記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Digestive Endoscopy  

Objectives: Reflux hypersensitivity (RH) is a form of refractory gastroesophageal reflux disease in which duodenogastroesophageal reflux (DGER) plays a role. This study aimed to determine the usefulness of an endoscopy system equipped with image-enhanced technology for evaluating DGER and RH. Methods: The image enhancement mode for detecting bilirubin and calculated values were defined as the Bil mode and Bil value, respectively. First, the visibility of the Bil mode was validated for a bilirubin solution and bile concentrations ranging from 0.01% to 100% (0.002–20 mg/dL). Second, visibility scores of the Bil mode, when applied to the porcine esophagus sprayed with a bilirubin solution, were compared to those of the blue laser imaging (BLI) and white light imaging (WLI) modes. Third, a clinical study was conducted to determine the correlations between esophageal Bil values and the number of nonacid reflux events (NNRE) during multichannel intraluminal impedance-pH monitoring as well as the utility of esophageal Bil values for the differential diagnosis of RH. Results: Bilirubin solution and bile concentrations higher than 1% were visualized in red using the Bil mode. The visibility score was significantly higher with the Bil mode than with the BLI and WLI modes for 1% to 6% bilirubin solutions (P < 0.05). The esophageal Bil value and NNRE were significantly positively correlated (P = 0.031). The area under the receiver operating characteristic curve for the differential diagnosis of RH was 0.817. Conclusion: The Bil mode can detect bilirubin with high accuracy and could be used to evaluate DGER in clinical practice.

DOI： 10.1111/den.14749

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

食道平滑筋収縮の変化および関連する炎症性反応について検討することによりアカラシアの病態を明らかにし、アカラシアの進展における食道細菌叢の意義を評価した。経口的内視鏡的筋層切開術を施行したII型アカラシア症例から得た食道粘膜および下部食道括約筋(LES)標本を解析した。患者由来の食道調整培養液をマウス食道に投与し、食道内環境がアカラシアと関連するか否かについて検討した。安静時および刺激時における対照群のLESでは、20-kDaミオシン軽鎖(LC20)の約30%がリン酸化されていた。アカラシア症例では状況に関わらずLC20のリン酸化は10%未満であった。アカラシアにおける低リン酸化は、ミオシンリン酸化阻害蛋白質CPI-17の発現低下と関連していた。IL-17A、IL-17F、IL-22、IL-23Aを含む関連サイトカインは、アカラシアでは発現が増加していた。食道細菌叢のα-Diversity指数、およびActinomycesおよびDialisterを含む数種類の細菌の割合がアカラシアで増加していた。ActinomycesレベルはIL-23Aレベルと正の相関が認められ、DialisterレベルはIL-17A、IL-17F、IL-22レベルと正の相関が認められた。マウスにおいて、食道IL-17F値は調整培地の経口投与後に増加した。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Gastroenterology  

Background: Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development. Methods: We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia. Results: Approximately 30% of 20-kDa myosin light chains (LC20) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC20 phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC20 in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media. Conclusions: In LES of patients with achalasia, hypophosphorylation of LC20, a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia.

DOI： 10.1007/s00535-024-02088-w

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

胃食道逆流症(GERD)は病的な酸逆流によって惹起される病態であるが、難治性GERDでは食道知覚過敏や食道運動異常症(EMDs)を考慮した病態評価が必要である。今回、高齢者ボノプラザン(P-CAB)抵抗性GERDの特徴を明らかにするため、75歳以上の高齢者20例と非高齢者51例の食道生理機能検査の結果を比較検討した。高解像度食道内圧検査では非高齢者の41%は正常であったが、高齢者では正常例は認めなかった。食道内多チャンネルインピーダンス・pHモニタリング検査では、非高齢者ではNERD、逆流過敏性食道、機能性胸焼けの3疾患を認めたが、高齢者では逆流過敏性食道は認めなかった。高齢者P-CAB抵抗性GERDでは、EMDsが目立ち食道知覚過敏の影響は小さい可能性がある。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

胃食道逆流症(GERD)は病的な酸逆流によって惹起される病態であるが、難治性GERDでは食道知覚過敏や食道運動異常症(EMDs)を考慮した病態評価が必要である。今回、高齢者ボノプラザン(P-CAB)抵抗性GERDの特徴を明らかにするため、75歳以上の高齢者20例と非高齢者51例の食道生理機能検査の結果を比較検討した。高解像度食道内圧検査では非高齢者の41%は正常であったが、高齢者では正常例は認めなかった。食道内多チャンネルインピーダンス・pHモニタリング検査では、非高齢者ではNERD、逆流過敏性食道、機能性胸焼けの3疾患を認めたが、高齢者では逆流過敏性食道は認めなかった。高齢者P-CAB抵抗性GERDでは、EMDsが目立ち食道知覚過敏の影響は小さい可能性がある。(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cellular and Molecular Gastroenterology and Hepatology  

Background & Aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. Conclusions: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.

DOI： 10.1016/j.jcmgh.2023.11.012

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DOI： 10.1016/j.jmmm.2023.171332

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

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出版者・発行元：東京医学社  

DOI： 10.24479/endo.0000000731

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gastrointestinal Endoscopy  

Background and aims: EUS-guided FNA/biopsy (EUS-FNA/B) is the citerion standard for diagnosing subepithelial lesions (SELs); however, its diagnostic ability for SELs <20 mm is low. We developed a new diagnostic method to differentiate between GI stromal tumor (GIST) and non-GIST by measuring high-frequency impedance (H-impedance) using an EUS-FNB needle. Methods: The H-impedance of gastric epithelial neoplasms from 16 cases were measured with a conventional impedance probe to confirm whether H-impedance is clinically useful for assessing cell density (study 1). The H-impedance values of exposed SELs from 25 cases with use of the conventional probe (study 2) and nonexposed SELs from 20 cases with use of the EUS-FNB needle probe (study 3) were measured to determine the diagnostic ability of H-impedance for differentiating GISTs from non-GISTs. Results: H-impedance significantly positively correlated with cell density (P =.030) (study 1). The H-impedance of GIST (99.5) measured with a conventional probe was significantly higher than with those of the muscular layer (82.4) and leiomyoma (89.2) (P <.01) (study 2). The H-impedance of GIST measured with the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs leiomyoma, 71.8; P =.015). The diagnostic yield of the impedance method for differentiating GISTs from non-GISTs had 94.4% accuracy, 88.9% sensitivity, 100% specificity, and 0.95 area under the curve. Diagnostic ability was not affected by lesion size (P =.86) (study 3). Conclusion: Auxiliary differential diagnosis between gastric GISTs and non-GISTs by the H-impedance measurement during EUS-FNB could be a good option, especially when the lesion is <20 mm.

DOI： 10.1016/j.gie.2022.11.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Digestive Diseases and Sciences  

Background: The specific role of the M3 muscarinic acetylcholine receptor in gastrointestinal motility under physiological conditions is unclear, due to a lack of subtype-selective compounds. Aims: The objective of this study was to determine the region-specific role of the M3 receptor in gastrointestinal motility. Methods: We developed a novel positive allosteric modulator (PAM) for the M3 receptor, PAM-369. The effects of PAM-369 on the carbachol-induced contractile response of porcine esophageal smooth muscle and mouse colonic smooth muscle (ex vivo) and on the transit in mouse small intestine and rat colon (in vivo) were examined. Results: PAM-369 selectively potentiated the M3 receptor under the stimulation of its orthosteric ligands without agonistic or antagonistic activity. Half-maximal effective concentrations of PAM activity for human, mouse, and rat M3 receptors were 0.253, 0.345, and 0.127 μM, respectively. PAM-369 enhanced carbachol-induced contraction in porcine esophageal smooth muscle and mouse colonic smooth muscle without causing any contractile responses by itself. The oral administration of 30 mg/kg PAM-369 increased the small intestinal transit in both normal motility and loperamide-induced intestinal dysmotility mice but had no effects on the colonic transit, although the M3 receptor mRNA expression is higher in the colon than in the small intestine. Conclusions: This study provided the first direct evidence that the M3 receptor has different region-specific roles in the motility function between the small intestine and colon in physiological and pathophysiological contexts. Selective PAMs designed for targeted subtypes of muscarinic receptors are useful for elucidating the subtype-specific function.

DOI： 10.1007/s10620-022-07637-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Surgical Endoscopy  

Background: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated. Methods: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020. Results: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27). Conclusion: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL’s pseudocapsule.

DOI： 10.1007/s00464-022-09419-z

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記述言語：日本語   出版者・発行元：(一社)日本消化管学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endoscopy  

DOI： 10.1055/a-1841-5907

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endoscopy  

DOI： 10.1055/a-1809-4967

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

食道運動障害性疾患(EMD)を診断するための新たな2所見を用いたバリウム食道造影検査(BE)によるスクリーニングを評価した。2013年1月から2020年10月にEMDが疑われ高解像度マノメトリー検査(HRM)とBEの両方が施行された244例を対象とした。EMDの診断はシカゴ分類第3.0版を用いてHRM所見に基づいて行った。BEは硫酸バリウムを用いて食道連続撮影を行った。従来からのBE所見(ニボー、数珠状/コルク栓抜き様所見、蠕動の消失/減弱)に加え、新規2所見(蠕動波出現、胃食道接合部上膨隆所見)を診断に用いた。新規2所見と従来の3所見を診断に用いた場合のBEスクリーニングの感度は79.4%、特異度は88%であった(受信者動作特性曲線下領域(AUC)=0.837)。新規2所見を診断に用いない場合には、感度は63.9%、特異度は96%(AUC=0.800)であった。アカラシアはニボー形成と特に関連性が強かった(88.7%)。収縮の消失は蠕動の消失/減弱と強く関連していた(85.7%)。遠位食道痙攣と数珠状/コルク栓抜き様所見との間(60%)およびアカラシアと蠕動波出現(59.7%)との間には比較的高い関連性が認められた。個々のBE所見の観察者内再現性、観察者間一致率はそれぞれ84.4%、75%であった。蠕動波出現は積算弛緩圧(IRP)高値および遠位潜時短縮と関連していた。食道胃接合部上膨隆はIRP高値と関連していた。新規の2所見を追加したBEスクリーニングによるEMDの診断は一般診療において有用である可能性が示された。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Gastroenterology  

Background: High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders (EMDs); however, it requires specialized equipment. The development of more accessible screening examinations is expected. We evaluated the utility of barium esophagography (BE) screening using two novel findings to diagnose EMDs. Methods: Between January 2013 and October 2020, 244 patients with suspected EMDs who underwent both HRM and BE were analyzed. The EMD diagnosis was based on HRM findings using Chicago Classification version 3.0. BE was performed using sequential esophagography with barium sulfate. Three conventional BE findings (air-fluid level, rosary-bead/corkscrew appearance, and absent/weak peristalsis) and two novel BE findings (wave appearance and supra-junctional ballooning) were used for diagnosis. Results: The sensitivity and specificity of BE screening using the two novel findings and conventional findings to diagnose EMDs were 79.4% and 88%, respectively [area under the receiver-operating characteristic curve (AUC) = 0.837]. Without these novel findings, they were 63.9% and 96%, respectively (AUC = 0.800), respectively. Achalasia was highly correlated with the air-fluid level (88.7%). Absent contractility was highly correlated with absent/weak peristalsis (85.7%). Relatively high correlations were observed between distal esophageal spasm and rosary-bead/corkscrew appearance (60%), and between achalasia and wave appearance (59.7%). The intra-observer reproducibility and inter-observer agreement for individual BE findings were 84.4% and 75%, respectively. Wave appearance was associated with higher integrated relaxation pressure (IRP) and shorter distal latency. Supra-junctional ballooning was associated with higher IRP. Conclusions: BE screening using two additional novel findings to diagnose EMDs could be useful in general practice.

DOI： 10.1007/s00535-022-01913-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs.

DOI： 10.1038/s41598-022-20863-8

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記述言語：英語   出版者・発行元：Endoscopy  

DOI： 10.1055/a-1662-4965

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified Klebsiella aerogenes, carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

DOI： 10.1126/scitranslmed.abj1895

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

消化管運動改善薬であるアコチアミドの、食道胃接合部流出路閉塞(EGJOO)に対する有効性を検討した。2014年10月から2020年3月までの間に、EGJOO 25例に対してアコチアミド(100mg、1日3回)を4週間投与した。治療開始直前と治療後に高解像度マノメトリー検査(HRM)を施行した。主要評価項目である積算弛緩厚(IRP)は、治療前(19.4、17.1-27.4mmHg)と比較して治療後(14.6、12.1-22.0mmHg)で有意に低かった。下部食道括約筋(LES)調節指数も、治療後(32.7,21.0-40.0mmHg)が治療前(39.3,31.2-50.2mmHg)と比較して有意に低かった。アコチアミドは、EGJOO25症例中13例(52%)でIRPを正常化(<15mmHg)し、IRPは25例のEGJOO症例中20例(80%)でIRPを減少させた。副次評価項目であるFSSGスコアには、治療前と治療後で有意な変化は認められなかった。アコチアミドが奏効した13例を対象としたサブグループ解析では、アコチアミドにより嚥下障害が有意に改善していた。アコチアミドは、基礎LES圧およびLES調節反応の両方を低下させることによりIRP値を減少させることで、EGJOO患者において治療効果を示すことが明らかになった。

記述言語：英語   出版者・発行元：Esophagus  

Objectives: We have found that an altered lower esophageal sphincter (LES) accommodation response is an underlying cause of esophagogastric junction outflow obstruction (EGJOO). The objective of this study was to examine the treatment effect of acotiamide, a prokinetic agent which improves impaired gastric accommodation in functional dyspepsia, in patients with EGJOO. Methods: A prospective observational longitudinal study was conducted between October 2014 and March 2020. Acotiamide (100 mg, 3 times a day) was administered to 25 patients with EGJOO for 4 weeks. High-resolution manometry (HRM) was performed just before and after 4 weeks of treatment. Results: As the primary outcome, the extent of integrated relaxation pressure (IRP) after treatment (14.6, 12.1–22.0 mmHg) was significantly lower than that before treatment (19.4, 17.1–27.4 mmHg). The extent of LES accommodation index after treatment (32.7, 21.0–40.0 mmHg) was also significantly lower than that before treatment (39.3, 31.2–50.2 mmHg). Acotiamide normalized the IRP (< 15 mmHg) in 13 of 25 patients with EGJOO (52%), and the IRP was decreased in 20 of 25 patients with EGJOO (80%). As the secondary outcome, the total FSSG score in 25 patients with EGJOO before and after acotiamide treatment showed no significant difference. In a sub-analysis of 13 patients in whom EGJOO was normalized by acotiamide, however, dysphagia was reported to be significantly improved by acotiamide. Conclusions: Acotiamide has a treatment effect on patients with EGJOO via a reduction in the IRP level through the lowering of both the basal LES pressure and LES accommodation response. Dysphagia is a key symptom to be evaluated and treated in patients with EGJOO.

DOI： 10.1007/s10388-021-00887-1

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

Ex vivoブタモデルの胃病変70ヵ所に対して、ProKnifeを用いた内視鏡的粘膜下層剥離術(P-ESD)または従来法の内視鏡的粘膜下層剥離術(C-ESD)を無作為に振り分け、12名の内視鏡医が施行した。各群1病変を粘膜肥厚のため除外したことにより、検討対象は各群34病変となった。処置時間はP-ESD群が36.3(28.4-46.8)分、C-ESD群が46(36.4-64.6)分で、有意にP-ESD群が短かった(P=0.0014)。技術的成功率には差は認められなかった(一括切除率は両群とも100%、完全切除率はP-ESD群94.1%、C-ESD群85.3%、P=0.23)。P-ESD処置中の注入回数は7.5(6-10)回で、C-ESD群の4(3-5)回よりも有意に多かった(P<0.001)が、注入薬液総量はP-ESD群が20(16-26.3)ml、C-ESD群が27.5(20-31.5)mlで、P-ESD群が有意に少なかった(P=0.0019)。多変量解析の結果、ESD未熟練(オッズ比(OR)3.9)、C-ESD法(OR3.8)がESD困難性の独立した予測因子であった。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：DEN Open  

Objective: To compare treatment outcomes between injection endoscopic submucosal dissection using ProKnife (P-ESD) and conventional ESD (C-ESD) for gastric lesions. Methods: In this randomized controlled trial, we compared treatment outcomes of P-ESD and C-ESD for simulated gastric lesions ≥3 cm in resected porcine stomachs. Predictive factors associated with ESD difficulties were investigated using logistic regression analysis. Results: Seventy lesions were screened; however, two lesions were excluded. A total of 12 endoscopists performed 68 ESDs: 34 P-ESDs and 34 C-ESDs. The ESD procedure time of P-ESD (36.3 [28.4–46.8] min) was significantly shorter than that of C-ESD (46 [36.4–64.6] min; p = 0.0014). The technical success rates did not differ between the P-ESD and C-ESD groups (en bloc resection rate, 100% in both groups; complete resection rate, 94.1% and 85.3%, respectively; p = 0.23). The number of injections during P-ESD (7.5 [6–10] times) was significantly higher than during C-ESD (4 [3–5] times; p < 0.001), but the total volume of injected solution during P-ESD (20 [16–26.3] ml) was significantly smaller than during C-ESD (27.5 [20–31.5] ml; p = 0.0019). In multivariate analysis, less ESD experience (odds ratio [OR], 3.9) and selection of C-ESD as the ESD method (OR, 3.8) were independent predictive factors associated with ESD difficulties. Conclusions: Compared with C-ESD, P-ESD had a shorter procedure time but also allowed for notable technical success and safety.

DOI： 10.1002/deo2.91

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.

DOI： 10.1038/s41598-021-87052-x

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Prostaglandin E2 (PGE2) plays a role in the pathogenesis of gastro-esophageal reflux disease (GERD). There are 4 subtypes of PGE2, PGE2 receptor 1, 2, 3 and 4 (EP 1-4). In GERD patents, PGE2, EP2 and EP4 are upregulated. However, the effects of PGE2 on esophageal motility remain elusive. We examined how PGE2 regulates motility in the porcine circular smooth muscle of the lower esophageal sphincter (LES), and the circular and longitudinal smooth muscle of the esophagus body in organ bath. PGE2 induced tonic relaxation in the LES and circular smooth muscle, but transient contraction in longitudinal smooth muscle. The relaxation of the LES and circular smooth muscle was similar in pattern and mechanism, but was much larger in the LES. The relaxation was completely blocked by a voltage-gated K+ channel blocker or 40 mM K+ depolarization, indicating the involvement of K+ channel. Longitudinal smooth muscle contraction was completely blocked by an L-type Ca2+ channel blocker, showing the contribution of Ca2+ movement. The involvement of the EP receptor in motility was examined with selective receptor agonists and antagonists. Activation of EP2 and EP4 caused relaxation in the LES and circular smooth muscle. Compatible with PGE2, EP2 and EP4 agonists caused more significant relaxation in the LES than in circular smooth muscle. EP1 contributed to the longitudinal smooth muscle contraction. The different effects of PGE2 in the LES, circular and longitudinal smooth muscle contributes to esophageal motility, their impairment might increase the amount and frequency of esophageal reflux.

DOI： 10.1016/j.ejphar.2019.172405

記述言語：その他   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM:Although basic research has shown that certain cytokines affect gastrointestinal motility, the clinical evidence is lacking. The objective of this study was to explore the association between mucosally expressed cytokines and the esophageal motility function in humans. METHODS:We enrolled a total of 57 patients with suspected esophageal motility disorders (EMDs) who underwent high-resolution manometry. RESULTS:The diagnoses of the patients were as follows: normal esophageal motility (n = 25), ineffective esophageal motility (n = 5), esophagogastric junction outflow obstruction (EGJOO; n = 10), distal esophageal spasm (n = 5), achalasia (n = 10), absent contractility (n = 1), and jackhammer esophagus (n = 1). The expression of tumor necrosis factor (TNF)-α in the esophagogastric junction (EGJ) was significantly higher in EGJOO (14.6, 14.0-15.8, n = 10) than in normal esophageal motility (13.3, 12.8-14.1, n = 25); however, there was no difference in the expression of TNF-α between achalasia (13.4, 13.0-14.1, n = 10) and normal esophageal motility (13.3, 12.8-14.1, n = 25). EGJOO was discriminated from achalasia/normal by a linear discriminant analysis (AUC = 0.917). A multivariable regression analysis revealed that interleukin (IL)-13 and IL-23A were predictive of the distal contractile integral, whereas TNF-α and IL-6 were predictive of the basal EGJ pressure. CONCLUSIONS:The esophageal motility was associated with mucosally expressed cytokines in humans; these cytokines could be useful targets for the diagnosis and treatment of EMDs.

DOI： 10.1159/000487708

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question.Isometric contraction was monitored in circular smooth muscle strips of porcine LES. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored in fura-2-loaded strips with front-surface fluorometry. The contribution of endogenous H2S to LES contractility was investigated by examining the effects of inhibitors of H2S-generating enzymes, including cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, on the LES function.Porcine LES strips myogenically maintained a tetrodotoxin-resistant basal tone. Application of AOA (cystathionine-β-synthase inhibitor) or L-aspartic acid (L-Asp; 3-mercaptopyruvate sulfurtransferase inhibitor) but not DL-PAG (cystathionine-γ-lyase inhibitor), decreased this basal tone. The relaxant effects of AOA and L-Asp were additive. Maximum relaxation was obtained by combination of 1 mM AOA and 3 mM L-Asp. Immunohistochemical analyses revealed that cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase, but not cystathionine-γ-lyase, were expressed in porcine LES. AOA+L-Asp-induced relaxation was accompanied by a decrease in [Ca2+]i and inversely correlated with the extracellular Na+ concentration ([Na+]o) (25-137.4 mM), indicating involvement of an Na+/Ca2+ exchanger. The reduction in the basal [Ca2+]i level by AOA was significantly augmented in the antral smooth muscle sheets of Na+/Ca2+ exchanger transgenic mice compared with wild-type mice.Endogenous H2S regulates the LES myogenic tone by maintaining the basal [Ca2+]i via Na+/Ca2+ exchanger. H2S-generating enzymes may be a potential therapeutic target for esophageal motility disorders, such as achalasia.

DOI： 10.1016/j.jcmgh.2017.11.004

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Duodenal reflux of fluids containing trypsin relates to refractory gastroesophageal reflux disease (GERD). Esophageal peristalsis and clearance are important factors in GERD pathogenesis. However, the function of trypsin in esophageal body contractility is not fully understood. In this study, effects of trypsin on circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of the porcine esophageal body were examined. Trypsin elicited a concentration dependent biphasic response, a major contraction and a subsequent relaxation only in CSM. In CSM, contraction occurred at trypsin concentrations of 100nM and relaxation at 1μM. A proteinase-activated receptor (PAR)2 activating peptide, SLIGKV-NH2 (1mM), induced a monophasic contraction. Those responses were unaffected by tetrodotoxin though abolished by the gap junction uncouplers carbenoxolone and octanol. They were also partially inhibited by a transient receptor potential vanilloid type 1 (TRPV1) antagonist and abolished by combination of neurokinin receptor 1 (NK1) and NK2 antagonists, but not by an NK3 antagonist, suggesting a PAR2-TRPV1-substance P pathway in sensory neurons. Substance P (100nM), an agonist for various NK receptors (NK1, NK2 and NK3) with differing affinities, induced significant contraction in CSM, but not in LSM. The contraction was also blocked by the combination of NK1 and NK2 antagonists, but not by the NK3 antagonist. Moreover, substance P-induced contractions were unaffected by the TRPV1 antagonist, but inhibited by a gap junction uncoupler. In conclusion, trypsin induced a biphasic response only in CSM and this was mediated by PAR2, TRPV1 and NK1/2. Gap junctions were indispensable in this tachykinin-induced response.

DOI： 10.1016/j.ejphar.2017.01.004

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Esophageal motility disorders (EMD) is characterized by impaired coordinated esophageal motility
function with symptoms including dysphasia, heartburn or noncardiac chest pain. Since EMDs is
functional disorders, it is usually difficult to make a diagnosis by conventional examinations including
endoscopy and esophagography. Recently developed high-resolution manometry allows us to evaluate
esophageal motility function precisely and to make a differential diagnosis of EMDs, together with
Chicago Classification (CC) version 3.0 (CC ver3.0). In this article, we reviewed diagnosis of EMDs
based on CC ver3.0 and current treatment strategy for EMDs.

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Esophageal motility disorders (EMDs) affect coordinated esophageal contractility. Recent developments in high-resolution manometry have improved diagnosis of EMDs; however, the etiology of EMDs remains to be determined. This study aimed to determine which clinical characteristics are associated with esophageal motility.From May 2013 to July 2014, 97 patients (54 women, 43 men; age, 16-89 years) with suspected EMDs were assessed by high-resolution manometry in Kyushu University Hospital. Esophageal motility was evaluated by measuring the distal contractile integral (DCI), basal lower esophageal sphincter pressure, and integrated relaxation pressure (IRP). Data on age, gender, body mass index (BMI), Brinkman Index, and blood tests were retrospectively collected and analyzed.Fifty patients were diagnosed as normal, nine with achalasia, twelve with esophagogastric junction outflow obstruction, four with distal esophageal spasm, one with jackhammer esophagus, six with absent peristalsis, ten with frequent failed peristalsis, and five with weak peristalsis. The median DCI was 1229.0 mmHg-s-cm, the median basal lower esophageal sphincter pressure was 25.3 mmHg, and the median IRP was 9.6 mmHg. Patients with major motility disorders were excluded from analysis. By multivariate regression analysis, BMI (P = 0.029) and total cholesterol (P = 0.023) were negatively associated with DCI, while BMI (P = 0.007) was negatively associated with IRP and glucose (P = 0.044) was positively associated with IRP.Both BMI and total cholesterol could be highly predictive factors for esophageal body contractility, while BMI and glucose could be predictive factors for lower esophageal sphincter contractile function.

DOI： 10.1111/jgh.13262

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0032-1326282

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

種別：査読等 

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