HT is stored in the gastrointestinal mucosa, its synthesis, release, reuptake, and receptor status abnormalities would lead to a series of pathophysiological changes.5-HT may bind to 5-HT 4 receptor (5-HT4R), activating adenylyl cyclase (AC) to increase cyclic adenosine monophosphate (cAMP), leading to activation of cAMP-dependent protein kinase A (PKA), which causes the hyperpolarization of smooth muscle cells and Ca2+ influx reduction, resulting in smooth muscle relaxation. The esophageal smooth muscle relaxation plays an important role in the maintenance of normal esophageal motility. 5-HT4R partial agonist tegaserod can reduce the postprandial esophageal acid reflux, lower esophageal mechanical pain threshold and reflux, and improve esophageal peristalsis.5-HT transporter inhibitor citalopram can reduce the esophageal sensitivity to chemical and mechanical stimuli. It indicates that the 5-HT signaling pathway damage may be the key factor in the pathogenesis of GERD, but the underlying mechanism need to be investigated in the future.
Objective:
To establish an animal model of GER to evaluate the reflux degree by esophageal pH monitor, to assess the extent of esophageal mucosal injury by pathological slides, and to detect 5-HT concentration, SERT and 5-HT4R mRNA transcription and protein expression in the esophageal tissue, so as to explore the role of 5-HT signaling pathway in the esophageal mucosal injury induced by reflux for providing a new strategy in the treatment of GERD.
Methods:
Fifty 8-week male SD rats were randomly divided into the GER model group (30 cases) and the sham operation control group (20 cases). GER model was established through gastric cardia muscle longitudinal cut, transverse suture and gastric fundus ligament ligation. Animals were executed after esophageal pH value monitor in the age of 12 weeks. The anatomical forms and histopathological changes of esophageal mucosa were observed. High performance liquid chromatography- electrochemical determination (HPLC-ECD) was used to detect 5-HT/5-HIAA concentrations of the esophageal tissue. SERT and 5-HT4R mRNA expression were investigated by real-time RT-PCR. The level of 5-HT4R protein expression was also measured by western blot method. The SERT inhibitor citalopram hydrobromide was used to treat GER and RE induced by reflux.
Results:
Four weeks after operation,27 rats in GER model group had survivors, and other three cases were dead. The increased average body weight in GER model group were significantly lower than the control group, and the values of esophageal pH were also significantly lower than the control ones. Anatomically, different degrees of esophageal mucosal congestion and erosion were observed in the most of GER model group, while esophageal mucosa was smooth in the control group. Histopathologically, twenty rats in GER model group had esophageal mucosal inflammation (reflux esophagitis, RE group), other seven cases had no obvious inflammation (no esophagitis, NE group). No inflammatory pathological changes were observed in the esophageal mucosa of control group. The 5-HT levels of esophageal tissue in the RE group were significantly higher than those in the control and NE groups. The differences of 5-HT levels in esophageal tissue between the NE group and control group had not reached significance. The 5-HIAA concentrations of esophageal mucosa both in RE group and in NE group were significantly higher than that in control group. The SERT mRNA expressions of esophageal mucosa both in RE group and in NE group were increased significantly than that in the control group, and the SERT mRNA levels in RE group was significantly higher than that in NE group. There were no significant differences in the 5-HT4R mRNA levels among RE group, NE group and control group. The 5-HT4R protein level of esophageal mucosa in RE group was significantly lower than that in the control group, but no significant difference of 5-HT4R protein level was observed between the NE and control group. The positive rate of esophageal mucosal inflammation after citalopram hydrobromide treatment in the GER model was decreased significantly both 20mg/kg group and 10mg/kg group compared with the model group without citalopram hydrobromide administration. However,20mg/kg citalopram hydrobromide-treated model group did not show better therapeutic effect than the 10mg/kg-treated model group.
Conclusions:
It was concluded that the 5-HT signaling pathway disorder might be a major factor in the pathogenesis of gastroesophageal reflux and reflux esophagitis.5-HT transporter inhibitors could be used for the treatment of reflux esophagitis.
胃食管反流(GER)是指胃内容物反流入食管甚至口咽部的一种生理现象,但如反流频率和持续时间增加到一定程度,达到病理状态和/或给机体带来不适时则称为胃食管反流病(GERD).典型的GERD症状往往认为与胃酸的反流有关,临床上采用抑制胃酸分泌作为常规治疗手段,其中质子泵抑制剂(PPI)常作为首选用药。但15-20%患者症状会持续,甚至增加剂量,许多患者在治疗期间还会发生酸或非酸反流。反流入食管的酸和非酸物质如不能有效清除,会导致食管黏膜的损伤,而引起反流性食管炎(RE)等并发症。
GERD属动力异常性疾病,其发病因素较多,发病机制尚未完全阐明。主要相关因素有：下食管括约肌(LES)功能失调、食管清除能力下降、食管黏膜屏障功能受损以及食管内脏高敏性。食管黏膜清除能力取决于食管动力功能,其在反流致食管黏膜损伤中起重要作用。正常食管蠕动功能有赖于食管平滑肌的协调性收缩和松驰,而其生理基础则是食管平滑肌对不同神经递质的正常反应性。有研究表明,酸反流或混合反流引起的RE与食管平滑肌反应性受损有关,认为食管平滑肌反应性受损是食管动力异常的关键因素。因此,食管平滑肌对不同神经递质的反应性在RE发病机制研究中受到重视。
研究发现,5-羟色胺(5-hydroxytryptamine,5-HT;亦称血清素serotonin)信号通路异常可导致胃肠道动力及分泌功能异常和内脏高敏感性,认为5-HT是调节胃肠道运动、分泌及感觉功能的重要神经递质。大约90%的5-HT储存于消化道黏膜,其合成、释放、再摄取和受体状态的异常,均可引起一系列病理生理改变。5-HT可通过与5-HT4受体(5-HT4R)结合,激活腺苷酸环化酶(AC),引起环磷酸腺苷(cAMP)增高,从而激活cAMP依赖性蛋白激酶A(PKA),引起平滑肌细胞超极化,Ca2+内流减少,而引起平滑肌松驰。食管平滑肌松驰在维持食管正常蠕动功能中发挥重要作用。5-HT4R部分激动剂替加色罗(tegaserod)可降低餐后食管酸反流；降低食管对机械扩张的疼痛阈值、减少反流发生；改善食管蠕动功能。5-HT转运体(SERT)抑制剂西酞普兰(citalopram),能降低食管对化学和机械刺激的敏感性。表明5-HT信号通路异常可能与GERD发病有关,但机制尚有待于阐明。
目的：
拟建立GER动物模型(部分贲门成形术),通过食管pH检测评价其反流程度；通过病理切片评估食管黏膜损伤程度；测定食管组织5-HT含量、SERT和5-HT4R mRNA及蛋白质水平的表达,探讨5-HT信号通路在反流致食管黏膜损伤中的作用,为GERD治疗提供新的方向。
方法：
选用清洁级8周龄雄性SD大鼠50只,随机分为GER模型组30只与假手术对照组20只。GER模型组参照文献采用食管下段喷门肌纵切横缝加胃底韧带结扎术建立GER模型。实验动物饲养至术后4周测定食管pH值后处死,肉眼观察食管黏膜大体变化及显微镜下病理组织学改变。采用高效液相色谱-电化学法(HPLC-ECD)测定食管组织5-HT及其主要代谢产物五羟吲哚乙酸(5-HIAA)的含量,运用荧光定量RT-PCR法检测SERT和5-HT4R mRNA的表达,采用Western-blot方法检测5-HT4R蛋白质的表达。进一步应用SERT抑制剂氢溴酸西酞普兰对GER模型大鼠进行干预,评价其疗效。
结果：
术后4周GER模型组大鼠存活27只,死亡3只,平均体重增长与食管下端pH值均低于对照组,差异均具有统计学意义。GER模型组食管黏膜大体观可见不同程度黏膜充血、部分可见糜烂,对照组黏膜均光滑完整。食管黏膜病理切片GER模型组中20例可见不同程度的炎症改变(食管炎,RE组),7例未见明显炎症表现(无食管炎,NE组)。对照组食管黏膜均未见炎症改变。食管组织5-HT含量RE组较对照组和NE组升高,差异有统计学意义；NE组和对照组之间差异无统计学。5-HIAA含量RE组和NE组均较对照组显著升高,差异有统计学意义。SERT mRNA表达量RE组和NE组均较对照组显著增加,差异有统计学意义,而RE组又高于NE组,差异有统计学意义。RE组、NE组和对照组之间5-HT4R mRNA表达的差异无统计学意义。5-HT4R蛋白质的表达RE组低于对照组,差异有统计学意义；而NE组和对照组之间差异无统计学意义。氢溴酸西酞普兰20mg/kg组和10/kg组食管黏膜炎症情况均较未给药模型组明显改善,与10/kg组相比,20mg/kg组并未表现出更佳的治疗效果。
结论：
5-HT信号通路异常在反流致食管黏膜损伤中发挥作用。5-羟色胺转运体抑制剂可望用于治疗反流性食管炎。
Gastroesophageal reflux (GER) is defined as the gastric contents reflux into the esophagus or oropharyngeal area. It is usually known as a physiological phenomenon. However, when the frequency and duration of reflux exceed a certain extent, leading to the pathological condition and (or) discomfort in individuals, it was termed gastroesophageal reflux disease (GERD). Typical GERD symptoms are often considered to be associated with the reflux of gastric acid, therefore decreasing the gastric acid secretion is clinically used as a routine treatment, including proton pump inhibitor (PPI) as the preferred drug. However,15-20% of patients had acid reflux or non-acid reflux during the treatments even after the dose was increased. If the refluent acid and non-acid materials were not effectively removed from the esophagus, it would induce the esophageal mucosal damage and even reflux esophagitis (RE).
GERD is a motility disorder disease. Its pathogenesis is still unclear. The main etiological factors related to GERD are lower esophageal sphincter (LES) dysfunction, decreased esophageal clearance capacity, esophageal mucosal barrier dysfunction and esophageal visceral hypersensitivity. Scavenging capacity of esophageal mucosa depends on esophageal motor function, which may play an important role in the reflux-induced esophageal mucosal injury. Normal esophageal peristalsis depends on the coordination of esophageal smooth muscle contraction and relaxation, and its physiological basis is the normal reaction of esophageal smooth muscle to different neurotransmitters. Some studies reported that RE induced by acid reflux or mixed reflux was associated with impaired esophageal smooth muscle reactivity, while the impaired esophageal smooth muscle reactivity is a key factor in esophageal motility disorders. Therefore, much attention should be paid to the role of esophageal smooth muscle reactivity to different neurotransmitters in the pathogenesis of RE.
It is found that 5-hydroxytryptamine (5-HT; serotonin) signaling pathway dysfunction might lead to gastrointestinal motility and secretion abnormalities and visceral hypersensitivity. Therefore 5-HT was an important neurotransmitter to regulate gastrointestinal motility, secretion and sensory function. About 90% of 5-HT is stored in the gastrointestinal mucosa, its synthesis, release, reuptake, and receptor status abnormalities would lead to a series of pathophysiological changes.5-HT may bind to 5-HT 4 receptor (5-HT4R), activating adenylyl cyclase (AC) to increase cyclic adenosine monophosphate (cAMP), leading to activation of cAMP-dependent protein kinase A (PKA), which causes the hyperpolarization of smooth muscle cells and Ca2+ influx reduction, resulting in smooth muscle relaxation. The esophageal smooth muscle relaxation plays an important role in the maintenance of normal esophageal motility. 5-HT4R partial agonist tegaserod can reduce the postprandial esophageal acid reflux, lower esophageal mechanical pain threshold and reflux, and improve esophageal peristalsis.5-HT transporter inhibitor citalopram can reduce the esophageal sensitivity to chemical and mechanical stimuli. It indicates that the 5-HT signaling pathway damage may be the key factor in the pathogenesis of GERD, but the underlying mechanism need to be investigated in the future.
Objective:
To establish an animal model of GER to evaluate the reflux degree by esophageal pH monitor, to assess the extent of esophageal mucosal injury by pathological slides, and to detect 5-HT concentration, SERT and 5-HT4R mRNA transcription and protein expression in the esophageal tissue, so as to explore the role of 5-HT signaling pathway in the esophageal mucosal injury induced by reflux for providing a new strategy in the treatment of GERD.
Methods:
Fifty 8-week male SD rats were randomly divided into the GER model group (30 cases) and the sham operation control group (20 cases). GER model was established through gastric cardia muscle longitudinal cut, transverse suture and gastric fundus ligament ligation. Animals were executed after esophageal pH value monitor in the age of 12 weeks. The anatomical forms and histopathological changes of esophageal mucosa were observed. High performance liquid chromatography- electrochemical determination (HPLC-ECD) was used to detect 5-HT/5-HIAA concentrations of the esophageal tissue. SERT and 5-HT4R mRNA expression were investigated by real-time RT-PCR. The level of 5-HT4R protein expression was also measured by western blot method. The SERT inhibitor citalopram hydrobromide was used to treat GER and RE induced by reflux.
Results:
Four weeks after operation,27 rats in GER model group had survivors, and other three cases were dead. The increased average body weight in GER model group were significantly lower than the control group, and the values of esophageal pH were also significantly lower than the control ones. Anatomically, different degrees of esophageal mucosal congestion and erosion were observed in the most of GER model group, while esophageal mucosa was smooth in the control group. Histopathologically, twenty rats in GER model group had esophageal mucosal inflammation (reflux esophagitis, RE group), other seven cases had no obvious inflammation (no esophagitis, NE group). No inflammatory pathological changes were observed in the esophageal mucosa of control group. The 5-HT levels of esophageal tissue in the RE group were significantly higher than those in the control and NE groups. The differences of 5-HT levels in esophageal tissue between the NE group and control group had not reached significance. The 5-HIAA concentrations of esophageal mucosa both in RE group and in NE group were significantly higher than that in control group. The SERT mRNA expressions of esophageal mucosa both in RE group and in NE group were increased significantly than that in the control group, and the SERT mRNA levels in RE group was significantly higher than that in NE group. There were no significant differences in the 5-HT4R mRNA levels among RE group, NE group and control group. The 5-HT4R protein level of esophageal mucosa in RE group was significantly lower than that in the control group, but no significant difference of 5-HT4R protein level was observed between the NE and control group. The positive rate of esophageal mucosal inflammation after citalopram hydrobromide treatment in the GER model was decreased significantly both 20mg/kg group and 10mg/kg group compared with the model group without citalopram hydrobromide administration. However,20mg/kg citalopram hydrobromide-treated model group did not show better therapeutic effect than the 10mg/kg-treated model group.
Conclusions:
It was concluded that the 5-HT signaling pathway disorder might be a major factor in the pathogenesis of gastroesophageal reflux and reflux esophagitis.5-HT transporter inhibitors could be used for the treatment of reflux esophagitis.
引文
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[5]江米足,周雪莲,陈洁,余金丹,张雁翼,章许平,等.4048例小儿食管动态pH监测结果分析.中华医学杂志,2007,87(48)：3443-3444.
[6]Nam SY, Choi IJ, Ryu KH, Kim BC, Kim CG, Nam BH. Effect of Helicobacter pylori infection and its eradication on reflux esophagitis and reflux symptoms. Am J Gastroenterol,2010,105(10):2153-2162.
[7]Coron E, Hatlebakk JG, Galmiche JP. Medical therapy of gastroesophageal reflux disease. Curr Opin Gastroenterol,2007,23(4):434-439.
[8]王宝西.胃食管反流病发病机制的研究进展.临床儿科杂志,2007,25(5)：321-323.
[9]Hu FZ, Donfack J, Ahmed A, Dopico R, Johnson S, Post JC, et al. Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14. Hum Genet,2004,114(6):562-572.
[10]Somani SK, Ghoshal UC, Saraswat VA, Aggarwal R, Misra A, Krishnani N, et al. Correlation of esophageal pH and motor abnormalities with endoscopic severity of reflux esophagitis. Dis Esophagus,2004,17(1):58-62.
[11]Kostovski A. Long-lasting reflux episodes in gastroesophageal reflux and its complications in children. Hepatogastroenterology,2003,50 Suppl 2(cccix-cccxi.
[12]Costedio MM, Hyman N, Mawe GM. Serotonin and its role in colonic function and in gastrointestinal disorders. Dis Colon Rectum,2007,50(3):376-388.
[13]Tugay M, Yildiz F, Utkan T, Muezzinoglu B, Erden F, Gacar N, et al. Esophagitis impairs esophageal smooth muscle reactivity in the rat model:an in vitro study. Dig Dis Sci,2003,48(11):2147-2152.
[14]Erbil Y, Turkoglu U, Barbaros U, Balik E, Olgac V, Kaya H, et al. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov,2005,12(3):219-225.
[15]Chitkara DK, Fortunato C, Nurko S. Esophageal motor activity in children with gastro-esophageal reflux disease and esophagitis. J Pediatr Gastroenterol Nutr, 2005,40(1):70-75.
[16]Chen CL, Yi CH, Cook IJ. Differences in oesophageal bolus transit between patients with and without erosive reflux disease. Dig Liver Dis,2008,40(5): 348-354.
[17]Nurko S, Rosen R. Esophageal dysmotility in patients who have eosinophilic esophagitis. Gastrointest Endosc Clin N Am,2008,18(1):73-89.
[18]Xu JY, Xie XP, Song GQ, Hou XH. Healing of severe reflux esophagitis with PPI does not improve esophageal dysmotility. Dis Esophagus,2007,20(4):346-352.
[19]Tugtepe H, Tugay M, Bozkurt S, Yildiz F, Utkan T, Yegen BC, et al. Esophageal smooth muscle reactivity is impaired in chronic reflux esophagitis by both receptor- and nonreceptor-mediated mechanisms. J Pediatr Surg,2007,42(4): 641-646.
[20]Spiller R. Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders:alterations in 5-HT signalling and metabolism in human disease. Neurogastroenterol Motil,2007,19 (Suppl 2):25-31.
[21]Mader R, Kocher T, Haier J, Wieczorek G, Pfannkuche HJ, Ito M. Investigation of serotonin type 4 receptor expression in human and non-human primate gastrointestinal samples. Eur J Gastroenterol Hepatol,2006,18(9):945-950.
[22]Hansen MB, Witte AB. The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol (Oxf),2008,193(4):311-323.
[23]Komada T, Matsuura T, Mikami T, Suzuki K, Sugimoto H, Kimura N, et al. Pharmacological characterization and determination of pharmacokinetic and pharmacodynamic relationship of PF-00885706, a novel partial agonist selective for the 5-HT(4) receptor. Pharmacol Res,2009,60(4):237-246.
[24]Zeng J, Zuo XL, Li YQ, Wei W, Lv GP. Tegaserod for dyspepsia and reflux symptoms in patients with chronic constipation:an exploratory open-label study. Eur J Clin Pharmacol,2007,63(6):529-536.
[25]Tonini M, De Giorgio R, De Ponti F. Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. Drugs,2004,64(4):347-361.
[26]Abdulnour-Nakhoul S, Tobey NA, Nakhoul NL, Wheeler SA, Vanegas X, Orlando RC. The effect of tegaserod on esophageal submucosal glands bicarbonate and mucin secretion. Dig Dis Sci,2008,53(9):2366-2372.
[27]Kindt S, Tack J. Mechanisms of serotonergic agents for treatment of gastrointestinal motility and functional bowel disorders. Neurogastroenterol Motil, 2007,19(Suppl 2):32-39.
[28]Koshino K, Adachi K, Furuta K, Ohara S, Morita T, Nakata S, et al. Effects of mosapride on esophageal functions and gastroesophageal reflux. J Gastroenterol Hepatol,2010,25(6):1066-1071.
[29]Manabe N, Wong BS, Camilleri M. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs,2010,19(6):765-775.
[30]Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract:a review. Naunyn Schmiedebergs Arch Pharmacol,2008,377(3):181-203.
[1]Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children:recommendations of the North American Society for Pediatric Gastroen-terology and Nutrition. J Pediatr Gastroenterol Nutr,2001,32(Suppl 2):S1-S31.
[2]Hassall E. Decisions in diagnosing and managing chronic gastroesophageal reflux disease in children. J Pediatr.2005,146(3 Suppl):S3-S12.
[3]EI-Serag HB, Gilger M, Carter J, Genta RM, Rabeneck L. Childhood GERD is a risk factor for GERD in adolescents and young adults. Am J Gastroenterol,2004, 99(5):806-812.
[4]Gold BD. Is gastroesophageal reflux disease really a life-long disease:do babies who regurgitate grow up to be adults with GERD complications? Am J Gastroenterol,2006,101 (3):641-644.
[5]王宝西.胃食管反流病发病机制的研究进展.临床儿科杂志2007,25(5)：321-23.
[6]Hu FZ, Donfack J, Ahmed A, Dopico R, Johnson S, Post JC,et al. Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14. Hum Genet,2004,114(6):562-572.
[7]江米足.儿胃食管反流病诊断进展.床儿科杂志2007,25(5)：324-328.
[8]Orenstein SR. Tests to assess symptoms of gastroesophageal reflux in infants and children. J Pediatr Gastroenterol Nutr,2003,37(Suppl 1):S29-S32.
[9]Kleinman L, Rothman M, Strauss R, Orenstein SR, Nelson S, Vandenplas Y, et al. The infant gastroesophageal reflux questionnaire revised:development and validation as an evaluative instrument. Clin Gastroenterol Hepatol,2006, 4(5):588-596.
[10]Aggarwal S, Mittal SK, Kalra KK, Rajeshwari K, Gondal R. Infant gastroe-sophageal reflux disease score:reproducibility and validity in a developing country. Trop Gastroenterol,2004,25(2):96-98.
[11]Deal L, Gold BD, Gremse DA, Winter HS, Peters SB, Fraga PD, et al. Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children:development and initial validation.J Pediatr Gastroenterol Nutr.2005,41(2):178-185.
[12]《中华儿科杂志》编辑委员会,中华医学会儿科学分会消化学组.儿胃食管反流病诊断治疗方案(试行).中华儿科杂志,2006,44(2)：96-96.
[13]Dranove JE.Focus on Diagnosis:New Technologies for the Diagnosis of Gastro-esophageal Reflux Disease.Pediatr Rev.2008,29(9):317-320.
[14]CondinoA,SondheimerJ,PanZ,Gralla J, Perry D, O'Connor JA.Evaluation of infantile acid and nonacid gastroesophageal reflux using combined pH monitoring and impedance measurement. J Pediatr Gastroenterol Nutr.2006,42(1):16-21.
[15]Lopez-Alonso M, Moya MJ, Cabo JA, Ribas J, del Carmen Macias M, Silny Jet al. Twenty-four hour esophageal impedance-pH monitoring in healthy preterm neonates:rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics,2006,118(2):e299-e308.
[16]Lee SH, Jang JY, Yoon IJ, Kim KM. Usefulness of multichannel intraluminal impedance-pH metry in children with suspected gastroesophageal reflux disea-se.Korean J Gastroenterol.2008,52(1):9-15.
[17]Croffie JM, Fitzgerald JF, Molleston JP, Gupta SK, Corkins MR, Pfefferkorn MD, et al. Accuracy and tolerability of the Bravo catheter-free pH capsule in patients between the ages of 4 and 18 years.J Pediatr Gastroenterol Nutr.2007,45(5):559-563.
[18]Gunnarsdottir A, Stenstrom P, Arnbjornsson E.48-hour wireless oesophageal pH-monitoring in children:are two days better than one? Eur J Pediatr Surg, 2007,17(6):378-381.
[19]Orel R, Markovic S. Bile in the esophagus:a factor in the pathogenesis of reflux esophagitis in children. J Pediatr Gastroenterol Nutr,2003,36(2):266-273.
[20]Oh DS, Hagen JA, Fein M, Bremner CG, Dunst CM, Demeester SR, et al. The impact of reflux composition on mucosal injury and esophageal function. J Gastrointest Surg,2006,10(6):787-797.
[21]Jiang MZ, Chen J, Chen FB,, Yu J, Liang J, Zhang Y, et al.Bile and acid reflux in the pathogenesis of reflux oesophagitis in children. J Paediatr Child Health, 2009,45(1-2):4-67.
[22]Farina R, Pennisi F, La Rosa M, Puglisi C, Mazzone G, Riva G, et al. Contrast-enhanced colour-Doppler sonography versus pH-metry in the diagnosis of gastro-oesophageal reflux in children.Radiol Med,2008,113(4):591-598.
[23]Argon M, Duygun U, Daglioz G, Omur O, Demir E, Aydogdu S.Relationship between gastric emptying and gastroesophageal reflux in infants and children.Clin Nucl Med,2006,31(5):262-265.
[24]Chitkara DK, Fortunato C, Nurko S.Esophageal motor activity in children with gastro-esophageal reflux disease and esophagitis.J Pediatr Gastroenterol Nutr, 2005,40(1):70-75.
[25]Soyer T, Karnak I, Tanyel FC, Senocak ME, Ciftci AO, Buyukpamukcu N.The use of pH monitoring and esophageal manometry in the evaluation of results of surgical therapy for gastroesophageal reflux Disease. Eur J Pediatr Surg,2007, 17(3):158-162.
[26]Gilger MA, EI-Serag HB, Gold BD, Dietrich CL, Tsou V, McDuffie A,et al. Prevalence of endoscopic findings of erosive esophagitis in children:a population- based study.J Pediatr Gastroenterol Nutr,2008,47(2):141-146.
[27]Corvaglia L, Rotatori R, Ferlini M, Aceti A, Ancora G, Faldella G. The effect of body positioning on gastroesophageal reflux in premature infants:evaluation by combined impedance and pH monitoring.J Pediatr,2007,151(6):591-596.
[28]van Wijk MP, Benninga MA, Dent J, Lontis R, Goodchild L, McCall LM, et al Effect of body position changes on postprandial gastroesophageal reflux and gastric emptying in the healthy premature neonate.J Pediatr.2007,151 (6):585-590.
[29]Simren M, Silng J, Holloway R, Tack J, Janssens J, Sifrim D. Relevance of ineffective oesophageal motility during oesophageal acid clearance. Gut,2003, 52(6):784-790.
[30]Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M. Metoclopr-amide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years. Evid Based Nurs,2005,8(3):74-74.
[31]Omari T.GastroesopHageal reflux in infants:can a simple left side positioning strategy help this diagnostic and therapeutic conundrum?Minerva Pediatr,2008, 60(2):193-200.
[32]Horvath A, Dziechciarz P, Szajewska H. The Effect of thickened-feed Interven-tions on gastroesophageal reflux in infants:systematic review and Meta-analysis of randomized, controlled trials. Pediatrics,2008,122(6):e1268-e1277.
[33]Miyazawa R, Tomomasa T, Kaneko H, Arakawa H, Shimizu N, Morikawa A. Effects of pectin liquid on gastroesophageal reflux disease in children with cerebral palsy. BMC Gastroenterol,2008,16(8):11-11.
[34]Semeniuk J, Kaczmarski M. Acid gastroesophageal reflux and intensity of symptoms in children with gastroesophageal reflux disease. Comparison of primary gastroesophageal reflux and gastroesophageal reflux secondary to food allergy. Adv Med Sci,2008,53(2):293-299.
[35]Hibbs AM, Lorch SA.Metoclopramide for the treatment of gastroesophageal reflux disease in infants:A systematic review.Pediatrics,2006,118(2):746-752.
[36]Cresi F, Marinaccio C, Russo MC, Miniero R, Silvestro L. Short-term effect of domperidone on gastroesophageal reflux in newborns assessed by combined intraluminal impedance and pH monitoring. J Perinatol,2008,28(11):766-770.
[37]Chicella MF, Batres LA, Heesters MS,Dice JE.Prokinetic drug therapy in children: a review of current options.Ann Pharmacother,2005,39(4):706-711.
[38]Bishop J, Furman M, Thomson M.Omeprazole for gastroesophageal reflux disease in the first 2 years of life:A dose-finding study with dual-channel pH monitoring. J Pediatr Gastroenterol Nutr,2007,45(1):50-55.
[39]Orel R, Brecej J, Homan M, Heuschkel R.Treatment of oesophageal bile reflux in children:The results of a prospective study with omeprazole. J Pediatr Gastroenterol Nutr,2006,42(4):376-383.
[40]Gilger MA, Tolia V, Vandenplas Y, Youssef NN, Traxler B, Illueca M. Safety and tolerability of esomeprazole in children with gastroesophageal reflux disease.J Pediatr Gastroenterol Nutr,2008,46(5):524-533.
[41]Tolia V, Bishop PR, Tsou VM, Gremse D, Soffer EF, Comer GM et al. Multi-center, randomized, double-blind study comparing 10,20 and 40 mg pantoprazole in children (5-11 years) with symptomatic gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr,2006,42(4):384-391.
[42]James L, Walson P, Lomax K, Kao R, Varughese S, Reyes J et al. Pharmaco-kinetics and tolerability of rabeprazole sodium in subjects aged 12 to 16 years with gastroesophageal reflux disease:An open-label, single- and multiple-dose study. Clin Thera,2007,29(9):2082-2092.
[2]Hassall E. Decisions in diagnosing and managing chronic gastroesophageal reflux disease in children. J Pediatr,2005,146(3 Suppl):S3-12.
[3]El-Serag HB, Gilger M, Carter J, Genta RM, Rabeneck L. Childhood GERD is a risk factor for GERD in adolescents and young adults. Am J Gastroenterol,2004, 99(5):806-812.
[4]Gold BD. Is gastroesophageal reflux disease really a life-long disease:do babies who regurgitate grow up to be adults with GERD complications? Am J Gastroenterol,2006,101(3):641-644.
[5]江米足,周雪莲,陈洁,余金丹,张雁翼,章许平,等.4048例小儿食管动态pH监测结果分析.中华医学杂志,2007,87(48)：3443-3444.
[6]Nam SY, Choi IJ, Ryu KH, Kim BC, Kim CG, Nam BH. Effect of Helicobacter pylori infection and its eradication on reflux esophagitis and reflux symptoms. Am J Gastroenterol,2010,105(10):2153-2162.
[7]Coron E, Hatlebakk JG, Galmiche JP. Medical therapy of gastroesophageal reflux disease. Curr Opin Gastroenterol,2007,23(4):434-439.
[8]王宝西.胃食管反流病发病机制的研究进展.临床儿科杂志,2007,25(5)：321-323.
[9]Hu FZ, Donfack J, Ahmed A, Dopico R, Johnson S, Post JC, et al. Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14. Hum Genet,2004,114(6):562-572.
[10]Somani SK, Ghoshal UC, Saraswat VA, Aggarwal R, Misra A, Krishnani N, et al. Correlation of esophageal pH and motor abnormalities with endoscopic severity of reflux esophagitis. Dis Esophagus,2004,17(1):58-62.
[11]Kostovski A. Long-lasting reflux episodes in gastroesophageal reflux and its complications in children. Hepatogastroenterology,2003,50 Suppl 2(cccix-cccxi.
[12]Costedio MM, Hyman N, Mawe GM. Serotonin and its role in colonic function and in gastrointestinal disorders. Dis Colon Rectum,2007,50(3):376-388.
[13]Tugay M, Yildiz F, Utkan T, Muezzinoglu B, Erden F, Gacar N, et al. Esophagitis impairs esophageal smooth muscle reactivity in the rat model:an in vitro study. Dig Dis Sci,2003,48(11):2147-2152.
[14]Erbil Y, Turkoglu U, Barbaros U, Balik E, Olgac V, Kaya H, et al. Oxidative damage in an experimentally induced gastric and gastroduodenal reflux model. Surg Innov,2005,12(3):219-225.
[15]Chitkara DK, Fortunato C, Nurko S. Esophageal motor activity in children with gastro-esophageal reflux disease and esophagitis. J Pediatr Gastroenterol Nutr, 2005,40(1):70-75.
[16]Chen CL, Yi CH, Cook IJ. Differences in oesophageal bolus transit between patients with and without erosive reflux disease. Dig Liver Dis,2008,40(5): 348-354.
[17]Nurko S, Rosen R. Esophageal dysmotility in patients who have eosinophilic esophagitis. Gastrointest Endosc Clin N Am,2008,18(1):73-89.
[18]Xu JY, Xie XP, Song GQ, Hou XH. Healing of severe reflux esophagitis with PPI does not improve esophageal dysmotility. Dis Esophagus,2007,20(4):346-352.
[19]Tugtepe H, Tugay M, Bozkurt S, Yildiz F, Utkan T, Yegen BC, et al. Esophageal smooth muscle reactivity is impaired in chronic reflux esophagitis by both receptor- and nonreceptor-mediated mechanisms. J Pediatr Surg,2007,42(4): 641-646.
[20]Spiller R. Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders:alterations in 5-HT signalling and metabolism in human disease. Neurogastroenterol Motil,2007,19 (Suppl 2):25-31.
[21]Mader R, Kocher T, Haier J, Wieczorek G, Pfannkuche HJ, Ito M. Investigation of serotonin type 4 receptor expression in human and non-human primate gastrointestinal samples. Eur J Gastroenterol Hepatol,2006,18(9):945-950.
[22]Hansen MB, Witte AB. The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol (Oxf),2008,193(4):311-323.
[23]Komada T, Matsuura T, Mikami T, Suzuki K, Sugimoto H, Kimura N, et al. Pharmacological characterization and determination of pharmacokinetic and pharmacodynamic relationship of PF-00885706, a novel partial agonist selective for the 5-HT(4) receptor. Pharmacol Res,2009,60(4):237-246.
[24]Zeng J, Zuo XL, Li YQ, Wei W, Lv GP. Tegaserod for dyspepsia and reflux symptoms in patients with chronic constipation:an exploratory open-label study. Eur J Clin Pharmacol,2007,63(6):529-536.
[25]Tonini M, De Giorgio R, De Ponti F. Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. Drugs,2004,64(4):347-361.
[26]Abdulnour-Nakhoul S, Tobey NA, Nakhoul NL, Wheeler SA, Vanegas X, Orlando RC. The effect of tegaserod on esophageal submucosal glands bicarbonate and mucin secretion. Dig Dis Sci,2008,53(9):2366-2372.
[27]Kindt S, Tack J. Mechanisms of serotonergic agents for treatment of gastrointestinal motility and functional bowel disorders. Neurogastroenterol Motil, 2007,19(Suppl 2):32-39.
[28]Koshino K, Adachi K, Furuta K, Ohara S, Morita T, Nakata S, et al. Effects of mosapride on esophageal functions and gastroesophageal reflux. J Gastroenterol Hepatol,2010,25(6):1066-1071.
[29]Manabe N, Wong BS, Camilleri M. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs,2010,19(6):765-775.
[30]Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract:a review. Naunyn Schmiedebergs Arch Pharmacol,2008,377(3):181-203.
[1]Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children:recommendations of the North American Society for Pediatric Gastroen-terology and Nutrition. J Pediatr Gastroenterol Nutr,2001,32(Suppl 2):S1-S31.
[2]Hassall E. Decisions in diagnosing and managing chronic gastroesophageal reflux disease in children. J Pediatr.2005,146(3 Suppl):S3-S12.
[3]EI-Serag HB, Gilger M, Carter J, Genta RM, Rabeneck L. Childhood GERD is a risk factor for GERD in adolescents and young adults. Am J Gastroenterol,2004, 99(5):806-812.
[4]Gold BD. Is gastroesophageal reflux disease really a life-long disease:do babies who regurgitate grow up to be adults with GERD complications? Am J Gastroenterol,2006,101 (3):641-644.
[5]王宝西.胃食管反流病发病机制的研究进展.临床儿科杂志2007,25(5)：321-23.
[6]Hu FZ, Donfack J, Ahmed A, Dopico R, Johnson S, Post JC,et al. Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14. Hum Genet,2004,114(6):562-572.
[7]江米足.儿胃食管反流病诊断进展.床儿科杂志2007,25(5)：324-328.
[8]Orenstein SR. Tests to assess symptoms of gastroesophageal reflux in infants and children. J Pediatr Gastroenterol Nutr,2003,37(Suppl 1):S29-S32.
[9]Kleinman L, Rothman M, Strauss R, Orenstein SR, Nelson S, Vandenplas Y, et al. The infant gastroesophageal reflux questionnaire revised:development and validation as an evaluative instrument. Clin Gastroenterol Hepatol,2006, 4(5):588-596.
[10]Aggarwal S, Mittal SK, Kalra KK, Rajeshwari K, Gondal R. Infant gastroe-sophageal reflux disease score:reproducibility and validity in a developing country. Trop Gastroenterol,2004,25(2):96-98.
[11]Deal L, Gold BD, Gremse DA, Winter HS, Peters SB, Fraga PD, et al. Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children:development and initial validation.J Pediatr Gastroenterol Nutr.2005,41(2):178-185.
[12]《中华儿科杂志》编辑委员会,中华医学会儿科学分会消化学组.儿胃食管反流病诊断治疗方案(试行).中华儿科杂志,2006,44(2)：96-96.
[13]Dranove JE.Focus on Diagnosis:New Technologies for the Diagnosis of Gastro-esophageal Reflux Disease.Pediatr Rev.2008,29(9):317-320.
[14]CondinoA,SondheimerJ,PanZ,Gralla J, Perry D, O'Connor JA.Evaluation of infantile acid and nonacid gastroesophageal reflux using combined pH monitoring and impedance measurement. J Pediatr Gastroenterol Nutr.2006,42(1):16-21.
[15]Lopez-Alonso M, Moya MJ, Cabo JA, Ribas J, del Carmen Macias M, Silny Jet al. Twenty-four hour esophageal impedance-pH monitoring in healthy preterm neonates:rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics,2006,118(2):e299-e308.
[16]Lee SH, Jang JY, Yoon IJ, Kim KM. Usefulness of multichannel intraluminal impedance-pH metry in children with suspected gastroesophageal reflux disea-se.Korean J Gastroenterol.2008,52(1):9-15.
[17]Croffie JM, Fitzgerald JF, Molleston JP, Gupta SK, Corkins MR, Pfefferkorn MD, et al. Accuracy and tolerability of the Bravo catheter-free pH capsule in patients between the ages of 4 and 18 years.J Pediatr Gastroenterol Nutr.2007,45(5):559-563.
[18]Gunnarsdottir A, Stenstrom P, Arnbjornsson E.48-hour wireless oesophageal pH-monitoring in children:are two days better than one? Eur J Pediatr Surg, 2007,17(6):378-381.
[19]Orel R, Markovic S. Bile in the esophagus:a factor in the pathogenesis of reflux esophagitis in children. J Pediatr Gastroenterol Nutr,2003,36(2):266-273.
[20]Oh DS, Hagen JA, Fein M, Bremner CG, Dunst CM, Demeester SR, et al. The impact of reflux composition on mucosal injury and esophageal function. J Gastrointest Surg,2006,10(6):787-797.
[21]Jiang MZ, Chen J, Chen FB,, Yu J, Liang J, Zhang Y, et al.Bile and acid reflux in the pathogenesis of reflux oesophagitis in children. J Paediatr Child Health, 2009,45(1-2):4-67.
[22]Farina R, Pennisi F, La Rosa M, Puglisi C, Mazzone G, Riva G, et al. Contrast-enhanced colour-Doppler sonography versus pH-metry in the diagnosis of gastro-oesophageal reflux in children.Radiol Med,2008,113(4):591-598.
[23]Argon M, Duygun U, Daglioz G, Omur O, Demir E, Aydogdu S.Relationship between gastric emptying and gastroesophageal reflux in infants and children.Clin Nucl Med,2006,31(5):262-265.
[24]Chitkara DK, Fortunato C, Nurko S.Esophageal motor activity in children with gastro-esophageal reflux disease and esophagitis.J Pediatr Gastroenterol Nutr, 2005,40(1):70-75.
[25]Soyer T, Karnak I, Tanyel FC, Senocak ME, Ciftci AO, Buyukpamukcu N.The use of pH monitoring and esophageal manometry in the evaluation of results of surgical therapy for gastroesophageal reflux Disease. Eur J Pediatr Surg,2007, 17(3):158-162.
[26]Gilger MA, EI-Serag HB, Gold BD, Dietrich CL, Tsou V, McDuffie A,et al. Prevalence of endoscopic findings of erosive esophagitis in children:a population- based study.J Pediatr Gastroenterol Nutr,2008,47(2):141-146.
[27]Corvaglia L, Rotatori R, Ferlini M, Aceti A, Ancora G, Faldella G. The effect of body positioning on gastroesophageal reflux in premature infants:evaluation by combined impedance and pH monitoring.J Pediatr,2007,151(6):591-596.
[28]van Wijk MP, Benninga MA, Dent J, Lontis R, Goodchild L, McCall LM, et al Effect of body position changes on postprandial gastroesophageal reflux and gastric emptying in the healthy premature neonate.J Pediatr.2007,151 (6):585-590.
[29]Simren M, Silng J, Holloway R, Tack J, Janssens J, Sifrim D. Relevance of ineffective oesophageal motility during oesophageal acid clearance. Gut,2003, 52(6):784-790.
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