Language：English   Publisher：American Journal of Gastroenterology  

Objectives: Controlling intraoperative bleeding during endoscopic submucosal dissection (ESD) is essential to ensure the safety and reliability of the procedure. ESD in spray coagulation mode (SCM-ESD) is expected to ensure more effective bleeding control. This study aimed to investigate the superiority of SCM-ESD over conventional forced coagulation mode ESD (FCM-ESD) in terms of hemostatic ability for treating early gastric neoplasms (EGNs).Methods:This multicenter randomized controlled trial (Spray-G Trial) was conducted at five Japanese institutions. Patients with intramucosal EGNs were enrolled and randomly assigned to either the SCM-ESD or FCM-ESD group. The primary outcome was ESD completion with an electrosurgical knife alone, that is, without the use of hemostatic forceps. The number and duration of hemostatic procedures using hemostatic forceps, procedure time, curability, and adverse events were also evaluated.Results:Each group included 65 patients. The rate of ESD completion without using hemostatic forceps was significantly higher for SCM-ESD than for FCM-ESD (83.1% vs. 13.8%, p<0.0001). SCM-ESD and FCM-ESD did not differ significantly in terms of procedure time (48.3 min vs. 56.0 min, p=0.1071), R0 resection (100% vs. 95.4%, p=0.2442), and rate of adverse events (3.1% vs. 6.2%, p=0.6801).Conclusions:SCM-ESD significantly improved ESD completion rates for intramucosal EGNs without using hemostatic forceps. SCM-ESD is a promising technique that may streamline ESD by eliminating the need to exchange devices and reducing costs.

DOI： 10.14309/ajg.0000000000003360

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PubMed

Language：Japanese   Publisher：(一社)日本内科学会  

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203718

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203711

CiNii Research

Publisher：南江堂  

DOI： 10.15106/j_naika134_603

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Molecular Medicine  

EP4 prostanoid receptor (EP4R) contributes to the intestinal epithelial Cl- secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M3 muscarinic acetylcholine receptor (M3R) also contributes to the intestinal epithelial Cl- secretion, it remains unclear whether M3R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M3R is involved in the regulation of the intestinal epithelial Cl- secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M3 positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M3R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M3R protects against small intestinal injury in indomethacin-treated mice. Both the PGE1 derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP4R antagonist and a M3R antagonist, respectively) or by removal of extracellular Cl-. PAM-369 enhanced the carbachol-induced Isc by potentiating M3R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M3R expression was significantly up-regulated, and PAM-369 potentiation of M3R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M3R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M3R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M3 positive allosteric modulator, was used to potentiate M3R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M3R is a promising target for treating or preventing NSAID-induced enteropathy.

DOI： 10.1007/s00109-024-02474-0

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Language：English   Publisher：Digestion  

Introduction: This study evaluated the psychometric properties of the newly developed chronic constipationtherapeutic efficacy and satisfaction test (CC-TEST) among patients with chronic constipation. Methods: Japanese patients with moderate or severe chronic constipation underwent a 4-week remedy. The baseline, 2-week, and 4-week assessments included the CC-TEST, Constipation Scoring System (CSS), Medical Outcome Study Short Form-8 Health Survey (SF-8), and Hospital Anxiety and Depression Scale (HADS). The CC-TEST comprises three domains: (1) symptoms; chronic constipation symptom severity (seven items), defecation status (five items), (2) impact for daily life; dissatisfaction with daily life level (DS; four items), and (3) therapeutic response; therapeutic efficacy measured by patients and medication compliance (four items). Results: Of 201 eligible patients at baseline, 110 completed the 4-week treatment and the survey responses. Cronbach's a values for the stool, defecation, and abdominal symptom subscales, as well as the total symptom score and DS subscale, showed good internal consistency reliability (0.72-0.80). Pearson's r for comparisons between corresponding items (CC-TEST symptoms with CSS, and CC-TEST DS with SF-8 physical and mental component summary scores) was significant. After 4 weeks, scores for symptoms, defecation status, and DS items/subscales notably decreased, with a significant effect size (p < 0.005, Cohen's d; 0.30-1.16). Statistically significant differences emerged between treatment responders and nonresponders using the three responder definitions, in changes in scores for most CC-TEST symptoms, defecation status, and DS items/subscales (p < 0.05). Conclusion: CCTEST demonstrates commendable reliability, convergent and known-group validity, and responsiveness to treatment effects. As a simple, comprehensive, and versatile patientreported outcome measure, CC-TEST may be well suited for clinical trials and primary care of Japanese patients with chronic constipation.

DOI： 10.1159/000539788

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PubMed

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞・われわれは慢性便秘症の病態解明と新規治療法の開発を目指し,腸内細菌が腸管運動機能に及ぼす影響とその機序について基礎およびトランスレーショナル研究を行っている.・単一菌種を定着させたノトバイオート動物モデルを用いて,腸内細菌が宿主自然免疫反応を介し,小腸筋間神経叢の血管作動性腸管ペプチド(VIP)神経の発現調節が腸管運動機能の発達・維持に重要な役割を果たすことを解明した.・慢性便秘症患者より採取した糞便を移植して作製したマウスモデルを解析したところ,慢性便秘症患者から採取した腸内細菌が大腸筋間神経叢に炎症性マクロファージを増加させ,Cajal介在細胞(ICC)のネットワーク障害をきたし,大腸運動低下に至る経路を見出した.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00974&link_issn=&doc_id=20240830040062&doc_link_id=10.15106%2Fj_naika134_603&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika134_603&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞●高解像度食道内圧検査(HRM)の開発と食道運動障害の国際分類であるシカゴ分類が提唱されたことで,食道運動障害(EMD)の診療が飛躍的に発展した.EMD診断のゴールドスタンダードはHRMとなったが,いまだ検査可能な施設は限られており,日常診療におけるEMDの拾い上げ検査として食道X線造影検査にかかる期待は大きい.本稿では古典的食道X線所見(正常,数珠様・コークスクリュー様,無蠕動・微弱蠕動)に加えて,筆者らが新規に提唱する波様,下部食道バルーニングも含めた各食道X線所見について解説した.これらの食道X線所見を用いることで,EMDの拾い上げに対する食道X線造影検査の感度(79.4%)と特異度(88%)は満足な結果であった.食道X線造影検査のみでHRMに基づくEMDの確定診断を行うことは困難であるが,日常診療におけるEMD拾い上げ検査としては,食道X線造影検査は有用な検査として位置付けられる.

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞はじめに 上部食道括約筋(upper esophageal sphincter;UES)から下部食道括約筋(lower esophageal sphincter;LES)の食道運動をリアルタイムに可視化する高解像度食道内圧検査(high-resolution manometry;HRM)の登場とその診断基準であるシカゴ分類の確立によって,食道運動の機能評価法は発展を遂げた.しかし,HRMとシカゴ分類では評価困難な食道運動障害(esophageal motility disorders;EMDs)が存在し,その原因として注目されるのが食道伸展性(拡張性)と伸展刺激で誘発される二次蠕動である.本稿では食道伸展性の評価法と二次蠕動に注目し解説する.

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Language：Japanese   Publisher：(一社)日本潰瘍学会  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

逆流過敏(RH)は胃食道逆流性疾患の一種であり、十二指腸胃食道逆流(DGER)が関与している。本研究の目的は、DGERおよびRH評価のための画像強調技術を装備した内視鏡システムの有用性を明らかにすることである。ビリルビンを同定する画像強調観察モードをBilモード、計算値をBil値と定義した。まず、Bilモードの可視性を、胆汁濃度0.01%から100%(0.002～20mg/dL)の液体を用いて検証した。次いで、ビリルビン溶液を豚食道に散布して、Bilモードの視認性スコアをブルーレーザーイメージング(BLI)および白色光イメージング(WLI)モードと比較した。その後、多チャンネル壁内インピーダンス-pHモニタリングを用いて食道Bil値と非酸性逆流イベント(NNRE)の相関について検討し、またRHの鑑別診断における食道Bil値の有用性を明らかにした。ビリルビン濃度が1%を超えるビリルビン溶液は、Bilモードで赤色に可視化された。1%から6%のビリルビン溶液に対しては、Bilモードを用いた場合の視認性スコアはBLIおよびWLIモードと比較して有意に高かった(P<0.05)。食道Bil値とNNREとの間には有意な正の相関が認められた(P=0.031)。RHの鑑別診断に対する受容者動作特性曲線下面積は0.817であった。以上より、Bilモードは正確にビリルビンを同定し、実臨床でDGERの評価に使用できる可能性が示された。

Language：English   Publisher：(NPO)日本食道学会  

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Language：English   Publisher：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。

Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(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)

Language：Japanese   Publisher：(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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Language：Japanese   Publisher：(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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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本消化管学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Publisher：日本メディカルセンター  

DOI： 10.19020/cg.0000002753

CiNii Research

Language：Japanese  

Language：Japanese  

＜文献概要＞胃食道逆流症(GERD)は「胃内容物の逆流により,不快な症状あるいは合併症を生じた状態」と定義される.日常診療で遭遇する,症状のみで食道粘膜傷害のない非びらん性逆流症(NERD)には,GERD以外の病態が紛れ込む.NERDと鑑別すべき重要な病態に食道運動機能障害(EMDs)があるが,EMDsの一つである無蠕動は高頻度にGERDを合併するため,疾患の理解を複雑化させている.最近,食道生理機能検査の発展に基づいてGERDの病態,鑑別疾患の理解が飛躍的に進歩した.本稿では,EMDsに起因するGERDと鑑別すべき関連諸疾患について概説する.治療抵抗性GERDに遭遇した際には食道生理機能検査を行い,機能性食道疾患,食道運動機能障害,行動障害などの鑑別を行うことが重要である.

Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞胃食道逆流症(GERD)は「胃内容物の逆流により,不快な症状あるいは合併症を生じた状態」と定義される.日常診療で遭遇する,症状のみで食道粘膜傷害のない非びらん性逆流症(NERD)には,GERD以外の病態が紛れ込む.NERDと鑑別すべき重要な病態に食道運動機能障害(EMDs)があるが,EMDsの一つである無蠕動は高頻度にGERDを合併するため,疾患の理解を複雑化させている.最近,食道生理機能検査の発展に基づいてGERDの病態,鑑別疾患の理解が飛躍的に進歩した.本稿では,EMDsに起因するGERDと鑑別すべき関連諸疾患について概説する.治療抵抗性GERDに遭遇した際には食道生理機能検査を行い,機能性食道疾患,食道運動機能障害,行動障害などの鑑別を行うことが重要である.

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞胃食道逆流症(GERD)は「胃内容物の逆流により,不快な症状あるいは合併症を生じた状態」と定義される.日常診療で遭遇する,症状のみで食道粘膜傷害のない非びらん性逆流症(NERD)には,GERD以外の病態が紛れ込む.NERDと鑑別すべき重要な病態に食道運動機能障害(EMDs)があるが,EMDsの一つである無蠕動は高頻度にGERDを合併するため,疾患の理解を複雑化させている.最近,食道生理機能検査の発展に基づいてGERDの病態,鑑別疾患の理解が飛躍的に進歩した.本稿では,EMDsに起因するGERDと鑑別すべき関連諸疾患について概説する.治療抵抗性GERDに遭遇した際には食道生理機能検査を行い,機能性食道疾患,食道運動機能障害,行動障害などの鑑別を行うことが重要である.

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Language：Japanese   Publisher：(NPO)日本食道学会  

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Language：Japanese   Publisher：(NPO)日本食道学会  

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Publisher：東京医学社  

DOI： 10.24479/endo.0000000731

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Gastroenterology  

<p>過敏性腸症候群の治療は食事と生活習慣を指導した後に，薬物療法の第1段階として消化管主体の治療を行う．第1選択薬として消化管運動機能調節薬，プロバイオティクス，高分子重合体を使用する．また，IBS分類に応じて下痢型には5-HT3拮抗薬，便秘型には粘膜上皮機能変容薬を投与する．症状の改善が不十分な場合は，優勢な症状に対して止痢薬，抗コリン薬，5-HT4刺激薬，下剤を追加する．さらに，漢方薬，抗アレルギー薬，胆汁酸関連薬や抗菌薬を考慮する．これらの薬物療法が無効な場合，第2段階として抗うつ薬，抗不安薬を用いた中枢機能の調整を含む治療を考慮する．さらに改善が得られない場合，心理療法を考慮する．</p>

DOI： 10.11405/nisshoshi.120.218

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Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：(一社)日本消化管学会  

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Language：Japanese   Publisher：(一社)日本消化管学会  

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Language：Japanese   Publisher：日本消化器病学会-九州支部  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastrointestinal Endoscopy  

INTRODUCTION: Endoscopic ultrasound guided fine-needle aspiration/biopsy (EUS-FNA/B) is the gold 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 gastrointestinal 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 using 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 using the conventional probe (Study 2) and non-exposed SELs from 20 cases using 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=0.030) (Study 1). The H-impedance of GIST (99.5) measured using conventional probe was significantly higher than those of the muscular layer (82.4) and leiomyoma (89.2) (P<0.01) (Study 2). The H-impedance of GIST measured using the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs. leiomyoma: 71.8, P=0.015). 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=0.86) (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 smaller than 20 mm.

DOI： 10.1016/j.gie.2022.11.022

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Language：English   Publisher：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。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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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

Language：English   Publisher：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。

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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&#37;), and the IRP was decreased in 20 of 25 patients with EGJOO (80&#37;). 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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Language：Japanese  

Language：English  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl--free solution. However, pretreatment with 100 μM Nω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.

DOI： 10.1016/j.ejphar.2021.174491

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. METHODS: We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. RESULTS: There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. CONCLUSIONS: The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.

DOI： 10.1007/s00535-021-01819-7

Language：English   Publishing type：Research paper (scientific journal)  

This longitudinal study was designed to elucidate whether gut microbiota is associated with relapse and treatment response in ulcerative colitis (UC) patients. Fifty-one patients with UC were enrolled between 2012 and 2017, and followed up through 2020. Colon mucosal biopsy were obtained at enrollment, and 16S ribosomal RNA sequencing was performed using extracted RNA. Of the 51 patients, 24 were in remission and 27 had active UC at enrollment. Of the 24 patients in remission, 17 maintained remission and 7 developed relapse during follow-up. The 7 patients with relapse showed lower diversity, with a lower proportion of Clostridiales (p = 0.0043), and a higher proportion of Bacteroides (p = 0.047) at enrollment than those without relapse. The 27 patients with active UC were classified into response (n = 6), refractory (n = 13), and non-response (n = 8) groups according to their treatment response in 6 months. The refractory and non-response groups showed lower diversity with a lower proportion of Prevotella (p = 0.048 and 0.043) at enrollment than the response group. This study is the first demonstration that reduced diversity and particular microbes are associated with the later clinical course of relapse events and treatment response in UC.

DOI： 10.1038/s41598-021-92870-0

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurogastroenterology and Motility  

Background/Aims: No screening test for esophageal motility disorder (EMD) has been established, the objective of this study is to examine the potential usefulness of our newly developed "Onigiri esophagography" combined with an obstruction level (OL) classification system in screening for EMD. Methods: A total of 102 patients with suspected EMDs who underwent both high-resolution manometry (HRM) and Onigiri esophagography between April 2017 and January 2019 were examined. The EMD diagnosis was performed based on the Chicago classification version 3.0 by HRM. Onigiri esophagography was performed using a liquid medium (barium sulfate) followed by a solid medium, which consisted of an Onigiri (a Japanese rice ball) with barium powder. The extent of medium obstruction was assessed by the OL classification, which was defined in a stepwise fashion from OL0 (no obstruction) to OL4 (severe obstruction). Results: The patients with OL0 (32.3&#37;), OL1 (50.0&#37;), OL2 (88.0&#37;), OL3 (100.0&#37;), and OL4 (100.0&#37;) were diagnosed EMDs by HRM. The area under the curve, as determined by a receiver operating characteristic analysis, for the OL classification was 0.86. Using the cutoff value of OL1, the sensitivity and specificity were 87.3&#37; and 61.3&#37;, respectively, while using a cutoff value of OL2, the sensitivity and specificity were 73.2&#37; and 90.3&#37;, respectively. Conclusion: In conclusion, Onigiri esophagography combined with the OL classification system can be used as a screening test for EMDs with a cutoff value of OL1.

DOI： 10.5056/jnm20138

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Language：Japanese  

Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10753-020-01358-y

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The pathological conditions of UC and CD involved in inflammatory bowel disease-unclassified (IBD-U), UC with primary sclerosing cholangitis (PSC-UC), and UC with autoimmune pancreatitis type 2 (AIP-UC) remain unclear. Therefore, it is difficult to decide the appropriate treatments for these subtypes of UC. Our aim was to examine whether the discriminant equation using the mucosally expressed mediators designed as our previous study for IBD, could characterize IBD-U, PSC-UC, or AIP-UC. METHODS: A total of 56 patients including UC (n = 24), CD (n = 15), IBD-U (n = 10), PSC-UC (n = 4), and AIP-UC (n = 3), along with 9 control patients were enrolled in this study. Mucosally expressed inflammatory mediators related to Th1, Th2, Th17, and Treg were measured using quantitative PCR in endoscopic biopsies from the inflamed intestines of the patients. The IBD-U, PSC-UC or AIP-UC were characterized using discriminant analysis and principle component analysis. RESULTS: Through discriminant analyses, combinations of 3 to 7 inflammatory mediators were used to discriminate between UC and CD. Moreover, the identified 3 markers could diagnose patients with IBD-U as UC or CD with high accuracy. The distribution graph of inflammatory mediators using the principal component analysis revealed that PSC-UC and AIP-UC exhibited CD-like and UC-like features, respectively. CONCLUSIONS: The discriminant equation using mucosally expressed mediators of IL-13, IL-21 and T-bet can be used as a universal diagnostic tool not only for IBD-U but also to assess pathological conditions in PSC-UC and AIP-UC.

DOI： 10.1186/s12876-021-01656-1

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消化管は断続的な食物の流入と1,000種に及ぶ腸内微生物叢の存在という独特の環境下で機能する臓器である。このような過酷な環境下でいかにして健康が維持され、何がその破綻を引き起こすのか、いまだ明らかになっていないことも多い。消化管における慢性炎症の持続は、炎症性腸疾患(Inflammatory bowel disease:IBD)のみならず、過敏性腸症候群(Irritable bowel disease:IBS)をはじめとする機能性疾患の病態にも関与することが示唆されている。本稿では、炎症、免疫の観点から、消化管疾患、とくにIBD・IBS研究の要点を見直し、最新の知見やその解釈の注意点も含め考察する。(著者抄録)

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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

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: The newly developed vonoprazan (a potassium-competitive acid blocker) has a greater ability to suppress gastric acid production than convention proton pump inhibitors (PPIs). The objective of the present study was to determine how vonoprazan influences the pathogenesis of refractory gastroesophageal reflux disease (GERD) in clinical practice. Methods: Between March 2013 and November 2018, a total of 73 refractory GERD patients (34 in the conventional PPI group versus 39 in the vonoprazan group) were enrolled in this retrospective study. We then compared the underlying disease conditions between the 2 groups, examined by high-resolution manometry and multichannel intraluminal impedance/pH (MII-pH) monitoring. Results: There was a significant difference in the proportion of underlying disease conditions, including erosive esophagitis, non-erosive reflux disease, reflux hypersensitivity, functional heartburn and oesophageal motility disorder (EMD), between the conventional PPI (6, 14, 23, 40 and 17&#37; respectively) and vonoprazan groups (0, 0, 10, 49, and 41&#37; respectively; p < 0.01). No cases of acid-related GERD were observed in the vonoprazan group. When the EMD patients were excluded, the lower oesophageal acid exposure time of the vonoprazan group (0.1&#37; [0.0-0.5&#37;], n = 23) was significantly lower than that of the conventional PPI group (0.35&#37; [0.1-3.9&#37;], n = 28; p < 0.05), and the gastric pH <4 holding time of the vonoprazan group (7.7&#37; [0.7-34.5&#37;]) was also significantly lower than that of the conventional PPI group (61.6&#37; [49.4-74.3&#37;], p < 0.01). Conclusions: Vonoprazan serves as a diagnostic tool to exclude acid-related GERD.

DOI： 10.1159/000503340

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: The newly developed vonoprazan (a potassium-competitive acid blocker) has a greater ability to suppress gastric acid production than convention proton pump inhibitors (PPIs). The objective of the present study was to determine how vonoprazan influences the pathogenesis of refractory gastroesophageal reflux disease (GERD) in clinical practice. Methods: Between March 2013 and November 2018, a total of 73 refractory GERD patients (34 in the conventional PPI group versus 39 in the vonoprazan group) were enrolled in this retrospective study. We then compared the underlying disease conditions between the 2 groups, examined by high-resolution manometry and multichannel intraluminal impedance/pH (MII-pH) monitoring. Results: There was a significant difference in the proportion of underlying disease conditions, including erosive esophagitis, non-erosive reflux disease, reflux hypersensitivity, functional heartburn and oesophageal motility disorder (EMD), between the conventional PPI (6, 14, 23, 40 and 17% respectively) and vonoprazan groups (0, 0, 10, 49, and 41% respectively; p < 0.01). No cases of acid-related GERD were observed in the vonoprazan group. When the EMD patients were excluded, the lower oesophageal acid exposure time of the vonoprazan group (0.1% [0.0-0.5%], n = 23) was significantly lower than that of the conventional PPI group (0.35% [0.1-3.9%], n = 28; p < 0.05), and the gastric pH <4 holding time of the vonoprazan group (7.7% [0.7-34.5%]) was also significantly lower than that of the conventional PPI group (61.6% [49.4-74.3%], p < 0.01). Conclusions: Vonoprazan serves as a diagnostic tool to exclude acid-related GERD.

DOI： 10.1159/000503340

Language：English   Publishing type：Research paper (scientific journal)  

AIM To compare the outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms using Clutch Cutter (ESD-C) or other knives (ESD-O). METHODS This was a single-center retrospective study. Gastric neoplasms treated by ESD between April 2016 and October 2017 at Kitakyushu Municipal Medical Center were reviewed. Multivariate analyses and propensity score matching were used to reduce biases. Covariates included factors that might affect outcomes of ESD, including age, sex, underlying disease, anti-thrombotic drugs use, tumor location, tumor position, tumor size, tumor depth, tumor morphology, tumor histology, ulcer (scar), and operator skill. The treatment outcomes were compared among two groups. The primary outcome was ESD procedure time. Secondary outcomes were en bloc, complete, and curative resection rates, and adverse events rates including perforation and delayed bleeding. RESULTS A total of 155 patients were included in this study; 44 pairs were created by propensity score matching. Background characteristics were quite similar among two groups after matching. Procedure time was significantly shorter for ESD-C (median; 49 min) than for ESD-O (median; 88.5 min) (P < 0.01). However, there was no significant difference in treatment outcomes between ESD-C and ESD-O including en bloc resection rate (100&#37; in both groups), complete resection rate (100&#37; in both groups), curative resection rate (86.4&#37; vs 88.6&#37;, P = 0.730), delayed bleeding (2.3&#37; vs 6.8&#37;, P = 0.62) and perforation (0&#37; in both groups). CONCLUSION ESD-C achieved shorter procedure time without an increase in complication risk. Therefore, ESD-C could become an effective ESD option for gastric neoplasms.

DOI： 10.4251/wjgo.v10.i12.487

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Background and Aims: 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. Methods: 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. Results: 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. Conclusions: 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

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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 100 nM and relaxation at 1 μM. A proteinase-activated receptor (PAR)2 activating peptide, SLIGKV-NH₂(1 mM), 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 NK₂antagonists, but not by an NK₃antagonist, suggesting a PAR2-TRPV1-substance P pathway in sensory neurons. Substance P (100 nM), an agonist for various NK receptors (NK₁, NK₂and NK₃) with differing affinities, induced significant contraction in CSM, but not in LSM. The contraction was also blocked by the combination of NK₁and NK₂antagonists, but not by the NK₃antagonist. 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 NK_1/2. Gap junctions were indispensable in this tachykinin-induced response.

DOI： 10.1016/j.ejphar.2017.01.004

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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.

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近年、高解像度食道内圧検査(HRM)が開発され、専門的な測定技術や経験がなくても上部食道括約筋から下部食道括約筋まで連続的に食道運動機能を評価できるようになった。このHRMの登場と共にシカゴ分類が提唱され、食道運動異常症の診断が飛躍的に発展した。最初に食道運動の機序について述べ、次いでHRMによる食道運動異常症のシカゴ分類に基づいた診断法と現状の治療戦略について概説した。

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Background and Aim:: 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. Methods:: From May 2013 to July 2014, 97 patients (54 women, 43 men; age, 16-89years) 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. Results:: 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 1229.0mmHg-s-cm, the median basal lower esophageal sphincter pressure was 25.3mmHg, and the median IRP was 9.6mmHg. 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. Conclusions:: 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

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DOI： 10.1016/S0016-5085(16)30272-4

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DOI： 10.1016/S0016-5085(16)31612-2

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The lower esophageal sphincter (LES) plays an important role in coordinated esophageal motility. The present study aimed to elucidate how trypsin affects LES contractility. Porcine LES circular smooth muscle strips were prepared. Contractile responses to trypsin were assessed. Trypsin (300 nM) induced a transient contraction. At concentrations of 1 μM or higher, trypsin induced biphasic responses, consisting of a transient contraction followed by a transient relaxation. Pretreatment with either 1 μM tetrodotoxin or carbenoxolone had no effect on these responses. In contrast, trypsin-induced responses were completely blocked by pretreatment with the serine protease inhibitor. Pretreatment with 10 μM FSLLRY-NH₂, a PAR₂ antagonist, significantly inhibited trypsin-induced biphasic responses. Trypsin (1 μM)-induced contractions were partially inhibited by pretreatment with 10 μM Y-27632. In addition, trypsin (10 μM)-induced relaxation was partially inhibited by pretreatment with 10 μM Y-27632, 10 μM PD98059 or 10 μM SB203580. Trypsin-induced relaxation was abolished by increasing the extracellular K⁺ concentration to 40 mM, but not by pretreatment with l-arginine methyl ester. Furthermore, trypsin-induced relaxation was partially inhibited by pretreatment with 10 μM glibenclamide or 1 μM 4-aminopyridine. Trypsin causes biphasic regulation of LES tone by directly acting on smooth muscle. Rho-associated protein kinase (ROK) is involved in trypsin-induced contraction, whereas ROK, ERK1/2, p38MAPK, and membrane hyperpolarization are involved in relaxation. The regulation of LES tone by trypsin may play a role in esophageal motility.

DOI： 10.1016/j.ejphar.2015.02.008

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AIM: To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy. METHODS: Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth II gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing, selectively applying contrast medium, and CO2 insufflations. RESULTS: The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96&#37; success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96&#37;), Billroth II reconstruction (94&#37;), or pancreatoduodenectomy (100&#37;), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89&#37;). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88&#37;), Billroth II reconstruction (89&#37;), or pancreatoduodenectomy (100&#37;), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100&#37;) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth II reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5&#37;); perforation of the long limb in a patient with Billroth II anastomosis. CONCLUSION: Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.

DOI： 10.3748/wjg.v18.i46.6843

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Background/Aims: Antithrombotic/nonsteroidal antiinflammatory drug (NSAID) therapies increase the incidence of upper gastrointestinal bleeding. The features of hemorrhagic peptic ulcer disease in patients receiving antithrombotic/NSAID therapies were investigated. Methods: We investigated the medical records of 485 consecutive patients who underwent esophagogastroduodenoscopy and were diagnosed with hemorrhagic gastroduodenal ulcers. The patients treated with antithrombotic agents/NSAIDs were categorized as the antithrombotic therapy (AT) group (n=213). The patients who were not treated with antithrombotics/NSAIDs were categorized as the control (C) group (n=263). The clinical characteristics were compared between the groups. Results: The patients in the AT group were significantly older than those in the C group (p<0.0001). The hemoglobin levels before/without transfusion were significantly lower in the AT group (8.24±2.41 g/dL) than in the C group (9.44±2.95 g/dL) (p<0.0001). After adjusting for age, the difference in the hemoglobin levels between the two groups remained significant (p=0.0334). The transfusion rates were significantly higher in the AT group than in the C group (p=0.0002). However, the outcome of endoscopic hemostasis was similar in the AT and C groups. Conclusions: Patients with hemorrhagic peptic ulcers receiving antithrombotic/NSAID therapies were exposed to a greater risk of severe bleeding that required transfusion but were still treatable by endoscopy.

DOI： 10.5009/gnl.2012.6.4.423

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Background/Aims: Colonic diverticular bleeding can stop spontaneously or be stopped by endoscopic hemostasis. We analyzed the clinical and colonoscopic features of patients with colonic diverticular bleeding to establish the predictive factors for rebleeding. Methods: A total of 111 patients (median age, 72 years) with colonic diverticular bleeding in Aso Iizuka Hospital between April 2007 and July 2010 were enrolled. Age, sex, body mass index (BMI), comorbidity, medication, location of bleeding, colonoscopic findings and hemostatic methods were analyzed retrospectively from the hospital records. Results: The most common sites of bleeding were the ascending (39.6&#37;) and sigmoid (29.7&#37;) colon. Overt rebleeding occurred in 30 patients (27.0&#37;). Spontaneous hemostasis was seen in 81 patients (73.0&#37;), and endoscopic hemostatic treatment was performed in 30 patients. The BMI in the patients with colonic diverticular rebleeding was significantly higher than in patients without rebleeding. Colonoscopic findings of actively bleeding or nonbleeding visible vessels in the responsible diverticula were more frequent in the group with rebleeding. Conclusions: A higher BMI and colonoscopic findings of actively bleeding or nonbleeding visible vessels can be used as predictive factors for colonic diverticular rebleeding. Patients with such findings should be carefully followed up after hemostasis of the initial colonic diverticular bleeding.

DOI： 10.5009/gnl.2012.6.3.334

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DOI： 10.1055/s-0031-1291715

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Inflammatory bowel disease (IBD) is frequently associated with extraintestinal manifestations such as hepatopancreatobiliary manifestations (HPBMs), which include primary sclerosing cholangitis (PSC), pancreatitis, and cholelithiasis. PSC is correlated with IBD, particularly ulcerative colitis (UC); 70-80&#37; of PSC patients in Western countries and 20-30&#37; in Japan have comorbid UC. Therefore, patients diagnosed with PSC should be screened for UC by total colonoscopy. While symptoms of PSC-associated UC are usually milder than PSC-negative UC, these patients have a higher risk of colorectal cancer, particularly in the proximal colon. Therefore, regular colonoscopy surveillance is required regardless of UC symptoms. Administration of 5-aminosalicylic acid or ursodeoxycholic acid may prevent colorectal cancer and cholangiocarcinoma. While PSC is diagnosed by diffuse multifocal strictures on cholangiography, it must be carefully differentiated from immunoglobulin G4 (IgG4)-associated cholangitis, which shows a similar cholangiogram but requires different treatment. When PSC is suspected despite a normal cholangiogram, the patient may have small-duct PSC, which requires a liver biopsy. IBD patients have a high incidence of acute and chronic pancreatitis. Most cases are induced by cholelithiasis or medication, although some patients may have autoimmune pancreatitis (AIP), most commonly type 2 without elevation of serum IgG4. AIP should be accurately identified based on characteristic image findings, because AIP responds well to corticosteroids. Crohn's disease is frequently associated with gallstones, and several risk factors are indicated. HPBMs may influence the management of IBD, therefore, accurate diagnosis and an appropriate therapeutic strategy are important, as treatment depends upon the type of HPBM.

DOI： 10.1007/s12328-011-0282-1

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A 73-year-old woman was referred to our hospital complaining of bloody stool. She had undergone high anterior resection with the double stapling technique for a sigmoid colon cancer 2 years prior to this admission. Colonoscopy revealed a soft submucosal tumor, 4cm in size, on the anal side of the previous anastomosis in the rectum. EUS revealed a cystic lesion located in the third and fourth layers of the rectal wall. EUS-FNA was performed, and the content of the cystic lesion was transparent mucinous liquid. Histologically, the specimen revealed PAS and Alcian blue-positive mucinous material and a small number of inflammatory cells such as foamy macrophages. Therefore, this cystic lesion was diagnosed as a rectal implantation cyst.

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Endoscopic submucosal dissection using a grasping-type scissors forceps for early gastric cancers and adenomas
Aim: To reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives, we developed a new grasping-type scissors forceps (GSF) that can grasp and incise the target tissue using electrosurgical current. The aim of the present study was to evaluate the efficacy and safety of ESD using GSF for the removal of early gastric cancers and adenomas. Methods: ESD using GSF was carried out on 35 consecutive patients with early gastric cancers or adenomas who had preoperative EUS diagnoses of mucosal tumor without lymph node involvement. Therapeutic efficacy and safety were assessed. Results: All lesions were treated easily and safely without unexpected incision. The mean size of epithelial tumors and resected specimens was 15.6 mm and 32.7 mm, respectively. Curative en-bloc resection rates according to tumor size and location were 96&#37; (26/27) in tumors ≤20 mm, 100&#37; (8/8) in tumors >20 mm, 100&#37; (18/18) of tumors in the lower portion, 100&#37; (8/8) of tumors in the middle portion, 89&#37; (8/9) of tumors in the upper portion, and 97&#37; (34/35) overall. The mean operating time according to tumor size and location was 93.4 min in tumors a;circ20 mm, 140 min in tumors >20 mm, 77.6 min for tumors in the lower portion, 113.4 min for tumors in the middle portion, 148.6 min for tumors in the upper portion, and 104.1 min overall. No intraoperative complication occurred, and postoperative bleeding was seen in 3&#37; (1/35). Conclusions: ESD using GSF allows simple and safe en-bloc resection of early gastric cancer or adenoma irrespective of tumor size and location.

DOI： 10.1111/j.1443-1661.2010.01037.x

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DOI： 10.1055/s-0030-1255696

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞・われわれは慢性便秘症の病態解明と新規治療法の開発を目指し,腸内細菌が腸管運動機能に及ぼす影響とその機序について基礎およびトランスレーショナル研究を行っている.・単一菌種を定着させたノトバイオート動物モデルを用いて,腸内細菌が宿主自然免疫反応を介し,小腸筋間神経叢の血管作動性腸管ペプチド(VIP)神経の発現調節が腸管運動機能の発達・維持に重要な役割を果たすことを解明した.・慢性便秘症患者より採取した糞便を移植して作製したマウスモデルを解析したところ,慢性便秘症患者から採取した腸内細菌が大腸筋間神経叢に炎症性マクロファージを増加させ,Cajal介在細胞(ICC)のネットワーク障害をきたし,大腸運動低下に至る経路を見出した.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞●高解像度食道内圧検査(HRM)の開発と食道運動障害の国際分類であるシカゴ分類が提唱されたことで,食道運動障害(EMD)の診療が飛躍的に発展した.EMD診断のゴールドスタンダードはHRMとなったが,いまだ検査可能な施設は限られており,日常診療におけるEMDの拾い上げ検査として食道X線造影検査にかかる期待は大きい.本稿では古典的食道X線所見(正常,数珠様・コークスクリュー様,無蠕動・微弱蠕動)に加えて,筆者らが新規に提唱する波様,下部食道バルーニングも含めた各食道X線所見について解説した.これらの食道X線所見を用いることで,EMDの拾い上げに対する食道X線造影検査の感度(79.4%)と特異度(88%)は満足な結果であった.食道X線造影検査のみでHRMに基づくEMDの確定診断を行うことは困難であるが,日常診療におけるEMD拾い上げ検査としては,食道X線造影検査は有用な検査として位置付けられる.

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞胃食道逆流症(GERD)は「胃内容物の逆流により,不快な症状あるいは合併症を生じた状態」と定義される.日常診療で遭遇する,症状のみで食道粘膜傷害のない非びらん性逆流症(NERD)には,GERD以外の病態が紛れ込む.NERDと鑑別すべき重要な病態に食道運動機能障害(EMDs)があるが,EMDsの一つである無蠕動は高頻度にGERDを合併するため,疾患の理解を複雑化させている.最近,食道生理機能検査の発展に基づいてGERDの病態,鑑別疾患の理解が飛躍的に進歩した.本稿では,EMDsに起因するGERDと鑑別すべき関連諸疾患について概説する.治療抵抗性GERDに遭遇した際には食道生理機能検査を行い,機能性食道疾患,食道運動機能障害,行動障害などの鑑別を行うことが重要である.

Language：Japanese   Publisher：(株)東京医学社  

Language：Japanese   Publisher：(一財)日本消化器病学会  

過敏性腸症候群の治療は食事と生活習慣を指導した後に,薬物療法の第1段階として消化管主体の治療を行う.第1選択薬として消化管運動機能調節薬,プロバイオティクス,高分子重合体を使用する.また,IBS分類に応じて下痢型には5-HT3拮抗薬,便秘型には粘膜上皮機能変容薬を投与する.症状の改善が不十分な場合は,優勢な症状に対して止痢薬,抗コリン薬,5-HT4刺激薬,下剤を追加する.さらに,漢方薬,抗アレルギー薬,胆汁酸関連薬や抗菌薬を考慮する.これらの薬物療法が無効な場合,第2段階として抗うつ薬,抗不安薬を用いた中枢機能の調整を含む治療を考慮する.さらに改善が得られない場合,心理療法を考慮する.(著者抄録)

Language：Japanese   Publisher：(株)先端医学社  

近年では,高齢炎症性腸疾患(IBD)患者が増え,悪性腫瘍の併存や既往があるIBD患者を診療する機会が増加している.IBD診療ではJAK阻害薬など多くの新規治療薬が使用可能となり,また悪性腫瘍の診療では免疫チェックポイント阻害薬の適応が広がっている.そのため,IBD治療の中止や継続,免疫チェックポイント阻害薬の使用の有無について,しばしば難しい判断が要求される.担癌・既往患者のIBD診療にて治療方針を決めるためには,IBD自体のリスクや治療薬のリスク,悪性腫瘍の治療について理解しておく必要がある.しかし,チオプリンや抗TNFα抗体製剤では長期のエビデンスが豊富であるものの,人種差の問題,さらに抗インテグリン抗体や抗IL12/23 p40抗体,JAK阻害薬における長期エビデンスの不足などまだまだ解決すべき点が多い.本稿は,現在報告されているエビデンスを中心に解説しており,今後の診療の一助となれば幸いである.(著者抄録)

Language：Japanese   Publisher：(株)日本臨床社