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The Physiological Mechanisms of Ion Fluxes in the Esophageal Epithelium and Neuromuscular Activities of Esophagus upon Acid Challenge
No full text胃食道逆流疾病(GERD)的致病、嚴重度和進展決定於攻擊因子，如胃酸，和保護因子，如胃食道屏障、食道肌肉蠕動清除能力和食道上皮功能之間的平衡結果。我們建立了一系列關於胃食道逆流疾病之致病機制的實驗動物模型，包括食道上皮細胞的電生理和食道神經肌肉活性，以及電針對食道肌肉收縮運動的作用，來探討酸刺激時食道上皮離子流和食道神經肌肉活性的生理機制。同於胃和十二指腸，食道上皮的黏液層較單薄而不足以有效地緩衝胃酸。雖然文獻指出酸刺激人、豬和負鼠的食道引起的碳酸氫根離子分泌來自食道黏膜下腺體;但人的食道黏膜下腺體的數量和垂直分佈狀態頗為歧異，個別差異也甚大。酸刺激食道鱗狀上皮是否會誘發離子流和碳酸氫根離子分泌，目前仍不清楚。我們提出一個假說，在黏膜下腺體缺少的食道區段其鱗狀上皮可能必須扮演對抗胃酸傷害的關鍵，碳酸氫根離子流可能扮演其中的角色。本研究以無食道黏膜下腺體的Wista大鼠食道上皮的離體活體來探討酸刺激引起的食道離子流之機制，另以離子替換法和藥理阻斷法探討所參與的離子和離子運輸器，並釐清辣椒素敏感性神經傳入徑和蕈毒鹼神經路徑的角色。結果顯示:缺少食道黏膜下腺體的大鼠的食道上皮具有基礎短路電流，5.03 ± 1.93 微安培/平方公分，和負的管腔端電位差值；主要與鈉離子和氯離子的吸收和碳酸氫根離子的分泌有關。酸刺激食道管腔面可引發急速的短路電流上升，同時管腔端負電位差呈7倍增加。在缺少碳酸氫根離子的緩衝液中，此現象很明顯地受到抑制；反之，不受鈉離子缺少的影響。先經di-isothiocyanatostilbene-2, 2''-disulphonic acid (DIDS)和5-(N-ethyl-N-isopropyl)-amiloride (EIPA)前處理過後，此離子流上升的現象可被抑制。經管腔面投予卡巴膽鹼(carbachol)、辣椒素、毛喉素(forskolin) 或 CFTRinh-172藥物，都不影響其基礎短路電流。酸刺激中途再投予CFTRinh-172不會抑制酸刺激所引起的上升的短路電流。經活體去除辣椒素敏感性神經後的大鼠，其食道上皮對酸刺激時的短路電流反應不會受改變。人體食道上皮也具有和大鼠同樣的基礎短路電流，而且對酸刺激也有同樣的短路電流上升的反應。由以上的結果，指出酸引發食道上皮細胞離子流的機制，主要依賴碳酸氫根離子的存在，以及陰離子交換器和鈉氫交換器的功能活性，與CFTR的活性無關，而且辣椒素敏感性神經傳入徑和蕈毒鹼神經路徑也不參與此作用。此意含著酸刺激時引起的離子流和碳酸氫根離子分泌可能扮演保護食道鱗狀上皮的功用；當離子流的調控異常時，可能會造成胃食道逆流疾病的致病性之提高。 們發現在離體的下食道括約肌的肉條實驗中，酸(1.2 N, 50 ~ 250 μL)刺激引起的LESP上升呈線性增加。為探討酸刺激下食道時其下食道括約肌的神經和肌肉活性和作用機制，我們在麻醉下的Wista大鼠的食道管腔內緊鄰的下食道括約肌處以0.1 N鹽酸灌注，同步記錄食道迷走神經活性(esophageal vagus nerve activity; EVNA)和下食道括約肌壓力(lower esophageal sphincter pressure; LESP)。結果發現，當急性酸刺激時，下食道括約肌和神經活性呈現三種強化的型態表現: (1) LES的時相收縮和EVNA的振幅和持續時間增強; (2) 強化的LES時相收縮和EVNA呈雙發性; (3) 強化的LES時相收縮和EVNA中， LES進一步激化成時相重疊收縮，而EVNA呈現叢聚性。經靜脈注射顛茄鹼(atropine) 或α,β-甲烯基三磷酸腺?(α,β-methylene ATP)會抑制基礎和酸刺激所強化的下食道括約肌的收縮活性，包含振幅和頻率。結論: 急性酸刺激下食道括約肌會經由嘌呤能路徑和蕈毒鹼路徑強化迷走神經傳導的大鼠下食道括約肌的收縮活性。這機制的生理意義可能是透過強化下食道括約肌張力，避免連續胃食道逆流以保護食道上皮持續受到傷害。下食道括約肌收縮活性過度強化是否和臨床上的食道疼痛症候群，例如非糜爛性逆流性疾病和非心因性胸痛，有關，值得未來進一步研究。 用Wista大鼠研究電針刺激合谷穴對食道管腔壓力(intraluminal esophageal pressure; IEP)的作用和其機制。在麻醉下的大鼠的右前掌相當於人的合谷穴位，分別給予低頻(2赫茲; LFEa)和高頻(10赫茲; HFEa)的電針刺激(electroacupuncture; Ea)，強度為運動閥值的20倍，脈動時間0.05毫秒，連續電針刺激10分鐘。結果: (1)正常鼠，合谷穴LFEa和HFEa會升高IEP和血壓(blood pressure; BP)。(2)兩側頸迷走神經截斷後，LFEa和HFEa對強化IEP的作用消失;但對升高BP的作用不變。(3)兩側頸迷走神經截斷後再經同側單邊臂神經叢截斷，則使LFEa和HFEa對強化IEP和BP的作用完全消失。結論:電針刺激合谷穴可調控食道管腔壓力和血壓，但兩者分別經由不同的體-自律神經反射路徑。其生理功能和機制仍有待在人體證實。進一步釐清針灸對食道運動功能的作用可能有助於尋找胃食道逆流疾病治療的替代或合併療法。The occurrence and severity of gastroesophageal reflux disease (GERD) is determined by the balance between the aggressive factor, e.g. acid, and the protective factors, e.g. gastroesophageal junction barrier, esophageal mechanical clearance (peristalsis), and esophageal epithelial functions. We have conducted a series of experiments in the aspects of neurophysiological mechanisms of GERD, including the ion fluxes in the esophageal epithelium, the neuromuscular activities of lower esophageal sphincter (LES) in response to acid, and the potential effect of electroacupuncture (Ea) on the esophageal motility.e investigated the mechanism of enhanced ion fluxes in response to luminal hydrochloric acid challenge in esophageal stratified squamous epithelium using an ex vivo rat model. The results showed that rat esophageal tissues devoid of submucosal glands displayed basal short-circuit current (Isc) of 5.03 ± 1.93 μA/cm2 and lumen-negative potential difference (PD) in association with net absorption of Na+ and Cl-, and secretion of HCO3-. Luminal hydrochloric acid (HCl) challenge (pH=1.6) triggered an acute rise of the Isc and increment of negative PD to seven-fold of baseline, which was diminished in HCO3--free, but not Na+- free buffer. The rise of Isc was inhibited by pretreatment with di-isothiocyanatostilbene-2, 2''-disulphonic acid (DIDS) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). Topical carbachol, capsaicin, forskolin or CFTRinh-172 had no effect on basal Isc. CFTRinh-172 did not reduce the acid-increased Isc. Functional ablation of capsaicin-sensitive nerves had no effect on the acid-induced Isc. The phenomenon of enhanced ion fluxes upon acid stimulation was confirmed in human esophageal specimens. It is concluded that the mechanism of acid-induced rapid transepithelial ion fluxes is dependent on the presence of bicarbonate ions as well as functional anion transporters and Na+/H+ exchanger, but independent of cystic fibrosis transmembrane conductance regulator (CFTR). The capsaicin-sensitive and muscarinic-dependent nerve pathways did not play roles in the mechanism. n our preliminary data in the in vitro LES muscle strip, LESP was amplified by acid (1.2 N, 50 ~ 250 μL) stimulation in a dose dependent response. We further evaluated esophageal vagus nerve activity (EVNA) and lower esophageal sphincter pressure (LESP) simultaneously by intra-esophageal acid (0.1 N hydrochloric acid) challenge to LES zone in rats. The results showed that in vivo rats, there were three patterns of amplified neuromuscular activity of LES upon acute acid challenge: (1) increased amplitude and duration of phasic LES contraction and EVNA; (2) bigeminy of amplified phasic LES contraction and EVNA; (3) exaggerated LESP and EVNA, characterzied with superimposed phasic LES contractions and clustered amplification of EVNA. The amplitude and frequency of LES contractile activity were attenuated by intravenous atropine and α,β-methylene ATP in both resting and acid-stimulated status. It is concluded that acute acid stimulation to esophagus may amplify vagus nerve-mediated LES contractile activity via purinergic and cholinergic pathways.e evaluated the effects and underlying mechanisms of electroacupuncture (Ea) stimulation on intraluminal esophageal pressure (IEP) in anesthetized rats. Ea stimulation (intensity of 20 times of motor threshold and pulse duration of 0.05ms) at Hoku acupoint (Li 4) of right forlimb was tested by a low frequency (2 Hz; LFEa) and a high frequency (20 Hz; HFEa) with total stimulation time of 10 minutes. The results showed that pressor effects on esophageal body (IEP) and blood vessels (BP) were elicited by LFEa and the HFEa. Bilateral cervical vagotomy completely abolished both the LFEa- and HFEa-induced pressor response on IEP, while the pressor effects on BP were not affected. Ipsilateral brachial nerve plexus transaction after bilateral cervical vagotomy completely abolished the LFEa- and HFEa-induced pressor response on IEP and BP. It is concluded that Ea stimulation at Li 4 can simultaneously modulate dual physiological response in blood vessels and esophageal body via different somato-autonomic reflex pathways.論文題目…………………………………….………………….....i文口試委員會審定書………………………………………..….ii謝………………………………………………………………..iii要…………………………………………………………… ....ivbstract………………………………………………… ......viii表目次………………………………………………………… ...xhapter 1 Opening Remarks……………………………………………… ….....1hapter 2 Luminal Hydrochloric Acid Stimulates Rapid Transepithelial Ion Fluxes in Rodent Esophageal Stratified Squamous EpitheliumIntroduction……………………………………...3Materials and Methods……………………......7Results………………………………….........15Discussion……………………………..........21Tables and Figures……………… ...........27 hapter 3 Acute HCl Challenge Amplifies Vagus Nerve-Mediated Lower Esophageal Sphincter Contractile Response via Purinergic and Muscarininc Receptors in Rats Introduction………………………………………….40Materials and Methods……………………........44Results……………………………………………....48Discussion…………………………………………...50Figures……………………………………………....56hapter 4 Electroacupuncture at HoKu (Li 4) Augments Intraluminal Esophageal Pressure in Anesthetized Rats Introduction………………………………………....63Materials and Methods…………………… ........67Results……………………………………………… …70Discussion…………………………………… .......72Figures………………………………………….......78hapter 5 Concluding Remarks……………………… .….….85eferences…………………………………………… ..........8
Abnormal gastroesophageal flap valve is highly associated with gastroesophageal reflux disease among subjects undergoing routine endoscopy in Taiwan
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Modulation of Platelet Aggregation by Areca Nut and Betel Leaf Ingredients: Roles of Reactive Oxygen Species and Cyclooxygenase
No full textThere are 2 to 6 billion betel quid (BQ) chewers in the world. Areca nut (AN), a BQ component, modulates arachidonic acid (AA) metabolism, which is crucial for platelet function. AN extract (I and 2 mg/ml) stimulated rabbit platelet aggregation, with induction of thromboxane B-2 (TXB 2) production. Contrastingly, Piper betle leaf (PBL) extract inhibited AA-, collagen-, and U46619-induced platelet aggregation, and TXB2 and prostaglandin-D-2 (PGD(2) ) production. PBL extract also inhibited platelet TXB2 and PGD(2) production triggered by thrombin, platelet activating factor (PAF), and adenosine diphosphate (ADP), whereas little effect on platelet aggregation was noted. Moreover, PBL is a scavenger of O-2(.-) and (OH)-O-., and inhibits xanthine oxidase activity and the .OH- induced PUC18 DNA breaks. Deferoxamine, 1,2-bis(2-aminophenoxy)ethane-N,N, N',N '-tetraacetic acid (BAPTA) and neomycin prevented AN-induced platelet aggregation and TXB2 production. Indomethacin, genistein, and PBL extract inhibited only TXB2 production, but not platelet aggregation. Catalase, superoxide dismutase , and dimethylthiourea (DMT) showed little effect on AN- induced platelet aggregation, whereas catalase and DMT inhibited the AN-induced TXB2 production. These results suggest that AN-induced platelet aggregation is associated with iron-mediated reactive oxygen species production, calcium mobilization, phospholipase C activation, and TXB2 production. PBL inhibited platelet aggregation via both its antioxidative effects and effects on TXB2 and PGD(2) production. Effects of AN and PBL on platelet aggregation and AA metabolism is crucial for platelet activation in the oral mucosa and cardiovascular system in BQ chewers. (C) 2002 Elsevier Science Inc
The Induction of Prostaglandin E2 Production, Interleukin-6 Production, Cell Cycle Arrest, and Cytotoxicity in Primary Oral Keratinocytes and KB Cancer Cells by Areca Nut Ingredients Is Differentially Regulated by MEK/ERK Activation
No full textThere are about 200–600 million betel quid (BQ) chew-ers
in the world. BQ chewing is one of the major risk
factor of hepatocarcinoma, oropharyngeal, and esopha-gus
cancers in Taiwan, India, and Southeast Asian coun-tries.
Thus, the precise molecular mechanisms deserve
investigation. We used cultured primary keratinocytes
and KB cells, RT-PCR, flow cytometry, Western blotting,
and ELISA to evaluate whether alterations in early gene
expression is crucial in the carcinogenic processes of
BQ. We observed the induction of c-Fos mRNA expres-sion
in human gingival keratinocyte (GK) and KB carci-noma
cells by areca nut (AN) extract and arecoline. A
maximal increment in c-fos gene expression was shown
at about 30 min after challenge. AN extract (100–800
g/ml) and arecoline (0.1– 0.8 mM) also stimulated ERK1/
ERK2 phosphorylation with a maximal stimulation at
5–10 min of exposure. Pretreatment by U0126 (30 M), a
MEK inhibitor, markedly inhibited the c-Fos, cyclooxy-genase-
2 (COX-2), and IL-6 mRNA expression of the KB
epithelial cells. In addition, U0126 and PD98059 (50 M)
also decreased AN extract- and arecoline-associated
PGE2 and IL-6 production in GK and KB cells. However,
U0126 by itself arrested the cells in G0 /G1 phase, but was
not able to prevent AN- and arecoline-induced cell death
or apoptosis. In contrast, U0126 enhanced the AN-in-duced
apoptosis of KB cells. AN ingredients thus play a
significant role in the pathogenesis of oropharyngeal
cancer by activation of MEK1/ERK/c-Fos pathway,
which promotes keratinocyte inflammation, cell sur-vival,
and affects cell cycle progression
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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