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Natural-orifice transluminal endoscopic surgery (NOTES) using flexible endoscopy has attracted attention as a minimally invasive surgical method that does not cause an operative wound on the body surface. However, minimizing the number of devices involved in endoscopic, compared to laparoscopic, surgeries has remained a challenge, causing endoscopic surgeries to gradually be phased out of use. If a flexible endoscopic full-thickness suturing device and a counter-traction device were developed to expand the surgical field for gastrointestinal-tract collapse, then endoscopic full-thickness resection using NOTES, which is seen as an extension of endoscopic submucosal dissection for full-thickness excision of tumors involving the gastrointestinal-tract wall, might become an extremely minimally invasive surgical method that could be used to resect only full-thickness lesions approached by the shortest distance via the mouth. It is expected that gastroenterological endoscopists will use this surgery if device development is advanced. This extremely minimally invasive surgery would have an immeasurable impact with regard to mitigating the burden on patients and reducing healthcare costs. Development of a new surgical method using a multi-purpose flexible endoscope is therefore considered a socially urgent issue.

Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states.

Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. Thus, the present study evaluated the effects of metformin on human CCA cell proliferation in vitro and in vivo and identified the microRNAs associated with its antitumor effects. Metformin inhibited the proliferation of the CCA cell lines HuCCT-1 and TFK-1 and blocked the G0 to G1 cell cycle transition, accompanied by AMP kinase pathway activation. Metformin treatment also led to marked decreases in cyclin D1 and cyclin-dependent kinase (Cdk) 4 protein levels and retinoblastoma protein phosphorylation. However, this drug did not affect p27kip protein expression. In addition, it reduced the phosphorylation of Axl, EphA10, ALK and PYK, as well as tumor proliferation in athymic nude mice with xenograft tumors. Furthermore, it markedly altered microRNA expression. These findings suggest that metformin may have clinical use in the treatment of CCA.

Although endoscopic mucosal resection is an established colorectal polyp treatment, local recurrence occurs in 13 % of cases due to inadequate snaring. We evaluated whether pre-clipping to the muscularis propria resulted in resected specimens with negative surgical margins without thermal denaturation.Of 245 polyps from 114 patients with colorectal polyps under 20 mm, we included 188 polyps from 81 patients. We randomly allocated polyps to the conventional injection group (CG) (97 polyps) or the pre-clipping injection group (PG) (91 polyps). The PG received three-point pre-clipping to ensure ample gripping to the muscle layer on the oral and both sides of the tumor with 4 mL local injection. Endoscopic ultrasonography was performed to measure the resulting bulge. Outcomes included the number of instances of thermal denaturation of the horizontal/vertical margin (HMX/VMX) or positive horizontal/vertical margins (HM+/VM+), the shortest distance from tumor margins to resected edges, and the maximum bulge distances from tumor surface to the muscularis propria.The numbers of HMX and HM+ in the CG and PG were 27 and 6, and 9 and 2 (P = 0.001), and VMX and VM+ were 8 and 5, and 0 and 0 (P = 0.057). The shortest distance from tumor margin to resected edge [median (range), mm] in polyps in the CG and PG was 0.6 (0-2.7) and 4.7 (2.1-8.9) (P = 0.018). The maximum bulge distances were 4.6 (3.0-8.0) and 11.0 (6.8-17.0) (P = 0.005).Pre-clipping enabled surgical margin-negative resection without thermal denaturation.

AIM: To compare closure methods, closure times and medical costs between two groups of patients who had post-endoscopic resection (ER) artificial ulcer floor closures. METHODS: Nineteen patients with duodenal adenoma, early duodenal cancer, and subepithelial tumors that received ER between September 2009 and September 2014 at Kagawa University Hospital and Ehime Rosai Hospital, an affiliated hospital of Kagawa University, were included in the study. We retrospectively compared two groups of patients who received post-ER artificial ulcer floor closure: the conventional clip group vs the over-the-scope clip (OTSC) group. Delayed bleeding, procedure time of closure, delayed perforation, total number of conventional clips and OTSCs and medical costs were analyzed. RESULTS: Although we observed delayed bleeding in three patients in the conventional clip group, we observed no delayed bleeding in the OTSC group (P = 0.049). We did not observe perforation in either group. The mean procedure times for ulcer closure were 33.26 ± 12.57 min and 9.71 ± 2.92 min, respectively (P = 0.0001). The resection diameters were 18.8 ± 1.30 mm and 22.9 ± 1.21 mm for the conventional clip group and the OTSC group, respectively, with significant difference (P = 0.039). As for medical costs, the costs of all conventional clips were USD $1257 and the costs of OTSCs were $7850 (P = 0.005). If the post-ER ulcer is under 20 mm in diameter, a conventional clip closure may be more suitable with regard to the prevention of delayed perforation and to medical costs. CONCLUSION: If the post-ER ulcer is over 20 mm, the OTSC closure should be selected with regard to safety and reliable closure even if there are high medical costs.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan Correspondence: Dr Hideki Kobara, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan. Telephone 81-87-891-2156, fax 81-87-891-2158, e-mail kobara@med.kagawa-u.ac.jp Received for publication December 31, 2014. Accepted January 12, 2015 CASE PRESENTATION An 80-year-old man with epigastric discomfort underwent upper gastrointestinal endoscopy. Endoscopic findings revealed a granular, elevated lesion (diameter 20 mm) localized to the posterior wall of the prepyloric ring (Figure 1). Abdominal ultrasonography revealed a hypoechoic mass localized to the submucosa. Although biopsy samples were acquired from the epithelium of this lesion to differentiate among gastric epithelial neoplasms, including carcinoma, lymphoma and other diseases, these samples could not histologically diagnose the lesion. After obtaining informed consent, a submucosal tunnelling procedure was selected, considering the antral stricture after endoscopic mucosal resection. We have developed a submucosal tunnelling technique for sampling submucosal tumours, which can visualize tumour surfaces and obtain tissue samples under direct visualization (1,2). After marking the normal mucosa around the lesion with 10 mm margins, a small incision was made to create a 10 mm opening flap (Figure 2). The submucosa was dissected toward the lesion, creating a submucosal tunnel. A whitish mass was visually identified in the submucosal tunnel, and several tissue samples were obtained using biopsy forceps (Radial Jaw 4 Standard Capacity, Boston Scientific, Japan) (Figure 3). The opening flap was completely closed by hemoclips (HX-610-135; Olympus, Japan) to prevent delayed complications. There were no complications associated with this procedure. Histological examination using Congo red staining was positive for amyloidal protein and exhibited green birefringence under polarized light microscopy. A diagnosis of gastric amyloid was made, and the patient was systemically examined, resulting in a lightchain fragment type of localized gastric amyloidosis.

A 42-year-old, obese woman was admitted to our hospital 3 h after the sudden development of abdominal pain. Her umbilical region was swollen and she was diagnosed with incarceration of an umbilical hernia by computed tomography. Although we tried, we were unable to reduce the hernia with a manipulative procedure. We decided to perform an emergency laparoscopy. Once general anesthesia was induced, we achieved hernia reduction. From a laparoscopic view, the portion of strangulated small intestine was neither necrotic nor perforated. The size of the hernial orifice was ∼2 × 2 cm, and thus, we selected a 12 × 12 cm composite mesh to cover the hernia defect by at least 5 cm in all directions. The surgical procedure was uneventful and the total operation time was 112 min. The patient recovered uneventfully and was discharged on postoperative day 9. She remains free of recurrence 20 months after surgery.

Objective Objective evaluation of resected specimen and tumor size is critical because the tumor diameter after endoscopic submucosal dissection affects therapeutic strategies. In this study, we investigated whether the true tumor diameter of gastrointestinal cancer specimens measured by flexible endoscopy is subjective by testing whether the specimen is correctly attached to the specimen board after endoscopic submucosal dissection resection and whether the size differs depending on the endoscopist who attached the specimen. Methods Seventy-two patients diagnosed with early gastric cancer who satisfied the endoscopic submucosal dissection expanded-indication guideline were enrolled. Three endoscopists were randomly selected before every endoscopic submucosal dissection. Each endoscopist separately attached the same resected specimen, measured the maximum resection diameter and tumor size, and removed the lesion from the attachment board. Results The resected specimen diameters of the 3 endoscopists were 44.5±13.9 mm (95% Confidence Interval (CI): 23–67), 37.4±12.0 mm (95% CI: 18–60), and 41.1±13.3 mm (95% CI: 20–63) mm. Comparison among 3 groups (Kruskal Wallis H- test), there were significant differences (H = 6.397, P = 0.040), and recorded tumor sizes were 38.3±13.1 mm (95% CI: 16–67), 31.1±11.2 mm (95% CI: 12.5–53.3), and 34.8±12.8 (95% CI: 11.5–62.3) mm. Comparison among 3 groups, there were significant differences (H = 6.917, P = 0.031). Conclusions Human errors regarding the size of attached resected specimens are unavoidable, but it cannot be ignored because it affects the patient’s additional treatment and/or surgical intervention. We must develop a more precise methodology to obtain accurate tumor size. Trial Registration University hospital Medical Information Network UMIN No. 000012915

A 74-year-old man was transferred to our hospital due to melena and syncope. He had a history of an abdominal aortic aneurysm treated with aortobifemoral grafting 15 years previously. One month before admission, he reported several episodes of melena for which he underwent repeated gastrointestinal endoscopic examinations. None of these examinations revealed the site of gastrointestinal bleeding. Aortoenteric fistulae can therefore be missed if they are not considered in the differential diagnosis of gastrointestinal bleeding due to their rarity. As a result, secondary aortoenteric fistulae should therefore be considered in any patient presenting with gastrointestinal bleeding and a history of aortic surgery.

Collection of multiple resected proximal colon polyps >10 mm in size through a scope channel via aspiration following an endoscopic mucosal resection (EMR) is difficult; thus, polyps are currently all grasped at once using net forceps. However, the simultaneous collection by net forceps makes it difficult to identify the accurate locations of all resected polyps.1 Therefore, we aimed to investigate a novel technique to identify the accurate location of resected polyps using colored ring-threads.

Endoscopic treatment for superficial non-ampullary duodenal tumors is technically difficult and challenging due to the anatomical characteristics of the duodenum. It is frequently complicated by procedural accidents, such as perforation. Surgical repair has long been the standard treatment for acute iatrogenic gastrointestinal perforation. However, endoscopic closure has recently emerged as an attractive alternative. In the patient presented herein, the over-the-scope-clipping system (OTSC system) was found to be useful for closing a duodenal perforation that had occurred during endoscopic submucosal dissection. For endoscopists who perform endoscopic treatment of the duodenum, endoscopic closure with the OTSC system is considered to be a technique that is necessary to master.

A 57-year-old man developed haematemesis and was referred to our institution. His discomfort had begun 3 weeks earlier and localised to the upper abdomen. Abdominal CT showed a defect of gastric mucosa and gastric wall thickening. Oesophagogastroduodenoscopy showed that he had an active gastric ulcer, 40 mm in diameter, on the lesser curvature in the upper third of the corpus and the presence of a pancreatic body at the ulcer base, penetration to the pancreas. Open gastrectomy was performed with a preoperative diagnosis of localised peritonitis caused by penetration of the stomach into the pancreas. Histopathology of resected specimens showed a benign peptic ulcer, 40×40 mm in size, was found on the lesser curvature in the antrum, and this had penetrated through the pancreas. The most serious complications of PUD include haemorrhage, perforation, penetration, and gastric outlet obstruction. Approximately 7% of patients experience perforation, which occurs when an ulcer erodes through the wall and leaks air and digestive contents into the peritoneal cavity. Antral and duodenal ulcers can penetrate into the pancreas. We report a case of gastric ulcer penetrating into the pancreas.

In this study, an integrated pressure and temperature sensor device for a flexible endoscope with long-term stability in in vivo environments was developed and demonstrated. The sensor, which is embedded in the thin wall of the disposable endoscope hood, is intended for use in endoscopic surgery. The device surface is coated with a Cr layer to prevent photoelectronic generation induced by the strong light of the endoscope. The integrated temperature sensor allows compensation for the effect of the temperature drift on a pressure signal. The fabricated device pressure resolution is 0.4 mmHg; the corresponding pressure error is 3.2 mmHg. The packaged device was used in a surgical simulation in an animal experiment. Pressure and temperature monitoring was achieved even in a pH 1 acid solution. The device enables intraluminal pressure and temperature measurements of the stomach, which facilitate the maintenance of internal stomach conditions. The applicability of the sensor was successfully demonstrated in animal experiments.

Traditional serrated adenoma (TSA) is a type of serrated polyp of the colorectum and is thought to be a precancerous lesion. There are three types of serrated polyps, namely, hyperplastic polyps, sessile serrated adenomas/polyps, and TSAs. TSA is the least common of the three types and accounts for about 5% of serrated polyps. Here we report a pediatric case of TSA that was successfully resected by endoscopic submucosal dissection (ESD). This rare case report describes a pediatric patient with no family history of colonic polyp who was admitted to our hospital with hematochezia. On colonoscopy, we found a polypoid lesion measuring 10 mm in diameter in the lower rectum. We selected ESD as a surgical option for en bloc resection, and histopathological examination revealed TSA. The findings in this case suggest that TSA with precancerous potential can occur in children, and that ESD is useful for treating this lesion.

Clinically available targeted agents to treat advanced renal cell carcinoma (RCC) include sunitinib, sorafenib and temsirolimus. Sorafenib and sunitinib have been associated with bleeding in selected trials, but clinical and endoscopic characteristics of gastrointestinal bleeding are not well described. Herein, we report four cases of advanced RCC in which endoscopic hemostasis effectively resolved high-grade, life-threatening gastrointestinal bleeding that occurred during targeted therapy. Although stomatitis and mucositis have occurred during targeted therapies, life-threatening gastrointestinal bleeding is less common. In these four patients, the origins of gastrointestinal bleeding were identified, and complete endoscopic hemostasis was achieved. Endoscopies revealed variable characteristics including angiodysplasia, multiple gastric ulcers and oozing bleeding of the normal mucosa. Although the most effective diagnostic and treatment strategies are disputed, endoscopic examinations are best performed before starting targeted therapies. Additionally, these patients should be monitored even for rare life-threatening events.

The aim of the present report was to investigate the efficacy of local steroid injection and oral administration contralateral to a severe contracted scar of large endoscopic submucosal dissection (ESD) for gastric cancer. Among 254 cases that underwent gastric ESD, seven patients underwent resection of more than three-quarters of the circumference of the stomach. Two patients were excluded because they did not meet curative resection criteria of Japan Gastroenterological Endoscopy Society. Therefore, in five patients, circumferentiality, symptom appearance period, and weight loss period were examined. Effect of a contralateral normal mucosa incision for releasing the stenosis followed by local injection and oral steroids were also examined. Abdominal bloating, vomiting, and loss of appetite appeared 42 days on average after gastric ESD, whereas weight loss5 kg was observed an average of 52.6 days after gastric ESD. Average contralateral mucosal incision length was 51 mm, whereas the average mucosal incision width was 31 mm. All patients underwent a mucosal incision and were given a local injection of 100 mg triamcinolone acetonide. Two patients received an additional 20 mg oral steroid. In cases combined with oral steroid, there was no re-stenosis after the mucosal incision, but two to three balloon dilatations were necessary in three cases in which oral steroids were not given. This method is considered useful for stenosis after large ESD for gastric cancer.

There are no established opinions concerning whether the amount of tissue affects the accuracy of histological analyses in gastrointestinal stromal tumors (GISTs). The aim of the present study was to investigate the appropriate amount of tissue sample needed for mitotic count based on the risk classification of GISTs and the Ki-67 index using the following three methods: endoscopic ultrasound-guided fine-needle aspiration (FNA), a novel sampling method called tunneling bloc biopsy (TBB), and biopsy forceps followed by TBB (Bf). Forty-three samples (12 FNA, 17 TBB and 14 Bf) diagnosed as GISTs by immunohistological analysis were utilized. The major and minor axes and overlay area of one piece of specimen (OPS) from the three sampling methods were measured using digital imaging software and were analyzed comparatively regarding the acquisition of histological data. The mean major and minor axes (mm) and overlay areas (mm2) were in the order of TBB > Bf > FNA. The evaluable rates by mitotic count and Ki-67 were, respectively, 75% (9/12) and 83.3% (10/12) for FNA samples, 100% (17/17) and 100% (17/17) for TBB samples, and 100% (14/14) and 100% (14/14) for Bf samples (P>0.05). Three FNA samples were judged unevaluable due to too small specimens in overall diagnosis including mitotic count and Ki-67, calculating the cut-off value for the overlay area of OPS as 0.17 mm2. Comparing the concordance rates between the pre- and post-operative samples, TBB samples was significantly better than FNA (P

A prospective observational study was conducted to establish the procedure of hybrid endoscopic full-thickness resection (EFTR) using an existing flexible endoscope. The present study included 16 patients who underwent hybrid EFTR between September 2009 and February 2013 for gastric gastrointestinal stromal tumor (GIST). The patients were selected using the following inclusion criteria for histological findings: Mitotic counts

Endoscopic submucosal dissection (ESD) of large gastric lesions often leads to severe gastric strictures, especially in cases of large ESD in the antrum of the stomach. It has recently been reported that balloon dilation, mucosal incision, and local steroid injections can successfully treat gastric strictures. However, there are some complications with existing methods and decreasing the quality of life. We have developed a novel method to prevent severe gastric strictures that does not involve balloon dilation, mucosal incision, or steroid injections after circumferential ESD. Our original method involves the submucosal injection of a mixed solution composed of triamcinolone acetonide and a general solution of glycerol, hyaluronic acid, and a small amount of indigo carmine and epinephrine during the ESD procedure; this mixture is called a mixed solution of triamcinolone (MST). According to standard ESD procedures, several milliliters of MST are injected into the submucosal layer for the purpose of elevating the submucosa during ESD resulting in prevention of severe strictures. Our method using MST take several advantages such as MST method suppress inflammation in ulcer from initial phase, prevention of stricture without obstructive symptoms, and does not require several ballooning. Therefore, MST method is safe and gentle, shorten the hospitalization duration. Here, we described two cases in which we prevented severe strictures of the gastric antrum after completing a circumferential ESD using MST without any complications.

A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg−1 twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.

ndoscopic full-thickness resection (EFTR) is a gastric Efull-thickness partial resection. As tumor enucleation surgery, EFTR may be less invasive than laparoscopic partial resection. However, EFTR has many difficult technical challenges, such as visualizing a clear operative field under a collapsed stomach and endoscopic suturing device. Regarding suturing devices, the only commercially available device is the Over-the-Scope Clip (Ovesco Endoscopy GmbH, Tuebingen, Germany), a clip-based suturing device that is easy to use. The recent development of the Overstitch System (Apollo Endosurgery, Austin, TX) enabled full-thickness suturing with a suturing thread. To obtain the operative field, the lifting method or the mechanical counter traction device have been reported; however, it was very difficult to obtain sufficiently the operative field at certain areas of the stomach, such as in the retroflexed view. We report a newly developed countertraction and full-thickness suturing device for the flexible endoscope.

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. microRNAs (miRNAs) are small non-coding RNAs that negatively regulate messenger RNA (mRNA). Recently, it was demonstrated that the aberrant expression of certain miRNAs plays a pivotal role in liver disease. The aim of the present study was to evaluate changes in miRNA profiles associated with metformin treatment in a NASH model. Eight-week-old male mice were fed a methionine- and choline-deficient (MCD) diet alone or with 0.08% metformin for 15 weeks. Metformin significantly downregulated the level of plasma transaminases and attenuated hepatic steatosis and liver fibrosis. The expression of miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p was enhanced among the 71 upregulated miRNAs, and the expression of miRNA-122, miRNA-194, miRNA-101b and miRNA-705 was decreased among 60 downregulated miRNAs in the liver of MCD-fed mice when compared with control mice. Of note, miRNA profiles were altered following treatment with metformin in MCD-fed mice. miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p were down-regulated, but miRNA-122, miRNA-194, miRNA-101b and miRNA-705 were significantly upregulated in MCD-fed mice treated with metformin. miRNA profiles were altered in MCD-fed mice and metformin attenuated this effect on miRNA expression. Therefore, miRNA profiles are a potential tool that may be utilized to clarify the mechanism behind the metformin-induced improvement of hepatic steatosis and liver fibrosis. Furthermore, identification of targetable miRNAs may be used as a novel therapy in human NASH.

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

To investigate surgical procedures for pure endoscopic full-thickness resection (EFTR) using a flexible endoscope and a prototype of a full thickness suturing device in animal experiments.Six beagles were divided into two groups: sutured with over-the-scope-clip (OTSC group, n = 3) and with a prototype of the double-arm bar suturing system (DBSS group, n = 3). The peritoneoscopy, omentectomy and EFTR procedures were performed through the transgastric route. We examined the surgical procedures required to accomplish pure EFTR and survival rates of these dogs after EFTR.The duodenal balloon occlusion method maintained a sufficient endoscopic view during peritoneoscopy. Grooves of 10-mm wide were created around the tumor down to the third layer for treating all blood vessels and adding landmark for full-thickness resection lines. Using the muscle layer thin-cutting method, hyaluronic acid was locally injected into the muscle layer and fine incisions were made. Creating tiny perforations provided safe access to the abdominal cavity. Although it was difficult to suture the resected site safely in the OTSC group, the DBSS prototype was useful and reliable for closing there section sites with 3-0 absorbable thread. After EFTR there were no complications in the DBSS group and the dogs were in good health on POD 30, whereas in the OTSC group two dogs died due to dehiscence and gastric juice leaks. Postmortem examinations showed abscess around the suturing sites and two OTSC were detached from the suturing sites.Pure EFTR is feasible with DBSS when systematic methods are established. The high safety of full-thickness resection suturing will permit their clinical application in the near future.

Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for colorectal cancer. However, due to technical difficulties and an increased rate of complications, ESD is not widely used in the colorectum. In some cases, endoscopic treatment alone is insufficient for disease control, and laparoscopic surgery is required. The combination of laparoscopic surgery and endoscopic resection represents a new frontier in cancer treatment. Recent developments in advanced polypectomy and minimally invasive surgical techniques will enable surgeons and endoscopists to challenge current practice in colorectal cancer treatment. Endoscopic full-thickness resection (EFTR) of the colon offers the potential to decrease the postoperative morbidity and mortality associated with segmental colectomy while enhancing the diagnostic yield compared to current endoscopic techniques. However, closure is necessary after EFTR and natural transluminal endoscopic surgery (NOTES). Innovative methods and new devices for EFTR and suturing are being developed and may potentially change traditional paradigms to achieve minimally invasive surgery for colorectal cancer. The present paper aims to discuss the complementary role of ESD and the future development of EFTR. We focus on the possibility of achieving EFTR using the ESD method and closing devices.

Aims Kidney cells in patients with diabetic nephropathy are reported to be senescent. However, the mechanisms that regulate cellular senescence in the diabetic kidney are still unknown. In the present study, we evaluated the contribution of high glucose to renal cell senescence in streptozotocin (STZ)-induced diabetic mice. Methods Non-diabetic and streptozotocin (STZ, 10mgkg −1 day −1 for 7days, i.p.)-induced type 1 diabetic C57BL/6J mice and cultured human proximal tubular cells were used in this study. Results Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4weeks after STZ injection. These changes were accompanied by an increase in senescence-associated β-galactosidase staining in tubular epithelial cells. Administration of insulin at doses that maintained normoglycemia or mild hypoglycemia suppressed the changes induced by STZ. Insulin did not affect the senescent markers in non-diabetic mice. Exposure of cultured human proximal tubular cells to 25mmol/L, but not 8mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2. Conclusions These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.

Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle‑related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.

Gastric hamartomatous inverted polyps (GHIP) are difficult to diagnose accurately because of inversion into the submucosal layer. GHIP are diagnosed using the pathological characteristics of the tumor, including the fibroblast cells, smooth muscle, nerve components, glandular hyperplasia, and cystic gland dilatation. Although Peutz-Jeghers syndrome, juvenile polyposis, and Cowden disease are hereditary, it is rare to encounter 2 cases of monostotic and asymptomatic gastric hamartomas. The pathogeneses of hamartomatous inverted polyps and inverted hyperplastic polyps remain controversial because of the paucity of reported cases. There are 3 hypotheses regarding the pathogenesis of complete gastric inverted polyps. Based on our experience with 2 successive, rare GHIP cases, we affirm the hypothesis that after a hamartomatous change occurs in the submucosal layer, some of these components are exposed to the gastric mucosa and, consequently, form a hypertrophic lesion. In Case 1, our hypothesis explains why a tiny hypertrophic change was first detected on the top of the submucosal tumor using a detailed narrow band imaging-magnified endoscopy. There was no confirmation that the milky white mucous and calcification structures were exuding directly from the biopsy site like Case 1, and in Case 2 the presence of this mucous was indirectly confirmed during an endoscopic submucosal dissection (ESD). Regarding the pathogenesis of GHIP, a submucosal hamartomatous change may occur prior to the growth of hypertrophic portions. An en bloc resection using ESD is recommended for treatment.

We previously reported that aldosterone impaired vascular insulin signaling in vivo and in vitro. Fructose-enriched diet induces metabolic syndrome including hypertension, insulin resistance, hyperlipidemia and diabetes in animal. In the current study, we hypothesized that aldosterone aggravated fructose feeding-induced glucose intolerance in vivo. Rats were divided into five groups for six-week treatment; uninephrectomy (Unx, n =8), Unx+aldosterone (aldo, 0.75 µg/h, s.c., n =8), Unx+fructose (fruc, 10% in drinking water, n =8), Unx+aldo+fruc, (aldo+fruc, n =8), and Unx+aldo+fruc+spironolactone, a mineralocorticoid receptor antagonist (aldo+fruc+spiro, 20 mg/kg/day, p.o., n =8). Aldo+fruc rats manifested the hypertension, and induced glucose intolerance compared to fruc intake rats assessed by oral glucose tolerance test, homeostasis model assessment of insulin resistance and hyperinsulinemic-euglycemic clamp study. Spironolactone, significantly improved the aldosterone-accelerated glucose intolerance. Along with improvement in insulin resistance, spironolactone suppressed upregulated mineralocorticoid receptor (MR) target gene, serum and glucocorticoid-regulated kinases-1 mRNA expression in skeletal muscle in aldo+fruc rats. In conclusion, these data suggested that aldosterone aggravates fructose feeding-induced glucose intolerance through MR activation.

re 1. A, Endoscopic view by using a flexible endoscope, showing a pulsatile bleeding site within wide ulcerations near the cervical opening. B, Endoic view showing an arterial vessel (blue arrows) detected by using a transparent cap (yellow arrows) and an endoscope with water jet function. C, scopic view showing successful endoscopic hemostasis by using hemostatic forceps for the ruptured vessel, which was coagulated consecutively 5 (2 seconds per 1 grasp) under direct vision. D, Endoscopic view showing the coagulation site treated completely by using the endoscopic hemoforceps. E, Endoscopic findings showing the disappearance of exposed vessels 2 days after treatment. F, Vaginal examination showing mucosal ng and scarring 25 days after treatment.

Plasmablastic lymphoma (PBL) is a very rare B-cell lymphoproliferative disorder was with an aggressive clinical behavior that recently characterized by the World Health Organization. Although PBL is most commonly observed in the oral cavity of human immunodeficiency virus (HIV)-positive patients, it can also be observed at extra-oral sites in HIV-negative patients. Epstein-Barr virus (EBV) may be closely related the pathogenesis of PBL. PBL shows different clinicopathological characteristics between HIV-positive and -negative patients. Here, we report a case of PBL of the liver in a 79-year-old HIV-negative male. The patient died approximately 1.5 mo after examination and autopsy showed that the main lesion was a very large liver mass. Histopathological examination of the excised lesion showed large-cell lymphoma with plasmacytic differentiation diffusely infiltrating the liver and involving the surrounding organs. The neoplastic cells were diffusely positive for CD30, EBV, Bob-1, and CD38. The autopsy findings suggested a diagnosis of PBL. To our knowledge, the present case appears to be the first report of PBL with initial presentation of the liver in a patient without HIV infection.

Heterotopic pancreas (HP) is pancreatic tissue found outside the usual anatomical location of the pancreas, typically in the upper gastrointestinal tract. Asymptomatic HP is considered a benign submucosal tumor (SMT) that can be followed without intervention. However, invasive surgery or endoscopic resection is often inappropriately applied in cases of HP due to the difficulty of preoperative diagnosis by endoscopic ultrasonography (EUS) and tissue sampling error. Therefore, it is very important to distinguish HP from neoplastic SMTs, such as gastrointestinal stromal tumor (GIST), preoperatively. Herein, we describe two asymptomatic gastric HP cases that were distinguished by endoscopic direct imaging (EDI) on submucosal endoscopy with a mucosal flap method (SEMF). In the two patients, EUS-guided fine needle aspiration (FNA) biopsy failed to accurately diagnose two SMTs, consistent with the suspicion of a GIST on EUS. Accordingly, we attempted to perform bloc biopsy using SEMF as a novel method for obtaining tissue samples for two indefinite SMTs. Direct endoscopic imaging via a dissected submucosal tunnel revealed a yellowish, multi-nodular mass identified as pancreatic tissue. Histopathology of the bloc biopsy confirmed the diagnosis of HP. Our findings indicate that the characteristic EDI findings of gastric HP may distinguish these lesions from neoplastic SMTs. Additional evaluations of this approach are warranted.